MM19 Conference Book V1final

The
California Naturopathic Doctors Association
presents
MERGING MEDICINE 19
TREAT the
Microbiome...
TREAT the
Whole Person
Saturday, June 10 10 and Sunday, June 11, 11, 2017
Torrance Marriott Redondo Beach
Los Los Angeles, California
Continuing Medical Education Program
1

B Vibrant America Clinical Labratory (Platinum)
C Koshland Compounding Pharmacy (Silver)
D Sovereign Laboratories (Platinum)
E APEX Energetics, Inc. (General)
1 US Biotek (Bronze)
2 Seroyal / Genestra Brands (General)
3 RLC Labs Inc (Bronze)
4 Microbiome Labs (Bronze)
5 Ayush Herbs, Inc.(General)
6 Precision Analytical, Inc.(DUTCH Test )(General)
7 Doctor’s Data, Inc. (Bronze)
8 IGeneX, Inc.(General)
9 Galen’s Way Herbal Extracts (General)
10 Canada RNA Biochemical, Inc. (Bronze)
11 Imprimis Pharmaceuticals, Inc.(General)
12 Thorne Research, Inc.(General)
13 Women’s International Pharmacy (General)
14 Researched Nutritionals (General)
15 Relax Saunas of Momentum98 (Gold)
16 Designs For Health (General)
17 NCMIC Naturopathic (Bronze)
18 NatureKue (General)
19 Nutrametrix (General)
20 Enviro Med Sciences (General)
21 Doctors Supplement Store (General)
24 Heron Botanicals (General)
25 Hevert Pharmaceuticals LLC (General)
26 Oxy Health, LLC (Platinum)
27 Great Plains Laboratory (General)
28 Integrative Therapeutics, LLC (General)
29 Salveo Diagnostics (General)
30 Sprague Israel Giles, Inc. (General)
31 Professional Formulas (General)
32 Allergy Research Group LLC (Platinum)
33 Sanashwa (General)
34 Great Earth Compounding Pharmacy (General)
35 Meridian (General)
Zen Breakfast Blend
2

The
California Naturopathic Doctors Association
Presents
Merging Medicine 19
Treat the Microbiome...
Treat the Whole Person
June 10-11, 2017
The Torrance Marriott Redondo Beach, Torrance, CA
10.5 CEs for all NDs*
*Approved by the CNDA and the OBNM
10.5 CEs for California Acupuncturists
Accredited by the California Acupuncture Board
5601 West Slauson Avenue, #275 | Culver City, CA 90230 | 310-670-8100 | www.calnd.org
3

Passport To Free CEs
Visit each exhibitor and ask them for their sticker. Attach to the matching square.
Complete for all exhibitors and hand it to CNDA staff to register for your FREE CE Event.
You will be entered into a drawing to win FREE admission to our next Merging Medicine Conference.
4

Merging Medicine 19 Schedule
Saturday June 10
7:30 - 8:45 am Registration and breakfast with exhibitors
8:45 am - 9:00 am Welcome and opening remarks
9:00 - 10:30 am Dr. Gary Weiner, ND, LAc
10:30 - 11:15 am Exhibitor break
11:15 - 12:45 pm Kiran Krishnan, Research Microbiologist
12:45 - 2:15 pm Lunch
2:15 - 3:45 pm Dr. Mi Jung Lee, ND, LAc
3:45 – 5:00 pm Exhibitor break
5:00 - 6:30 pm Dr. Eric Yarnell, ND, RH (AHG)
6:30 - 8:00 pm Wine reception with exhibitors
Sunday June 11
7:45 - 9:00 am Registration and breakfast with exhibitors
9:00 - 10:30 am Dr. Michael Traub, ND, DHANP, FABNO
10:30 - 11:15 am Exhibitor break
11:15 - 12:00 pm CNDA update
12:00 - 1:30 pm Lunch
1:30 - 3:00 pm Dr. Laura Stuve, Phd, Biochemist
3:00 - 3:30 pm Exhibitor break
3:30 - 5:00 pm Dr. Nalini Chilkov, LAc, OMD
Doctor/Exhibitor Lunch
This year, in addition to breakfast, we are including a buffet lunch for all our attendees. Just head over to
the exhibit hall after the morning session. Pick the exhibitor you want to join and drop your stuff off at
your seat. Enjoy the buffet!
While we want you to catch up with colleagues, we are asking you to allow the exhibitor to share
information about their product or service during this time. They will not take up more than 10 minutes.
5

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International seminars (CME credits available),
as well as news, abstracts, and reviews.
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Join for free at www.clinicaleducation.org/linkedin
6

Merging Medicine 19 Presentations
Saturday June 10
9:00 - 10:30 am The Role of an Elemental Diet in the Treatment of Inflammatory Bowel Disease,
Small Intestinal Bacterial Overgrowth, and Other Conditions Related to a
Disordered Microbiome
-Dr. Gary Weiner, ND, LAc
11:15 - 12:45 pm How the Microbiome Shapes the Systemic Immune System in Health and Disease
- Kiran Krishnan, Research Microbiologist
2:15 - 3:45 pm Subverted Enteroendocrine System in Obesity, Infection, and Inflammation
-Dr. Mi Jung Lee, ND, LAc
5:00 - 6:30 pm Natural Approach to Urology
Sunday June 11
- Dr. Eric Yarnell, ND, RH (AHG)
9:00 - 10:30 am The Clinical Impact of Gut & Microbiome on Skin Disease
-Dr. Michael Traub, ND, DHANP, FABNO
1:30 - 3:00 pm Meet your Inner Ecosystem; Your Key to Rebalancing Immune Dysfunction
-Dr. Laura Stuve, PhD, Biochemist
3:30 - 5:00 pm THE ESTROBOLOME: The Influence of the Microbiome Upon Estrogen
Metabolism and Estrogenic Cancer
-Dr. Nalini Chilkov, LAc, OMD
7

8

Saturday Speakers
Gary Weiner, ND, LAc
Gary Weiner, N.D., L.Ac. is co-founder and clinical director of Pearl Natural Health
in downtown Portland Oregon. Dr. Weiner graduated from the National University
of Natural Medicine (NUNM) in 1997, and holds degrees in both Naturopathic
Medicine and Classical Chinese Medicine. He is a member of the American
Association of Naturopathic Medicine, the Oregon Association of Naturopathic
Medicine, and a member of the Advisory Committee of the Northwest Crohn’s and
Colitis Foundation of America. He is a clinical supervisor at NUNM, and supervises
an NUNM certified residency in his clinic, supported by the National Education
and Research Consortium (NERC). Dr. Weiner specializes in gastrointestinal and
endocrine disorders, with a particular focus on Inflammatory Bowel Disease (IBD),
offering an IBD Complementary Care Program in his clinic. He has published two
large articles on IBD for the Naturopathic Doctors News & Review (NDNR), and
presented on the subject for the American Association of Naturopathic Physicians
(AANP) and the California Naturopathic Doctors Association (CNDA), and most
recently at the 2016 SIBO Symposium.
Kiran Krishnan, Research Microbiologist, CSO
Kiran Krishnan is a Research Microbiologist and has been involved in the dietary
supplement and nutrition market for the past 16 years. He comes from a strict
research background having spent several years with hands-on R&D in the fields
of molecular medicine and microbiology at the University of Iowa. Mr. Krishnan
earned his Bachelor of Science degrees in Microbiology at the University of Iowa;
his undergraduate education was followed up with post graduate research and
advanced course work in Molecular Biology and Virology. He left University
research to establish a Clinical Research Organization where he designed and
conducted clinical trials in human nutrition. Most recently, Kiran is acting as
the Chief Scientific Officer at Physician’s Exclusive, LLC. and Microbiome Labs.
He is a frequent lecturer on the Human Microbiome at Medical and Nutrition
Conferences. He conducts the popular monthly Microbiome Series Webinars
through the Rebel Health Tribe Group practitioner training program, he is a regular
expert guest on National Radio and Satellite radio and has been a guest speaker on
several Health Summits as a microbiome expert. He is currently involved in 4 novel
human clinical trials on probiotics and the human microbiome. Kiran offers his
extensive knowledge and practical application of the latest science on the human
microbiome as it relates to health and wellness.
9

10

Saturday Speakers (cont.)
Dr. Mi Jung Lee, ND, LAc
Dr. Mi-Jung Lee, ND, LAc practices integrative medicine at Tahoma Clinic,
researches and consults functional medical testing methods at Meridian Valley
Laboratory. In her practice, she incorporates traditional Asian herbal medicine and
restorative acupuncture along with clinical nutrition and conventional medicine to
optimize health. As a physician consultant, she reviews, reports and recommends
functional test results for practitioners. Prior to joining Tahoma Clinic and
Meridian Valley Laboratory in 2012, Dr. Lee practiced in Los Angeles, California
with psychiatrist and internist, helping professionals suffering with mental
disorders from depression and anxiety to ADHD with naturopathic medicine
and acupuncture. In that period, Dr. Lee learned the importance of normalizing
gastrointestinal health in order to effectively address mental health issue. She also
has assisted patients with concerns related to menopause and andropause, and
helped seniors enhance their health and vigor with Asian tonic medicines passed
down to her from her herbalist mother and midwife grandmother in Korea. With
her extensive training and practice in hormone replacement past 5 years, Dr. Lee
has been exploring her research to the area of enteroendocrine system in order to
find the causes and treatments for chronic metabolic conditions.
Dr. Eric Yarnell, ND, RH (AHG)
Eric Yarnell, ND, RH(AHG) (Bastyr ’96) is professor of botanical medicine at Bastyr
University. He has been in private practice focusing on herbs, men’s health,
urology, nephrology, and gastroenterology for 20 years. He is former chair of
botanical medicine at SCNM and former editor of the Journal of Naturopathic
Medicine. He is author of Natural Approach to Gastroenterology 2nd ed, Natural
Approach to Men’s Health and Urology 2nd ed, and Clinical Botanical Medicine
among many other texts and articles.
11

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12

Sunday Speakers
Dr. Michael Traub, ND, DHANP, FABNO
Dr. Traub, ND, DHANP, FABNO, completed pre-med studies at the University of
California at Irvine. He graduated from National College of Naturopathic Medicine
in 1981 and completed a residency there in Family Practice and Homeopathy. Dr.
Traub was recognized for his many years of service in the American Association
of Naturopathic Physicians, including President from 2001-2003, when he
was honored with the 2006 Physician of the Year Award. His father was a
dermatologist, and this inspired Dr. Traub to undertake extra study in this subject
and become the leading expert in dermatology in the naturopathic profession.
He has taught dermatology at five of the seven accredited naturopathic medical
schools in North America and is the author of “Essentials of Dermatologic
Diagnosis and Integrative Therapeutics.” He has been medical director of Lokahi
Health Center in Kailua Kona, Hawaii for the past 32 years. Dr. Traub is a fellow
of the American Board of Naturopathic Oncology. He has been actively engaged
in clinical research throughout most of his career. His most recent publication is
“Impact of Vitamin D3 Dietary Supplement Matrix on Clinical Response” (JCEM
2013). He is currently a co-investigator in The Canadian/US Integrative Oncology
Study.
Dr. Laura Stuve, PhD, Biochemist
Dr. Laura Stuve, is a PhD molecular biologist and an advanced instructor and
practitioner of BodyTalk Mind-Body medicine. She spent 26 years doing research
on the molecular genetics of human disease in academia and the biotechnology
industry. Laura got her PhD at UCSF in biochemistry and then did a postdoctoral
fellowship at Stanford working on the Human Genome Project. She was a Senior
Director of Research and Development at two California biotech companies
before changing careers in 2008. Laura moved into full time practice, research and
teaching of a healthcare system that dramatically changed her own health. She has
been teaching BodyTalk and courses of her own design in science-based mind-body
medicine for alternative healthcare practitioners for 8 years. Her focus is to bring
the latest paradigm-changing scientific discoveries into the hands of healthcare
practitioners to make a difference in clinical treatment of chronic disease. Laura
developed a 4-day workshop presenting the latest scientific understanding of the
microbiome and immune disease, together with new BodyTalk clinical treatment
strategies in this area. She has been teaching this course and lecturing in this field
for the past 3 years.
Dr. Nalini Chilkov, LAc, OMD
Dr. Nalini Chilkov, L.Ac., O.M.D. is a leading edge authority and pioneer in the field
of Integrative Cancer Care, Cancer Prevention and Immune Enhancement.. She is
the Founder of the American Institute of Integrative Oncology www.aiiore.com
and IntegrativeCancerAnswers.com and the author of the number one best-selling
book “32 Ways to Out Smart Cancer: How to Create A Body Where Cancer Cannot
Thrive.” Dr. Chilkov brings over 30 years of clinical experience, combining the best
of Functional Medicine and Oriental Medicine. She has lectured at the School of
Medicine at UCLA and UC Irvine in California and the Medical Academy in London,
UK. She is a member of the Scientific Advisory Board of Mederi Foundation
and is a regular contributor to the Healthy Living section of the Huffington Post.
She featured as a cancer expert on TAPIntegrative.com and on NBCTV and has
been recognized as one of the top 10 Online Influencers for Breast Cancer by Dr.
Mehmet Oz and WebMD. Her private practice is in Santa Monica, California.
13

14

MM19 Exhibitors
Allergy Research Group LLC
www.allergyresearchgroup.com
510-263-2000
Booth 32
Allergy Research Group® offers the highest quality
hypoallergenic nutrional supplements, following strict cGMP.
Countless allergic/sensive customers rely on ARG products.
ARG cutting‐edge supplements are formulated by alternave
medicine giants, including Nicholas Gonzalez MD (Glandular
Nutrion), Garth Nicolson PhD (Fluid Mosaic Membrane
Model), Marn Pall PhD (NO/ONOO‐ theory), Stephen Levine
PhD (Anoxidant Adaptaon), and Todd A. Born ND. Allergy
Research Group®: since 1979, the supplement provider‐ofchoice
for healthcare practioners around the world!
APEX Energetics, Inc.
www.apexenergetics.com
800-736-4381
Booth E
For over 25 years, Apex Energetics has served the healthcare
community by sponsoring cutting- edge functional medicine
education and offering an innovative portfolio of researchguided
nutritional formulas. Our unique approach to nutrition
involves capturing and integrating science and healthcare
practitioner insights into successful performance -based health
strategies for patients. At Apex Energetics, you and your
patients are at the center of everything we do. TM
Ayush Herbs, Inc.
www.ayush.com
800-925-1371
Booth 5
Ayush Herbs is a family-owned company designed for
physicians and dedicated to combining modern medical science
with the ancient wisdom of Ayurveda. Our herbs are grown in
the pristine valleys at the base of the Himalayas and are USDA
certified organic. We use exhaustive in-house and third-party
testing to ensure that we provide the purest products. Our
formulations were created by the Sodhi brothers, Ayurvedic
and naturopathic physicians, and have been validated by 25
years of clinical use.
Canada RNA Biochemical,
Inc.www.canadarna.com
604-273-2233
Booth 10
We specialize in niche natural medicine for practitioners:
Boluoke (lumbrokinase), the most potent and best researched
fibrinolytic agent hands down; CordImmune (Cordyceps
sinensis), the only Cordyceps on the market that tests for
and declares its cordycepin content; and Corio PSP (Coriolus
versicolor), the best researched mushroom species for
immune support. Remember to stop by our booth for a FREE
coagulation health check ($85 value)!
Enviro Med Sciences
www.enviromedsciences.com
714-865-3850
Booth 20
Reduce Your Environmental Toxic Burden!
Virus, Bacteria, Allergens, Chemicals, Heavy Metals and
Pharmaceuticals Pro-Actively Removed From Indoor Air,
Surfaces and Drinking Water! Peace of Mind Protection for
Your Home, Office and Patients.
Designs For Health
www.designsforhealth.com
978-729-6303
Booth 16
Designs for Health is a family- owned professional brand,
offered exclusively to health care professionals and their
patients. For over 25 years, we have been the health care
professional’s trusted source for research backed nutritional
products of superior quality. By providing comprehensive
support through our product line, clinical education, and
practice development programs, we maximize the potential
for successful patient treatment outcomes.
Doctor’s Data, Inc.
www.doctorsdata.com
630-377-8139
Booth 7
Doctor’s Data, Inc. has provided innovative specialty testing to
healthcare practitioners around the world from our advanced
CLIA licensed clinical laboratory since 1972. A specialist and
pioneer in essential and toxic elemental testing, the laboratory
provides a wide array of functional testing to aid in decision
making and better patient outcomes.
Choose DDI to help you assess and treat heavy metal
burden, nutritional deficiencies, gastrointestinal function,
cardiovascular risk, liver and metabolic abnormalities,
hormone status and more.
Galen’s Way Herbal Extracts
www.galenswaystore.com
253-376-6604
Booth 9
Galen’s Way is an independently owned and operated herbal
company dedicated to handcrafting the highest quality herbal
extracts and therapeutically active herbal skin care. Our
products include CCOF Certified Organic Extracts, Glycerites,
Infused Oils, and herbal skincare. Galen’s Way recognizes
the intricate coupling of individual health to environmental
health, and formulates impeccable whole plant products
with responsibly obtained botanicals. We stand behind our
products as the best of their kind on the market.
15

16

MM19 Exhibitors
Great Earth Compounding Pharmacy
www.greatearthpharmacy.com
310-550-1822
Booth 34
Great Earth Compounding Pharmacy is proud to offer
personalized preparations created by high quality experts
using state of the art technology. We are dedicated to
providing a superior client experience, whether you are a
doctor or the patient. We are proud to be the pharmacy you
can rely on to deliver high-quality, consistent compounds at
affordable prices. We will only deliver quality and consistency,
backed by a 100% Guarantee on every order that we fill!
Helen Kizler Pharm.D current owner of Great Earth
Compounding Pharmacy has provided sought-after
compounding pharmaceutical services. She is a faculty
member at the Institute of Integrative Medicine and can
frequently be seen participating in seminars on the cutting
edge of her field. She is an advisor on the art of Hormone
Replacement Therapy and she continuously offers training to
physicians in this area.
Great Plains Laboratory
www.greatplainslaboratory.com
913-341-8949
Booth 27
The Great Plains Laboratory, Inc. (GPL) is the leader in metabolic
testing for patients with neurological, gastrointestinal, and
other chronic health disorders. We offer tests for organic acids,
amino acids, essential fatty acids, inflammation, metal toxicity,
non metal chemical toxicity, and food allergies, as well as
comprehensive genetic testing. Our newest test, GPL MycoTOX
screens for the presence of nine different mycotoxins in urine.
Our laboratory provides the most reliable, comprehensive, and
understandable scientific results, using the latest technology.
Heron Botanicals
www.heronbotanicals.com
360-297-3400
Booth 24
Founded in 1982, Heron Botanicals produces artisan-quality
herbal extracts for practitioners across North America.
Located in the Pacific Northwest, we use local species and
fresh plant material whenever possible. We produce over 300
products utilizing Western, Chinese, and Ayurvedic herbs, as
well as obscure herbs, an array of glycerites, and topicals. We
are committed to staying on the cutting edge while honoring
tradition and maintaining our dedication to quality and
sustainability.
Hevert Pharmaceuticals, LLC
www.hevert.com/market-us/en_US
720-598-3037
Booth 25
Hevert is dedicated to the development of high-quality
natural medicines. Founded in Germany in 1956, Hevert
is an independent, family-owned company run today by
Mathias and Marcus Hevert, its third-generation Managing
Co-Directors. The company’s mission is to combine its long
tradition of homeopathic expertise with the exacting precision
of modern pharmaceutical manufacturing. Careful sourcing of
raw ingredients and rigorous quality control delivers maximum
active ingredient potency, making Hevert one of the ten
leading manufacturers of homeopathic medicines worldwide.
IGeneX, Inc.
www.igenex.com
800-832-3200
Booth 8
IGeneX, Inc. is a specialized clinical reference laboratory
focusing on Lyme disease and other associated Tick-Borne
diseases. IGeneX, Inc. was founded in 1991 and since then has
provided personalized service to private practice physicians,
hospitals, and other clinical reference laboratories worldwide.
IGeneX is recognized worldwide as offering the most accurate
testing available by hiring highly skilled professional laboratory
personnel and using the most advanced techniques and
instruments.
Imprimis Pharmaceuticals, Inc.
www.imprimisrx.com
858-433-2800
Both 11
ImprimisRx® pharmacies, are dedicated to delivering highquality
and innovative medicines to physicians and patients
TODAY at accessible prices. ImprimisRx offers compounded
formulations commonly prescribed by naturopathic physicians
specializing in integrative oncology, autoimmunity, chronic
infectious diseases, hormone therapy, and more. ImprimisRx
can assist you with unique formulations for intravenous
nutritionals, therapeutic combinations for skin care, and antiaging
strategies for weight loss and a multitude of dosage
forms for achieving hormone balance.
Integrative Therapeutics, LLC
www.integrativepro.com
920-492-0343
Booth 28
Integrative Therapeutics is a top- tier manufacturer of
nutritional supplements. We strive to offer both products and
education to healthcare professionals to provide choices to
their patients to lead healthy lives. Integrative Therapeutics
supports educational opportunities to practitioners and
students, and individuals and organizations who push the
industry to new standards.
17

Trust Your Gut
Microbiome
Functional Testing by
Doctor’s Data and Labrix
Comprehensive
Stool Analysis
Neurotransmitters
Steroid Hormones
HPA Axis/Adrenals
Zonulin
The Changing Paradigm in the World of Probiotics
MEGASPOREBIOTIC REPRESENTS THE NEXT EVOLUTION IN PROBIOTIC THERAPY
Key Features of
MegaSporeBiotic
• Modulation and Training of the Immune System
• Assist in the Digestion of Food
• Help Control the Microbiota
• Produce Key Nutrients in the Gut at Site of Absorption
“MegaSporebiotic is the first Probiotic that I could personally feel a difference
when I started taking it. Whether my patients have digestive or other health
issues, I recommend it. I love the additional benefit of the antioxidant property
of this Probiotic. I would recommend every doctor try it for themselves.”
Dr. Delilah A. Anderson DC, DABCI, DACBN
To learn more visit www.gomegaspore.com
18

MM19 Exhibitors
Koshland Compounding Pharmacy
www.koshlandpharm.com
510-725-1019
Booth C
Koshland Pharm: Custom Compounding Pharmacy is dedicated
to improving people’s health and well-being. Located in San
Francisco and serving all of California, Koshland Pharm partners
with doctors to develop innovative treatment plans for
individual patients. Accredited by the Pharmacy Compounding
Accreditation Board (PCAB), Koshland Pharm makes highquality,
customized prescriptions with a focus on optimal patient
outcomes. Compounding solutions for naturopathic practices
include patient-specific thyroid treatments, individualized
hormone therapy, topical treatments for onychomycosis and
eczema, and sterile injectables.
Meridian Valley Lab
www.meridianvalleylab.com
206-209-4200
Booth 35
Meridian Valley Lab is a world leader and pioneer in urine
hormone (dried and 24 hour), food sensitivity (serum and
bloodspot), and blood viscosity testing. Founded in 1976,
Meridian Valley Lab has always been at the forefront of
laboratory testing. Every test ordered comes with a free
consultation with Meridian Valley Lab’s very own consulting
physicians. Dried Urine Hormone Testing, now available!
Microbiome Labs
www.gomegaspore.com
815-999-6385
Booth 4
MegaSporeBiotic and MegaQuinone are dispensed by
Microbiome Labs which was born out of the desire to improve
the tools that integrative physicians have to improve the
health and well being of their patients. Microbiome Labs was
founded by a practicing doctor and is dedicated to creating
nutritional supplements with the highest quality, potency, and
efficacy for health care professionals.
NatureKue
www.naturekue.com
800-930-6956
Booth 18
NatureKue, Inc. is a U.S. based naturopathic healthcare
supplement company dedicated to Promoting a Healthier
World through Innovation, Integration and Prevention. We are
firmly rooted in our commitment to providing the best Mother
Nature has to offer, combined with the latest in scientific
research and modern technology. NatureKue’s premium
line of products significantly enhances our commitment to
continuously provide pharmaceutical-grade and evidencebased
nutraceuticals to our Healthcare Providers.
NCMIC Naturopathic
www.ncmicnaturopath.com
800 -769- 2000
Booth 17
NCMIC is proud to offer Naturopathic Doctors outstanding
malpractice insurance. We have over 70 years of experience
providing this valuable coverage to healthcare professionals.
You can rely on NCMIC’s Naturopathic Malpractice Insurance
Plan for a powerful claims defense, coverage options to
suit your needs and the personalized service you deserve.
This plan is offered through NCMIC Diversified Health RPG
Assn. and underwritten by NCMIC Insurance Company.
Call 1- 800- 769- 2000, ext. 8341, for details. Or, visit www.
ncmicnaturopath.com.
nutraMetrix
www.nutrametrix.com
714-234-4930
Booth 19
At nutraMetrix, we believe patients should have access
to recommendations for healthy living and products
that promote optimal wellness from their trusted health
professionals. Therefore, everything is focused on helping
health professionals implement customized wellness programs
that benefit patients and the practice. By providing health
professionals with science based nutritional interventions,
revolutionary technology, wellness based education systems
and trained implementation consultants, nutraMetrix is
changing the face of health care, one professional and one
patient at a time.
Oxy Health, LLC
ww.oxyhealth.com
562-906-8888
Booth 26
OxyHealth is the world’s leading provider of hyperbaric
chambers. Presently, OxyHealth is the pioneer of the industry
with over 12,000 chambers in use, more than all other
providers combined. OxyHealth continues to remain at the
forefront of superior performance, quality and cutting-edge
design concepts that far exceed industry safety standards.
Precision Analytical, Inc.(DUTCH Test )
www.dutchtest.com
503-687-2050
Booth 6
Precision Analytical offers a revolutionary new model of hormone
testing called DUTCH - a Dried Urine Test for Comprehensive
Hormones. By using four simple, dried urine collections, DUTCH
takes the advantages of a 24‐hour urine test and adds the
pattern of free cortisol (which has traditionally been acquired from
saliva). Hormone and metabolite values correlate to 24‐hour
urine values. Free cortisol concentrations accurately replace its
testing in saliva.
19

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‣ IgE, IgG, IgA Antibody Panels for Food & Inhalant
‣ Candida, Celiac Panel
IgA/IgG panels – Finger stick on Dried Blood Spot
‣ Comprehensive Urinary Metabolic Profile
Measures 36 organic acids using LC/MS/MS
platform
Analytes are markers of cellular respiration, fatty
acid and amino acid metabolism, neurotransmitter
metabolism, detoxification and intestinal health
‣ Environmental Pollutants Profile
Measures 13 analytes of 7 different chemicals,
including solvents, phthalates, and arabens
Performed on LC/MS/MS platform
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Come to our booth
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Boluoke , simply the best in:
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1-866-287-4986
www.canadaRNA.com
20

MM19 Exhibitors
Professional Formulas
www.professionalformulas.com
800-952-2219
Booth 31
For more than 30 years, Professional Formulas has provided
healthcare praconers with individualized products that are
easy to use and clinically proven,even for tough cases. Our
formulas are simply categorized by function to achieve more
from your exisng supplement protocols. So it is easy to develop
individualized treatment plans that stimulate the body’s healing
mechanisms, address underlying dysfunction and improve
patient outcomes.
Relax Saunas of Momentum98
www.momentum98.com
626-800-8454
Booth 15
The Relax Sauna is the only portable far infrared sauna
using medical grade technology. We have received literally
thousands of oral testimonies on the benefits people have
experienced from being in the Relax Sauna. We have put over
100,000 people in the Relax sauna, and have experienced
seeing about 20,000 minor or major experiences, about 500
which have been captured on video in the form of a video
testimony, many of which can be seen on YouTube.
Researched Nutritionals
www.researchednutritionals.com
800-755-3402
Booth 14
Physician-only line of clinically researched formulations:
H2 Absorb- to scavenge hydroxyl free radical & promote
healthy oxidative stress level; ATP Fuel®-mitochondrial
product w/researched showing 31% fatigue reduction; Tri-
Fortify liposomal glutathione clinically proven to increase
intracellular glutathione by 28% & Natural Killer cell function
by 400%; Transfer Factor Multi-Immune with 620% increase
in Natural Killer Cell function. Plus CytoQuel® to promote
healthy cytokine activity.
RLC Labs Inc
www.rlclabs.com
877-797-7997
Booth 3
Two natural thyroid solutions. Because no two people are
alike.
Nature-Throid® and WP Thyroid® are all natural T4 and T3
hormone replacement medications, which utilizes desiccated
porcine extract. Since Nature-Throid® and WP Thyroid®
contain both T4 and T3 hormones; they can provide a more
natural body response. Nature-Throid® is the classic solution
for hypothyroid treatment. WP Thyroid® with fewer inactive
ingredients is now available for patients that require a purer
formula. Both medications are formulated using hypoallergenic
inactive ingredients. RLC Labs also manufactures a-Drenal®
and i-Throid®, (iodine 12.5mg & 6.25mg) which can be used
alone or with either Nature-Throid® or WP Thyroid® for a wellrounded
thyroid protocol.
Please get more info. At www.getrealthyroid.com
Salveo Diagnostics
www.salveodiagnostics.com
804-519-8985
Booth 29
Salveo Diagnostics is the premier chronic disease-focused
laboratory, providing a unique and compelling program to help
physicians and patients uncover the root cause of their chronic
disease symptoms, enabling disease-specific therapies. Peer
reviewed, evidence-based literature is used to develop a lab
report with interpretative comments that guide physicians
to appropriate therapies. Nutritional and lifestyle support is
included to assist physicians in improving outcomes.
Sanashwa
www.sanashwa.com
510-912-5894
Booth 33
Before suggesting a dietary supplement for management of
stress in your patients if you are faced with questions like
whether the product is: safe; proven to be effective; has right
ingredients in correct dosages; has third party certifications
for safety purity and quality; and offers any advantage over
currently available treatment options? SanAshwa® is your
answer and choice of anti stress supplement. For more
information please visit website www.sanashwa.com
21

NCMIC’s Malpractice Insurance Plan for Naturopathic Doctors will offer
New & Expanded Coverage
The CNDA Conference is the perfect time to learn more about NCMIC and our malpractice insurance plan.
Stop by and talk with NCMIC Representative Lesley Dolan about our enhanced coverage and the many
benefits of choosing NCMIC, including …
Comprehensive Coverage True Consent to Settle Feature Claims Advice Hotline
Powerful Claims Defense Complete, Personalized Service Support of the Naturopathic Profession
Visit NCMIC’s booth to learn more.
Or, call 1-800-769-2000, ext. 8341.
Get an instant quote at www.ncmicnaturopath.com/CNDA
The NCMIC Naturopathic Malpractice Insurance Plan is offered through NCMIC Diversified Health RPG Assn. Coverage is underwritten by NCMIC Insurance Company, and is available in AK, AZ, CA, CT, DC,
HI, KS, MD, ME, MN, MT, ND, NH, OR, UT, VT and WA. Policy features may vary by state and may be subject to underwriting approval.
NFL 8341-171505
®
NOT ALL THYROID MEDICATIONS ARE CREATED EQUAL
GET REAL. ABOUT HYPOTHYROIDISM
GetRealThyroid.com
TOLL FREE 877-797-7997
22

MM19 Exhibitors
Seroyal Genestra Brands
www.seroyal.com
905-508-2050
Booth 2
Genestra Brands® Exceptional quality, consistency, stability
and reliability Genestra Brands® supplements support
individualized treatment plans with 350+ professional‐grade
products offered in a variety of formats. Our products have
been proven safe, effective and reliable for over 30 years, and
are backed by clinical or traditional evidence.
Sovereign Laboratories
www.sovereignlaboratories.com
928-202-4031
Booth D
Sovereign Laboratories, LLC. is dedicated to developing
natural supplements that provide the most efficacious
solutions for optimal health. Company founder Douglas Wyatt
is the world’s leading authority on colostrum, often referred
to as the “Modern Father of Colostrum,” and is credited with
establishing the gold standard in colostrum supplements. Mr.
Wyatt has supported scientific research for over 24 years and
initiated the first studies demonstrating that colostrum can
heal intestinal damage caused by NSAIDs.
Sprague Israel Giles, Inc.
www.siginsures.com
800-526-0635
Booth 30
Founded in 1958, SIG is an insurance brokerage located in
Seattle Washington. We specialize is Medical Professional
Liability (Malpractice) Insurance for Naturopathic Doctors
and have done so for close to a decade. We insure hundreds
of NDs around the country and are known to provide very
comprehensive coverage typically not available to NDs. Please
stop by our booth to learn more about our Natural Insurance
Program or call David Gollersrud at 206 957-7051.
Thorne Research, Inc.
www.thorne.com
208-263-1337
Booth 12
Thorne Research sets the standard for manufacturing
quality nutritional supplements available through healthcare
practitioners. Through recent ventures, Thorne Research
offers products to address nutritional deficiencies in cancer
patients and those with cardiovascular disease, plus a product
line for athletes, an organic skin-care line, and related practice
management programs. www.thorne.com
US BioTek Laboratories
www.USBioTek.com
877-318-8728
Booth 1
Antibody Assessments by ELISA: IgA/IgE/IgG for Foods,
Inhalants, Spices & Herbs; Candida Antibodies & Antigen and
Celiac Panels. Automated ELISA platform employs advanced
robotics for duplicate specimen testing to assure the highest
level of precision and accuracy. Urinary Steroid Hormones,
Organic Acids and Environmental Pollutants measured though
LC/MS/MS and GC/MS instrumentation. Patient-specific
report commentaries available for our chemistry profiles by
request. Blood or urine spot specimen collection offered for
most assays. CLIA-certified and accredited, COLA-compliant
and CAP-surveyed. Competitively Priced. Serving the World.
Vibrant Wellness Laboratories
www.vibrant wellness.com/gutzoomer
866 -364- 0963
Booth B
Vibrant Wellness is a personalized health analytics company
founded out of our passion to serve you, your physicians,
nutritionists and exercise physiologist. The Vibrant Wellness
platform provides a toll for you to track and analyze your guy
microbiome, leaky gut, wheat sensitivity and food sensitivity.
Women’s International Pharmacy
www.womensinternational.com
608-221-7800
Booth 13
Women’s International Pharmacy specializes in custom
compounded bioidentical hormone prescriptions for men
and women. Our pharmacy earned accreditation through
the Pharmacy Compounding Accreditation Board (PCAB)
by following stringent proficiency and quality assurance
standards. Our pharmacists focus on meeting individual needs
for licensed medical practitioners and their patients. Whether
you are a practitioner or patient you can be assured Women’s
International Pharmacy is here for you and we respect your
freedom of informed personal choice.
Zen Breakfast Blend
www.zenbreakfastblend.com
626-676-9394
Zen Breakfast Blend is a new type of functional food developed
by Dr. Jennifer Wicher ND. It’s a flax & chia protein smoothie
that’s ideal for patients with typical signs of metabolic disease.
Our mission is to help change people’s lives by changing their
breakfast. It’s naturally vegan and gluten free, and takes less
than a minute to make.
23

24

The Role of an Elemental Diet
in the Treatment of Inflammatory Bowel
Disease, Small Intestinal Bacterial
Overgrowth, and Other Conditions
Related to a Disordered Microbiome
Dr. Gary Weiner, ND, LAc
www.pearlnaturalhealth.com
The use of an elemental diet as a viable treatment strategy in inflammatory bowel disease has
been discussed for many years. More recently the elemental diet has come into focus as an
alternative strategy to resolving small intestinal bacterial overgrowth (SIBO). A greater variety of
elemental diet products have become available to physicians and patients, while increasing education
on cost-effective “home-made” elemental diets has emerged providing an opportunity for the
diet to be implemented more affordably. The elemental deserves its place among other short term
dietary interventions that can lead to statistically significant and rapid alternations in composition of
the intestinal microbiota, explaining its utility not only in the treatment of IBD and SIBO, but use in
other conditions that have less obvious relationship to the microbiota such as dyslipidemias, hypertension,
allergic disease, and mental and emotional disorders.
Biography
Gary Weiner, N.D., L.Ac. is co-founder and clinical director of Pearl Natural Health in downtown
Portland Oregon. Dr. Weiner graduated from the National University of Natural Medicine (NUNM)
in 1997, and holds degrees in both Naturopathic Medicine and Classical Chinese Medicine. He is a
member of the American Association of Naturopathic Medicine, the Oregon Association of Naturopathic
Medicine, and a member of the Advisory Committee of the Northwest Crohn’s and Colitis
Foundation of America. He is a clinical supervisor at NUNM, and supervises an NUNM certified residency
in his clinic, supported by the National Education and Research Consortium (NERC). Dr. Weiner
specializes in gastrointestinal and endocrine disorders, with a particular focus on Inflammatory
Bowel Disease (IBD), offering an IBD Complementary Care Program in his clinic. He has published
two large articles on IBD for the Naturopathic Doctors News & Review (NDNR), and presented on the
subject for the American Association of Naturopathic Physicians (AANP) and the California Naturopathic
Doctors Association (CNDA), and most recently at the 2016 SIBO Symposium.
25

© 2017 Gary W einer, N.D., LAc
Adapted from World J Gastroenterol 2014 January 7; 20(1): 6-21
Adapted from World J Gastroenterol 2014 January 7; 20(1): 6-21
5/17/2017
Elemental Diets
in the Treatment of Inflammatory Bowel Disease, SIBO
and other conditions related to a Disordered Microbiota
Disclosures
Educational consultant to Integrative Therapeutics, Inc.
GARY WEINER, N.D., L.Ac.
GI Microbiota distribution
Jejunum - 10 2
Streptococcus
Lactobacillus
Proximal Ileum -10 3
Streptococcus
Lactobacillus
Duodenum 10 2
Streptococcus
Lactobacillus
Stomach 0-10 2
Lactobacillus
Candida
Streptococcus
Heliobacter pylori
Peptostreptococcus
Distal Ileum 10 7 -10 8
Clostridium
Streptococcus
Bacteriodes
Actinomycinae
Corynebacteria
Colon 10 11 -10 12
Streptococcus
Bacteriodes
Clostridium
Bifidobacterium
Enterobacteriaceae
2012
Adapted from Am J Gast roent erol Suppl 2012; 1:15–21
Lumin
Food Componsents
Symbionts &
Commensals
Pathobionts
Lumin
Food Components
IgA
IgA
IgA
IgA
Symbionts &
Commensals
Pathobionts
Mucus
Epithelium
Lamina Propria
Pattern Recognition Receptors
Anti-microbial peptides
Mucins
IgA
IgA
IgA
IgA
Goblet
cell
Paneth Cell
Macrophage
Dendrite
Cytokines
Innate Lymphoid
Tight Junctions
Blood vessel
Mucus
Epithelium
Lamina Propria
TH-0
IL-6
Paneth Cell
Dendrite
TH-1
TH-17
Activated
Macrophages
Stromal
Cell
Goblet
Cell
Apoptotic Cell
MMP’s
Myofibroblasts
Blood vessel
Neutrophils
TH-2
© 2017 Gary Weiner, N.D., LAc
26
1

5/17/2017
Alteration of a “normal” microbiome
Eubiosis
genetics
birth
geography hygeine stress
route
Microbiome
Complexity & Stability
diet
nutrition
Digestion
Train and Stimulate Immune function
Protection against pathogens
Supply nutrients, energy, vitamins, SCFA
drugs
Firmicutes
Bacteriodes
Proteobacteria
(Enterobacteriaceae)
Actinobacteria
Inflammation
Altered metabolite
production)
Oxidative Stress
Increased gram negative bacteria
Symbionts
Commensals
Pathobionts
Infectious, metabolic, and inflammatory disorders
Disease
Birth Adult Elderly
Age 3
Early
onset
Adult
onset
Late
Onset
© 2017 Gary Weiner, N.D., L.Ac.
Adapted from Gast roent erology. 2014 May ; 146(6): 1489–1499. m:
Dysbiosis
Elemental
DECREASE
Alpha Helminths diversity
Bacteriodes and Firmicutes
Clostridia, Ruminococcaceae
Bifidobacterium, Lactobaccilus
Fecalibacterium Prauznitzii
IBD
MAP?
EBV?
Fungal organisms?
Increase in
gammaproteobacteria
Fusobacterium
E. coli, specifically AIEC
INCREASE
Full Definition of ELEMENTAL
1 a : of, relating to, or being an element: specifically:
existing as an uncombined chemical element
b : (1) : of, relating to, or being the basic or essential
constituent of something : FUNDAMENTAL < elemental
biological needs > (2) : SIMPLE, UNCOMPLICATED
< elemental food >
c : of, relating to, or dealing with the rudiments of
something: ELEMENTARY < taught elemental crafts
to the children >
d : forming an integral part : INHERENT < an elemental
sense of rhythm >
2 : of, relating to, or resembling a great force of nature
< the rain comes with elemental violence >
© 2017bGary Weiner, N.D., L.Ac.
https://www.merriam-webster.com/dictionary/elemental
14-18% of calories from protein in the form of amino acids, 42-76% calories from carbohydrate in the form of monosaccharaides, and 6-43% of calories
Elemental Diet (ED)
Unique Properties
Macronutrients
Proteins Carbohydrates Fats
Water
Possible to administer as liquid
Can be use for tube feeding Soluble
pediatric and geriatric use
And those unable to masticate
Decreased antigens exposed to
Intestinal lumen
Hypoallergenic
Exact composition varies.
14-18% f kcal from protein
42-76% kcal from from carbs
Flexible 6-43% from fatty acids.
Composition Usually low in fats, some formulas 1-3%
All essential and non-essential
nitrogen, minerals,, vitamins
and fats + up to 30000 kcal/day
High + 25 % of hydration requirements
nutritional
Efficacy
Upper SI As
Low residu
Bypass nee
and biliary
Little micel
low fat
FREE FORM AMINO ACIDS
© 2017 Gary Weiner, N.D., L.Ac.
SIMPLE DIGESTALBE
CARBOHYDRATES
FATTY ACIDS AS TRIGLYCERIDE
VITAMINS AND MINERALS
Low
Low digestible bulk Residue
Reduced stool weight
Decreased elimination
Minimal
Digestion
Upper SI assimilation
Low residue entering colon
Bypass GI secretions
Bypass micelle formation d/t low fat
Monomeric
Free of intact proteins
Avoids LCT favoring MCT
Favors monosaccharides or
easily digestible oligosaccharides
© 2017 Gary Weiner, N.D., L.Ac
Source of information: Gut,1975,16,68-79
27
2

5/17/2017
The Elemental Diet in Context
Western Diet and IBD
Dietary
Management
Enteral
Nutrition
Feeding
through GI
IV
Feeding
Parenteral
Nutrition
Polymeric Diet
Non-hydrolyzed
Semi-Elemental Diet
Partially-hydrolyzed
Elemental Diet
+
Fully hydrolyzed
Recommended
Whole Food Diet
Exclusion Diet?
Exclusive
Elemental Diet
“Half” or “Partial”
Elemental Diet
Exclusion Diet?
SCD?
AI?
FODMAPS?
•Increased risk of IBD (CD
and UC) for diet high in
total fat, omega-6 fatty
acids and animal proteins
Researched
therapeutic •Decreased risk of CD for
diet?
high in fruits and fiber
•Decreased risk of UC for a
diet high in vegetables.
Individualized?
© 2017 Gary Weiner, N.D., L.Ac.
Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol. 2011 Apr;106(4):563-73.
Elemental Beginnings
Elemental Beginnings
William C. Rose.
Burrill B. Chron
"It has been my
misfortune (or perhaps
my fortune) to spend
most of my
professional life as a
student of constipation
and diarrhea…”
Robert D. Simoni et al. J. Biol. Chem. 2002;277:e25
©2002 by American Society for Biochemistry and Molecular Biology
©U.S. National Library of medicine, National Institutes of health, Health & Human Services
1980 Study
1990 Retrospective Study
• 32 CD cases requiring hospitalization
• 4 week elemental diet
• Resolution of abdominal pain, diarrhea,
weakness, fever, weight loss after 2 weeks.
• Normal biomarkers (SED, albumin,
hemoglobin) after 4 weeks.
• 1990 10-year retrospective study
• ED-induced improvements in 96 of 113
cases (85%)
• Unsuccessful response in only 17 patients
(15%)
Br Med J. 1980 Nov 1;281(6249):1173-5
Gut, 1990, 31, 1133-1137
28
3

for 6 mo, while none of those on the carbohydraterich
diet remained in remission
5/17/2017
Exclusion Diets
Elemental and Elimination Diet
[E]xclusion diet allowed 51 out of 77
patients to remain well on diet alone for
periods of up to 55 months, and with an
anual relapse rate of less than 10%
Lancet. 1985 Jul 27;2(8448):177-80.
A 2-year probability of relapse was lower
in the group treated with elimination diets.
Excluded foods… most relevant and
appearing commonly were dairy
products, cereals, and yeasts.
Lancet. 1993 Nov 6;342(8880):1131-4
The Long and the Short of It
Enteral and Elemental Research
Alternative enterotype states are
associated with long term diet.”
Science. 2011 Oct 7;334(6052):105-8.
• Favorable influences on:
- Body composition
- Weight
- Nutritional Status
- Pro-inflammatory cytokines
- Intestinal permeability
- Clinical and endoscopic disease
- Mucosal healing
Enteral and Elemental Research
Enteral and Elemental Research
First line therapy induction of remission CD
(Critch et all, 2012)
Remission of pediatric CD (Wu et all. 2013)
equivalent to corticosteroid therapy in
inducing clinical remission and superior in
inducting histologic remission (Garard et all 1993;
- Mucosal healing
Borrelli et all , 2006).
Efficacy in adult patients with CD may be
less (then steroids) due to poor
compliance or greater exposure to
immunosuppressive therapies (Lee et al. 2015).
Partial elemental nutrition shown to be
efficacious in both adult and pediatric
CD in maintenance remission.
29
4

5/17/2017
reasons not fully understood.
Ulcerative Colitis
IBD Pathogenesis
• No published evidence for consistent effectiveness
• Improved clinical responses noted in limited research
• Studies criticized for being small, poorly constructed
and containing insufficient data
• May be underutilized for unsubstantiated reasons
• Some physicians implement in refractory cases.
• Recommended in UC cases with under-nutrition
and SIBO.
Apthous
Ulcers Apthous
Ulcers
Apthous
Ulcers
Apthous
Ulcers
Apthous
Ulcers
Limited to colon
(with ”backwash ilietus)
Affects only mucosa
Begins in rectum
Progresses proximally
contiguously and circumferentially
Smoking
Geography
Stress/Psychological
Antigens
164 gene loci
30 for CD
23 for UC Host
Genetics
Diet
Environment
IBD
Microbiota
Medications
Antibiotics, NSAIDS
Micro and nano-particles
Altered by Environmental Factors
In context of host genetics
Impaired
Immunity
Breakdown of Innate immunity
Adaptive Immune response
Pathophysiological consequences
Under-nutrition and malnutrition in IBD
Anemia,
uveitis,fever,
Primary
sweats,
Sclerosing
Indeterminate Colitis jaundice
Cholangitis
Anxiety &
Depression
Apthous
Ulcers
↓
↑
↑ Nutritional requirements
↓ Food Consumption
Medication Side Effects
Lack of appetite
Nausea/Vomiting
Abdominal
pain
Diarrhea,
blood,
mucus
Nutritional Loss
Crohn’s
Disease
Skin rash, pyoderma,
erythema nodosum
Ulcerative
Colitis
Arthritis
arthralgia
Weight
Loss
↑
↑
↑
↓ GI Secretions
Protein losing enteropathy
Pancreatic insufficiency
Bile acid malabsorption
Gastric Acid Insufficiency
↑ Malabsorption ↓ Absorption
Inflamed mucosa Fistula formation
SIBO
Strictures
Bowel Resection
GI losses
Diarrhea
Blood
Mucus
Malnutrition in IBD
Diarrhea
Abdominal pain
Hematochezia (blood in
stool)
Mucus Fever
Malnutrition
Weight Loss
Malnutrition in IBD IBS?
. “Clinically apparent malnutrition is more
frequent [in IBD] and may serve as a
clinical marker of poor IBD prognosis…”
Compr Ther. 1994;20(9):523-30
Protein-
Energy
Malnutrition
Altered Body
Composition
Micronutrient
Deficiencies
Vitamin A, D, E, K, B6,
B12, Folic Acid
FE, Zn, Sn
Systemic
Complications
Poor
Treatment
Outcomes
Morbidity ↑
Mortality ↑
Wound Healing ↓
Infections ↑
Complications ↑
Convalescence ↓
30
5

5/17/2017
Malnutrition in IBS?
Malnutrition in IBS?
…Patients with IBS may have subcliical
protein deficiency in absence of
demonstrable organic bowel disease.
Hum Nutr Clin Nutr. 1983 Jan;37(1):37-41
About 41.67% of the IBS-D patients
meeting Rome Ⅲ criteria have SIBO
[which] can affect nutritional status in IBS-
D patients.
Zhonghua Yi Xue Za Zhi. 2016 Jun 28;96(24):1896-902
. The nutritional consequences of intestinal
bacterial overgrowth include vitamin
deficiencies, fat malabsorption, and
malnutrition.
Compr Ther. 1994;20(9):523-30
Elemental Diet and IBS
Proposed IBS pathogenesis
• 93 subjects with IBS and abnormal LBT.
• 14 or 21 day elemental diet
• 74 (80%) had a normal LBT on day 15 of the
elemental diet as well as amelioration of IBS
symptoms. When those who continued to
day 21 were included, five additional
.patients normalized the breath test (85%)
DIET
-Fat
-Fermentable CHO
ALTERED INTESTINAL IMMUNE FUNCTION
-Bacterial recognition by TLR
-Cytokine and chemokine secretion
-Secretion of antimicrobial peptides
-
IMMUNE ACTIVATION
-Low Grade Inflammation
Unstable Microbiota leads to gut dysfunction
Host factors alter
microbial habitat
-
DYSBIOSIS
IBS
STRESS AND PSYCHOLOGICAL CO-MORBIDITIES
-HPA activation
-Sympathetic activation
ALTERED INTESTINAL PHYSIOLOGY
-Motility and transit
-Mucin secretion
-Intestinal Permeability
-Enteric neural function
Unstable microbiota
contribute to unstable
habitat
-
Elemental Diet
A Servant with Two Masters?
Intersection
ibs
U
ibd
=
{?}
31
6

A substantial number of IBD patients
with normal faecal calprotectin level
experience IBS-type symptoms. These
patients exhibit similar features to
people diagnosed with IBS in the
general community, suggesting that the
conditions are not mutually exclusive
and may coexist in a considerable
number of IBD patients. A systematic
diagnostic approach is required to
assess IBD patients with IBS-type
symptoms as sub-clinical inflammation
may play a role in a proportion of
cases. Aliment Pharmacol Ther. 2013
Jul;38(1):44-51.
- Am J Gastroenterol. 2003;98:412-
419.`
“Symptoms compatible with IBS
were higher in patients with IBD
compared to non-IBD controls,
even those in remission.”
-Am J Gastroenterol. 2012 Oct;107(10):1474-18
{
Symptoms compatible with IBS were
significantly higher in patients with IBD
compared with non-IBD controls, even
among those felt to be in remission. IBStype
symptoms were also significantly
more common in CD than in UC
patients, and in those with active
disease. Management strategies for IBD
patients with symptoms suggestive of IBS
are required. Am J Gastroenterol. 2012
Oct;107(10):1474-82.
ibs
U
diarrhea
constipation
ibd
abd. pain/bloating
weight loss
motility disruption
&dysfunction
disturbed
microbiome
maldigestion &
malabsorption
malnutrition
“…57% of patients with CD and
33% of patients with UC in longstanding
remission, as assessed by
laboratory, clinical, and
endoscopical parameters, have
IBS-like symptoms.
-Am J Gastroenterol 2002;97(2):389–96. `
-World J Gastroenterol 2014 Oct
14;20(38):13999-4003
“OCTT was
significantly
delayed in IBD
patients, and more
in CD compared to
UC, and is thought
to be the cause of
=
the increased SIBO
in these patients.”
{
DRIVE CAREFULLY
HIDDEN INTERSECTION
-Dig Dis Sci. 2013 Sep;58(9):2594-8.
“almost non-existent” in
predominantly diarrheal
conditions of CD and UC, and
was more prevalent in IBS than in
either CD or UC. Dig Dis Sci. 2003;48(1):86-92
“…57% of patients with CD and
33% of patients with UC in longstanding
remission, as assessed by
laboratory, clinical, and
SIBO
endoscopical parameters, have
IBS-like symptoms.
-Am J Gastroenterol 2002;97(2):389–96. `
21).
“About 41.67% of IBS-D patients meeting
Rome III criteria have SIBO…” Zhonghua Yi Xue Za Zhi.
2016
Jun 28;96(24):1896-902.
S
ibs
U
Connecting the dots:
ibd
SIBO
{
is a cause of IBS
intestine does occur in
some IPAA patients and
needs to be kept in the
differential diagnosis.
- j.crohns.2014.01.007. Epub 2014 Jan
SIBO
IBS often co-exists with IBD
IBD causes SIBO
=
{
IBD, IBS & SIBO often present together
Separation Anxiety
5/17/2017
-J Gastroenterol Hepatol. 2015
Jun;30(6):990-4. doi: 10.1111/jgh.12908.
From [ileal] biopsie
microbiome
there appears a d
the UCafflicted
intestinal
(Ileum) even in the
absence of inflam
implicating barrier
microbial change
primary abnormal
UC that may play
causative role in d
development
- J Crohns Colitis. 2015 Dec 9
“OCTT is dela
is higher in UC
2014 Aug;8(8):859
10.1016/j.crohns.2014.0
IBD
IBS
IBS
IBS
IBD
Altered mucosal permeability
Interaction of luminal flora & mucosal immune system
Immune activation
Inflammation
Alterations in gut motility
Role for sustained life stressors in symptom expression
Psychological and neuroendocrine plays role in symptom
expression
Together At Last
Confusion of Identity
Inflammation
Immune Activation
Intestinal Permeability
Cytokine imbalances
IBS
SIBO
IBD
Altered microbiome
Interaction between microbiota and immune system
Role for pyscho-emotional, neuroendocrine & stress
IBD
Elemental Diet
IBS
MILD
IMMUNE ACTIVATION
INTENSIE
GUT INFLAMATION
SIBO
Continuum?
32
7

5/17/2017
↓ Bacterial
translocation
↓ Lipid peroxidation
Elemental mechanism?
Elemental Mechanism?
↑ Anti-oxidants
Modified Immune
Response & Mucosal Repair
Elemental diet
↓ gastric, biliary,
and pancreatic secretions
↓ Pro-inflammatory
Cytokines
↓ Intestinal Permeability
↓ Bacterial translocation
↓ malabsorption
↓ SIBO
↑ Nutrient status
Proximal
Absorption
Favorable micobiome
Alteration
Bowel rest
↓ Antigen Exposure
↑ Supply of trophic AA’s
↑ energy (glucose)
Improved fatty acid and
eicosanoid profile
↓ Mesenteric
adipose tissue
↑ Immune
Regulation
↑ Intestinal
Permeability
↓ Lipid
Peroxidation
↑ Trophic
Amino Acids
↓Cyokines
↑ Antii-
Oxidants
Altered
Microbiome
↓ Antigens
↓Malabsorption
Bowel Rest
↓ SIBO
Improved
Fatty Acid
Profile
Proximal
Absorption
↓ Mesenteric
Adiposity
↑ Micronutrient
Repletion
↓GI
Secretions
Proximal
Absorption
Summary of Elemental Actions on Microbiome
Elemental Diet and RA
•Short term alteation Nutrients 2014, 6, 5298-5311
Altered
Microbiome
•Reduction of total GI microbiota without increase of
any specific group Journal of Crohn's and Colitis
(2013) 7, 460–466
•Reduction of enterococci Buonos et al 1974
An elemental diet for 2 weeks resulted in
subjective clinical improvements…as effective
as a course of oral prednisone, 15mg/day.
Blood parameters ESR, SED and Hg improved in
the steroid group only.
•Reduction diversity Dig Dis Sci, 2009 Sep;54(9):1892-900
Postgrad Med J. 2007 Feb;83(976):128-31.
© 2017 Gary Weiner, N.D., L.Ac.
Elemental Diet and Eosinophilic Esophagitis
Strict elemental diets have been reported to
induce remission in 88%-96% of children with
Eosinophilic Esophagitis, and 72% of adults.
Elemental Diet and…..
?
• Hypertension
• NAFLD
• Alcoholic Liver Disease
•Overweight/Obesity
Gastroenterology. 2014 Dec;147(6):1238-54.
•Colorectal cancer
•Autoimmune disorders
•Psycho-emotional disorders
•Diabetes and other metabolic disorders
33
8

5/17/2017
✓
The Six Elemental Steps
© 2017 Gary Weiner, N.D., L.Ac.
Bottom-Up and Top-Down
Certolizumab pegol (Cimzia®)
Adalimumab (Humira®)
Infliximab (Remicade®)
Natalizumab (Tysabri®))
Azathioprine (Imuran®)
6-Mercaptopurine (Purinethol®)
Methotrexate, MTX (many generics)
Tacrolimus (Prograf® & others)
Cyclosporin
Ciprofloxacin
Metronizadole
Rifaximin
INDUCE
Total Colectomy, Ileostomy,
ileoanal anastomoses,
Strictureplasty
Etc.
REMISSION
Surgery
Biologics
Immunomodulators
Corticosteroids
Antibiotics
Aminosalicylates
Dietary Management
Prednisone
Prednisilone
Methylprednisilone (“Medrol”)
Budesonide MAINTAIN
(Entocort® &
Uceris®)
Hydrocortisone
Sulfasalazine (Azulfadine®)
Mesalamine:
Canasa®
Rowasa®
Asacol®
Pentasa®
Lialda®
Apriso®
Osalazine (Dipentum®)
Balsalazide (Colazol®)
The management objective?
Exclusive or Partial Diet
INDUCE
REMISSION?
Or “support”
of induction?
MAINTAIN
REMISSION?
Or “support” of
maintenance?
RESOLVE
MALNUTRITION?
Or supplement
“undernutrition”
MANAGE
SIBO?
100% of
calories
Exclusive
Elemental
Diet
”Half or “Partial”
Elemental
Diet
~ 900-1200 Kcal
Remaining calories
From whole food
Induction
SIBO
Nutritional
Support
Maintenance
Aminosalicylates
The Six Elemental Steps
Calcuate
✓ ✓
Men: BMR = (10 x weight in kg) + (6.25 x height in cm) – (5x age in years) +5
Women: BMR = (10 x weight in kg) + (6.25 x height in cm) – (5 x age in years) - 161
First calculate BMR using Harris-Benedict Equation:
Then multiply the BMR x an activity factor
Activity level
Activity
Factor
Little to no exercise 1.2
Light exercise (1-3 days per week) 1.375
Moderate Exercise (3-5 days per week) 1.55
Heavy Exercise (6-7 days per week) 1.725
Very heavy exercise (twice daily, extra heavy workouts) 1.9
© 2017 Gary Weiner, N.D., L.Ac.
34
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5/17/2017
Step 2 - Calculate
First calculate the BMR
The Six Elemental Steps
Case Example
• A 37 year old, sedentary woman
• Height: 5 foot, 9 inch (175.3 cm), Weight: 164 pounds (74.4 kg)
✓ ✓✓
First calculate the BMR
[(10 x 74.4) + (6.25 x 175.3) – (5 x 37) – 161] = [744 + 1095.6 – 185 -161 = 1493.6 kcal
Then multiply the BMR x an activity factor
1493.6 kcal x 1.2 (sendentary activity factor) = 1792.32 kcal per day
~ 1800 kcal daily
Dose
Dose
For example: RX=1800 kcal/day
Exclusive
Elemental
Diet
Divide total number of calories into
servings of 300 calories
Take one serving every 2-3 hours
Exclusive
Elemental
Diet
8AM 300 kcal
10AM 300kcal
100% kcal
12PM 300 kcal}Elemental Diet
2PM 300 kcal
4PM 300 kcal
6PM 300 kcal
50% Kcal
Duration
Dose
Exclusive
Elemental
Diet
Induction of Remission
Nutritional support
SIBO
3-6 weeks
3-6 weeks
2-3 weeks
Prescribe up to half of the daily
calorie requirements, between
900-1200 kcal.
Then divide them into 300 calorie
servings servings to be consumed
every two hours during one half of
the day, either AM or PM
”Half or “Partial”
Elemental
Diet
Remaining calories
from whole food
Patient eats whole food diet during
OTHER half of the day.
35
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5/17/2017
Dose
Dose
7AM 300 kcal ED
9AM 300kcal ED
11AM 300 kcal ED
RX=1800 kcal/day
1PM 450 kcal LUNCH
5PM 450 kcal DINNER
}
50%
}
50% Kcal
Elemental Diet AM
Kcal
Whole Food PM
Limited evidence for greater efficacy at 1200+ kcal/day
Remaining calories
from whole food
”Half or “Partial”
Elemental
Diet
8AM 450 kcal BREAKFAST
12PM 450 kcal LUNCH
}
2PM 300 kcal ED
4PM 300 kcal ED
6PM 300 kcal ED
5PM 450 kcal ED
}
RX=1800 kcal/day
50% Kcal
Whole Food PM
50% Kcal
Elemental Diet AM
Limited evidence for greater efficacy at 1200+ kcal/day
Remaining calories
from whole food
”Half or “Partial”
Elemental
Diet
Duration
PARQ*
Published recommended duration
has not been established.
Continuous, intermittent, periodic,
or pulsed use can be considered in
each case.
Remaining calories
from whole food
”Half or “Partial”
Elemental
Diet
Exclusive
Elemental
Diet
Strengths and limitations
Slow Feeding
Hydration
Cautions and warnings
about typical problems
Remaining calories
from whole food
”Half or “Partial”
Elemental
Diet
*Procedures, Alternatives, Risks, Questions
The Six Elemental Steps
Weekly Follow-ups
✓ ✓✓✓
• Weekly follow-up for at least four weeks, or
until stability achieved.
• Track progress symptomatically and run periodic
labs to monitor nutritional stability, and inflammation
(SED, CRP, CALPROTECTIN, LACTOFERRIN)
• Prepare patient for transition to whole food strategy
• Manage medications, coordinate care, and address
elemental obstacles.
© 2017 Gary Weiner, N.D., L.Ac.
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5/17/2017
Address elemental obstacles
The Six Elemental Steps
TIP: find flavored products with
Natural, hypoallergenic ingredients
TIP: dilute
TIP: blend with ice
Taste
TIP: Plan on weight loss first week pf EED
Weight Loss
TIP: Avoid EED with very low
BMI’s
Weight Loss
TIP: Adequate
hydration and slow
Hunger feeding
✓ ✓✓✓✓
TIP: lemon, lime, sat,
vanilla
TIP: Treat with prior
or concomitant
anti-fungals
Fungal
Ailments
Elemental
Obstacles
Osmotic
Diarrhea
Fatigue
TIP: Additional blood
sugar and adrenal
support
TIP: monitor/treat anemia
TIP: monitor deficiencies;
Supplement IV and IM
prn
© 2017 Gary Weiner, N.D., L.Ac.
TIP: Adequate
hydration and sow feeding
© 2017 Gary Weiner, N.D., L.Ac.
Step 5 – Reintroduction of Whole Food
Step 5 – Reintroduction of Whole Food
Elemental diet is as effective in producing
[E}xclusion diet allowed 51 out of 77 patients to
remission of Crohn’s disease (CD) as is
remain well on diet alone for periods of up to
corticosteroid treatment, but most patients
55 months, and with an anual relapse rate of
relapse soon after resumption of a normal
less than 10% ( Lancet. 1985 Jul 27;2(8448):177-80)
diet. (Lancet. 1985 Jul 27;2(8448):177-80)
Dynamic &
Flexible
Specific
Carbohydrates
Hypoallergenic
Antiinflammatory
Fats
Specific
Exclusion
Fiber & Residue
Techniques
Considerations
Texture
Modifications
© 2017 Gary Weiner, N.D., L.Ac.
© 2017 Gary Weiner, N.D., L.Ac.
Specific Carbohydrate Diet (SCD)
Sidney Haas, MD
Used it to treat celiac
Disease in 1930s
Elaine Gotshall
Popularized SCD in
popular book
Removes
all grains
milk products except
for yoghurt fermented
greater than 24 hours
Sugars except honey
d
Fruits
Dairy/Beans Meat, Vegetables
Fish
Legal Juice or
Gelatin Only
Grape Juice (100%)
Apple Ciider 100%
Peeled,
deseeded & well
cooked
Carrot(cooked for 4 hours
and pureed for moderate to
severe symptoms)
`
Roasted, Boiled
or Broiled:
Fish, chicken, beef,
turkey, lean pork, lean
game meats (no ham
or bacon),
Eggs
INTRO PHASE 1 PHASE 2 PHASE 3 PHASE 4
any style (keep fats to
minimum because
hard to digest)
Peeled, deseeded,
well cooked,
pureed
homemade applesauce,
homemade pear sauce.
Raw
Banana (very ripe)
Peeled, deseeded &
well cooked (pureed)
Acorn squash, butternut squash,
spinach, zucchini (and other
summer squash)
Roasted, Boiled,
or Broiled
Eggs
any style (keep fats to
minimum because
hard to digest)
24-hour : yoghurt
SCD, homemade
yoghurt
Peeled, deseeded, Peeled & cooked Raw & Peeled Raw
Apple, apricot, avocado,
Blueberry, boysenberry,
Apple, blueberry, blackberry,
well cooked
cantaloupe, cherry, date,
blackberry, cantaloupe,
cherry, date, elderberry, fig,
Apricot, avocado (cooked),
elderberry, fig, gooseberry,
cherry, cranberry, date,
gooseberry, grapes, olive,
peach, pineapple, plum,
grapefruit, grapes, kiwi fruit,
elderberry, fig, gooseberry,
peach, pear, persimmon, plum,
tomato
kumquat, lemon, lime, mango,
grapefruit, kiwi, kumquat,
raisin, raspberry, strawberry,
orange, papaya, passion fruit, tomato
lemon, lime, loganberry,
Raw
peach, pear, persimmon,
mango, orange, papaya,
pineapple, pomegranate, plum, Dried
passion fruit, rhubarb,
tangerine, tomato, watermelon
Avocado
raspberry, strawberry,
Sparingly, with caution
tangerine, watermelon
Peeled,
Cooked
Raw
deseeded, well Beet., cauliflower, celeriac,
celery, Chinese cabbage, Beet., cauliflower, celeriac, celery, Chinese cabbage, collard,
cooked pureed collard, cucum Bok choy, cucum Bok choy, broccoli, cabbage, carrober, daikon radish,
broccoli, cabbage, carrober, kale, leek, lettuce, mushroom, olive, onion, peppers, radish,
daikon radish, kale, leek, rhubarb, shallots, snow peas, sugar snaps peas, spinach, Swiss
Artichoke, asparagus, cucumber, lettuce, mushroom, olive, onion, chard, watercress
garlic, green beans, mushrooms, peppers, radish, rhubarb,
peppers, pumpkin and other shallots, snow peas, sugar snaps
winter squash (no spagetti squash) peas, spinach, Swiss chard,
watercress
watercress
Pan Fried: crisp-fried Battered/Deep-fried
Baked
Dried Jerky
pork or “legal” bacon
can be added
Nut Milk
Blanched cashew,
hazelnut,
macadamia nut
Nut Butter
Pecan, blanched
almond
Eggs
any style (keep fats to
minimum because
hard to digest)
Nut Flour
Pecan, blanched almond,
hazelnut
Nut Butter
Blanched cashew,
hazelnut, macadamia
Eggs
any style (keep fats to
minimum because
hard to digest)
Nut Flour
Blanched hazelnut, cashew,
macadamia nut, walnut, ,
Nut Pieces
Blanched almond, pecan,
shredded coconut
No peanuts!
Beans
Cooked (prepared
according toBTVC): Haricot
beans, Lentils, Lima beans,
Navy beans, Split peas
PHASE 5
Whole Nuts
(chew well!)
Blanched hazelnut,
cashew,
macadamia nut,
walnut, ,
Beans
Cooked (prepared
according to BTVC): Black
beans, Kidney beans
, ,
, ,
37
12

0%
5/17/2017
The Six Elemental Steps
Step 5 – Flexible model of dietary mangement
✓ ✓
✓
✓ ✓
✓
Elemental
Formula
Whole Food
Diet
Empirically
Determined
Proportions
Quiescent IBD
100%
+ Conventional Management
As Required
0%
© 2017 Gary Weiner, N.D., L.Ac.
Adapted from ideas presented in Gastroenterology. 2015 May; 148(6): 1087–1106.
Step 5 – Dietary Management model?
The Six Elemental Steps
Relapse
✓ ✓
✓
✓ ✓
✓
Active Inflammation
Quiescent IBD
Induction
Strategy
Maintenance
Strategy
100%
Exclusive
Elemental
Diet
Elemental
Formula
Whole Food
Diet
Empirically
Determined
Proportions
0%
Adapted from ideas presented in Gastroenterology. 2015 May; 148(6): 1087–1106.
© 2017 Gary Weiner, N.D., L.Ac.
It’s elemental,
my dear Watson!
A 39 year-old male
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13

5/17/2017
28 year-old female
35 year-old female
CASE
#1
“I’m very
hungry!”
Key Points
Key Points
• EED appears to make short term alterations that need
reinforcement with ongoing dietary manipulation
• Enterotype change requires long term dietary
modification
• ED can be a primary or complementary treatment
• Large evidence base for induction & maintenance of CD
• Large evidence base for undernutrition in CD & UC,
perioperative nutrition, and short bowel syndrome
• Sufficient evidence base for resolution of lactulose
breath test in SIBO
© 2017 Gary Weiner, N.D., L.Ac.
• Multiple proposed mechanisms of action allows
ED to address many levels of pathophysiology
• Flexible composition permits modification
• EED must be followed with whole food strategies and/or
other viable maintenance
• “Half” or Partial ED must be coupled with whole
food strategies and/or other viable maintenance
• IBD generally requires coordination of care and a degree
conventional management.
• ED is safe and generally free of side effects, however,
cautions required
© 2017 Gary Weiner, N.D., L.Ac.
Cautions
• Do not use exclusively, long term.
• Caution in diabetes, kidney disease, fungal dysbiosis.
underweight patients
• Must be consumed slowly
• Largest obstacle compliance (taste, hunger, boredom)
• Careful supervision and follow-up required
Thank you!
Gary Weiner, N.D., L.Ac.
Pearl Natural Health
drgary@pearlnaturalhealth.com
© 2017 Gary Weiner, N.D., L.Ac.
39
14

40

How the Microbiome Shapes the
Systemic Immune System in
Health and Disease
Kiran Krishnan, Research Microbiologist
www.gomegaspore.com
It is estimated that over 80% of our immune tissue is found in the gastrointestinal tract. This same
space is occupied by over 100 trillion microorganisms, practically from the day we are born. Overwhelming
scientific evidence illustrates the critical role these microbes play in both the function and
dysfunction of the immune system. Microbiome initiated immunological dysregulation is a primary
cause of many non-infectious diseases such as autoimmunity, allergies, asthma, and cancer.
Biography
Kiran Krishnan is a Research Microbiologist and has been involved in the dietary supplement and
nutrition market for the past 16 years. He comes from a strict research background having spent
several years with hands-on R&D in the fields of molecular medicine and microbiology at the University
of Iowa. Mr. Krishnan earned his Bachelor of Science degrees in Microbiology at the University
of Iowa; his undergraduate education was followed up with post graduate research and advanced
course work in Molecular Biology and Virology. He left University research to establish a Clinical
Research Organization where he designed and conducted clinical trials in human nutrition. Most
recently, Kiran is acting as the Chief Scientific Officer at Physician’s Exclusive, LLC. and Microbiome
Labs. He is a frequent lecturer on the Human Microbiome at Medical and Nutrition Conferences. He
conducts the popular monthly Microbiome Series Webinars through the Rebel Health Tribe Group
practitioner training program, he is a regular expert guest on National Radio and Satellite radio
and has been a guest speaker on several Health Summits as a microbiome expert. He is currently
involved in 4 novel human clinical trials on probiotics and the human microbiome. Kiran offers his
extensive knowledge and practical application of the latest science on the human microbiome as it
relates to health and wellness.
41

5/16/2017
How the Microbiome Shapes the
Systemic Immune System in Health and
Disease
Kiran Krishnan
Microbiologist, Clinical Researcher
FINANCIAL DISCLOSURE
CURRENT POSITIONS AND FINANCIAL ASSOCIATIONS
‣ Microbiome Labs, LLC. – Chief Science Officer
‣ Nu Science Trading, LLC. – V.P. Science and Business Development
‣ DMS Natural Health, LLC. – Scientific Advisor
‣ HB Specialty Foods, Inc. – Scientific Advisor
‣ SilverFern Brands, Inc. – Scientific Advisor
‣ WR Group – Probiogen – Scientific Advisor
‣ Sun Genomics Labs – Member, Board of Director
‣ Body & Eden – Member, Board of Directors
‣ The Human Longevity Project - Investor
THE IMMUNE SYSTEM
A NEW PERSPECTIVE:
HUMAN IS MERELY A
COLLECTION OF
SYMBIONTS OR
BIONTS WHO FORM A
HOLOBIONT – A SUPER
ORGANISM
“Symbiogenesis is the result of the
permanent coexistence of various bionts to
form the holobiont (namely, the host and its
microbiota”
Ricardo Guerrero et al, Aug 2013
“Eukaryotic individuals can be analyzed as
coevolved, tightly integrated, prokaryotic
communities; in this view, natural selection
acts on the holobiont as if it were an
integrated unit.”
Ricardo Guerrero et al, Aug 2013
• Human immune system begins to develop in the embryo.
• Starts with hematopoietic (from Greek, "blood-making") stem cells.
• Stem cells differentiate into major cells in the immune system
• granulocytes, monocytes, and lymphocytes
• The only major system in the body designed to protect us
• Immune system is an army with no general – requires training.
• Takes at least 6 months for the immune system to start working on its own
• Stem cells continue to be produced and differentiate throughout ones lifetime.
COMPONENTS OF THE HUMAN IMMUNE SYSTEM
THE IMMUNE SYSTEM
Immunity and Immune Response
Made up of two cellular systems:
• Humoral or circulating antibody system
• B cells produced antibodies
• Cell mediated immunity
• T cells primarily
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5/16/2017
INNATE VS. ADAPTIVE IMMUNITY
INNATE IMMUNITY (our first line of cellular defense)
‣ ANTIGEN PRESENTING CELLS – Macrophages and Dendritic cells – find and present potential
problems.
• They sit amongst trillions of bacteria in the mucosal system and have to actively recognize
friend and foe!
• These APCs are produced by the thymus and other lymphoid centers but are recruited to the
gut mucosa by our commensal organisms.
• The microbiome helps these cells by expressing something called Toll-like receptors (TLRs) –
These TLRs neutralizes immune response to offer “tolerance”.
• The microbiome also goes as far as producing ATP (energy) to help these cells differentiate
and function.
‣ NEUTROPHILS – Key part of first line of defense
• Killer cells that directly target harmful organisms. Very important to maintain infection free in
the cold and flu season.
• Dependent on the microbiota to stimulate their expression and even to equip them with the
tools to perform their killing function – nitric oxide, super oxides, etc.
INNATE VS. ADAPTIVE IMMUNITY
INNATE IMMUNITY (our first line of cellular defense)
‣ NATURAL KILLER CELLS – Highly important in viral infections. These cells identify infected
tissue and eliminates it. With dysfunction in NK cells, an individual would face chronic,
consistent infections.
• The microbiota stimulates the production of NK cells.
• The microbiota effects the potency of the cells as well.
‣ MAST CELLS – Highly important regulatory cells in the lamina propia.
• They control blood flow and coagulation in the LP.
• They control smooth muscle cell peristalsis.
• Fight against gut permeability
• Control electrolyte exchange
• Poor microbiota and low diversity leads to fewer mast cells in the gut and more in circulation
– one mode of action for increasing allergies.
‣ INTESTINAL EPITHELIAL CELLS (IEC) – The barrier cells that have some immune function
• Releases key antimicrobials to protect the barrier
• Releases chemokines and cytokines to recruit immune cells to the location
• The microbiota stimulates the IEC to release these antimicrobials and chemical messengers.
INNATE VS. ADAPTIVE IMMUNITY
INNATE VS. ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY – The second line of defense and the long term protection
B-Cells: (antibody secreting cells)
‣ Gut associate B-cells primarily secret IgA – this is the antibody that
is made in the highest concentration and we make about 7g of it
each day!
‣ B-cells originate in the Peyers patches
‣ The amount of B-cells/Peyers patches and their potency is directly
controlled by commensal bacteria.
‣ IgA, unlike IgM, has low “memory” and mostly recognizes current
crop of commensals and invading organism. It requires constant
stimulation and up-regulation to provide new IDs and protection.
‣ Low microbiota diversity, low microbial exposure, low antigenic
species in our environment leads to low levels of IgA production
and actually higher IgE production!
ADAPTIVE IMMUNITY – The second line of defense and the long term protection
T-Cells – (Our Immune Orchestrators)
CD4+ T cells are the T cells that can differentiate into Th1, Th2, Th17 or Treg cells.
HAVING BALANCE IN THESE 4 SUB-TYPES IS CRITICAL TO HEALTH
‣ Th1 protects against intracellular microbial infections
‣ Th2 protects against parasites
‣ Th17 is pro-inflammatory and acts in the heat of battle
‣ Uncontrolled Th expression causes disease: Too much Th1 and Th17 is linked to autoimmune conditions. Too
much Th2 is linked to allergic and sensitivity reactions.
‣ Treg regulates the balance and favors tolerance. When Treg expressions are low, it leads to autoimmune
conditions and severe allergies
‣ A weak microbiome leads to Th1/Th2 imbalance and typically leans towards Th2
‣ The microbiota is responsible for stimulation and maturation of Tregs, when the microbiota is weak we see
increased colitis risk. We find a low level of colonic Treg cells and so T-cells in the colon attack the tissue and
commensals.
MICROBIAL ENDOCRINE SYSTEM
CROSS-TALK AND COMMUNICATION BETWEEN THE
MICROBIOME AND THE HOST COMPONENTS
Hadar Neuman et al. FEMS
Microbiol Rev 2015;femsre.fuu010
© FEMS 2015. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com
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5/16/2017
MICROBIAL ENDOCRINE SYSTEM
MICROBIAL-IMMUNE-METABOLIC AXIS OF COMMUNICATION
Host effects on the microbiota.
Hadar Neuman et al. FEMS Microbiol Rev
2015;femsre.fuu010
© FEMS 2015. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com
Tissue Barriers. 2015; 3(1-2): e982426. Published online 2015 Jan 15. doi: 10.4161/21688370.2014.982426
MICROBIOME AND THE INNATE IMMUNE SYSTEM
MICROBIOME AND THE INNATE IMMUNE SYSTEM
Microbiome–innate-immune-system interactions
are involved in multifactorial diseases.
Many inflammatory disorders are
influenced by alterations in the
crosstalk between innate
immunity and the microbiome.
Modulation of the severity of a
disorder through dietary
interventions and their influence
on microbiome–immune
interactions is an exciting area of
research.
Nature 535, 65–74 (07 July 2016) doi:10.1038/nature18847
PPRs control the
circadian clock of
epithelium and
control release of
glucocorticoids
which fights
inflammation,
allergies, asthma,
etc.
NOD 1 expression from
CCL20 activation
stimulates genesis of
lymphoid tissue
Intestinal epithelial cells orchestrate the host–microbiota interface.
PPRs/TLRs and
NOD expression
from gut
commensals
stimulates the
release of
antimicrobial
peptides from
epithelium
Histamine, taurine
and indole from the
microbiome
stimulate NLRP6 and
Type 1 interferon
which act as viral
detectors
Nature 535, 65–74 (07 July 2016) doi:10.1038/nature18847
MICROBIOME AND THE INNATE IMMUNE SYSTEM
The hierarchy of anatomy in microbiome–innate-immune-system interactions.
Microbiome influence on the innate immune
system works via feedback loops. IL-18 is a
prototypical communication cytokine for this
system.
The impact of the microbiome loops into the
lamina propia through PRR ligands,
metabolites and antigens. Some commensal
bacteria components can even reach the
lymph node and cause an activation of
dendritic cells that activate anticommensal-T
cells to promote microbial containment.
Nature 535, 65–74(07 July 2016) doi:10.1038/nature18847
MICROBIOME AND THE ADAPTIVE IMMUNE SYSTEM
The microbiota in adaptive immune homeostasis and disease
Microbiome cells or their
antigens bind to the
epithelium alerting M
Cells
These cellular
components of
antigens are then
presented to dendritic
cells in the lamina
propia.
Activated Dendritic cells
then differentiate CD4+
T cells to T Follicular
helper cells. T FS cells
active B cells which
causes IgA release
This process produces both high affinity and low affinity IgA to protect the host and allow
for adaptation with a changing microbiome.
Nature 535, 75–84 (07 July 2016) doi:10.1038/nature18848
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5/16/2017
The impact of antibiotics on the microbiota and the expansion of enteric
pathogens.
Modulation of enterohaemorrhagic E.coli virulence through nutrients provided by the microbiota.
a, A diverse and non-disturbed microbiota confers resistance to
colonization by enteric pathogens in the intestinal epithelium. b,
Treatment with antibiotics decreases the diversity of the microbiota
and leads to expansion of the C. difficile population. Toxins that are
released from C. difficile (TcdA and TcdB) enter and damage the cells
of the epithelium, which leads to inflammation (colitis) and cell
death. c, Treatment with antibiotics also leads to an increase in the
levels of free sialic acid (from the host) and succinate (from the
microbiota) in the lumen of the intestine. Elevated sialic acid
promotes the expansion of the S. Typhimurium population, which
can lead to inflammation (gastroenteritis) if the bacterium invades
the cells of the intestinal epithelium. Elevated levels of sialic acid
and succinate further promote the expansion of the C.
difficile population and the development of colitis and cell death.
Nature
535,
85–93
(07 July 2016)
doi:10.1038/nature18849
The effect of intestinal inflammation on nutrient availability.
THE BOTTOM LINE
Chart ©2015 Avalon Yoga International, Inc.
MICROBIAL CONTROL OF EUKARYOTIC CELL EXPRESSION
OUTER MEMBRANE VESICLES AND HUMAN EXOSOMES:
‣ OMVs are bacterial produced excretory nanoparticles that can be tissue trophic
‣ OMVs can contain peptides, neurotransmitter and microRNA – microRNA is best studied
‣ Exosomes are human epithelia cell produced extracellular nanoparticles that effect the
microbiome.
‣ This is a display of inter-kingdom communication and influence
‣ OMVs can be produced by viruses, fungi and even our food!
WHAT IS A HEALTHY MICROBIOME?
A DIVERSE MICROBIOME!
Diversity Gives Strength:
1) Can do more functions
2) More functional redundancies
3) Diverse communities are more
resistant to invasion
What Effects The Microbiome?
1) Age
2) Diet
3) Antibiotic Use
4) Physiology
5) Genetics - loosely
Methylation and Phosphorylation control
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5/16/2017
The Importance of Microbiome Diversity
“Using comparative microbiome profiling of a cohort of CRS (chronic rhinosinusitis ) patients and
healthy subjects, we demonstrate that the sinus microbiota of CRS patients exhibits significantly
reduced bacterial diversity compared with that of healthy controls.”
Abreu NA, Nagalingam NA, Song Y, et al. Sinus Microbiome Diversity Depletion and Corynebacterium
tuberculostearicum Enrichment Mediates Rhinosinusitis. Science translational medicine.
2012;4(151):151ra124. doi:10.1126/scitranslmed.3003783.
”High diversity has been generally associated with health and temporal stability”
“Conversely, a relative lack of diversity is apparent in the gut microbiome in diseases ranging
from obesity to inflammatory bowel disease and types 1 and 2 diabetes; and in the skin
microbiome in atopic dermatitis and psoriasis.”
Lloyd-Price J, Abu-Ali G, Huttenhower C. The healthy human microbiome. Genome Medicine.
2016;8:51. doi:10.1186/s13073-016-0307-y.
HOW DO WE INFLUENCE OUR MICROBIOME
INTERMITTENT FASTING
INTERMITTENT FASTING
Cell Metab. 2014 Dec 2;20(6):1006-17. doi: 10.1016/j.cmet.2014.11.008.
Diet and feeding pattern affect the diurnal dynamics of the gut microbiome.
Zarrinpar A 1 , Chaix A 2 , Yooseph S 3 , Panda S 4 .
Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against
Diverse Nutritional Challenges. Cell Metabolism
Abstract
The gut microbiome and daily feeding/fasting cycle influence host metabolism and contribute
to obesity and metabolic diseases. However, fundamental characteristics of this relationship
between the feeding/fasting cycle and the gut microbiome are unknown. Our studies show
that the gut microbiome is highly dynamic, exhibiting daily cyclical fluctuations in
composition. Diet-induced obesity dampens the daily feeding/fasting rhythm and diminishes
many of these cyclical fluctuations. Time-restricted feeding (TRF), in which feeding is
consolidated to the nocturnal phase, partially restores these cyclical fluctuations.
Furthermore, TRF, which protects against obesity and metabolic diseases, affects bacteria
shown to influence host metabolism. Cyclical changes in the gut microbiome from
feeding/fasting rhythms contribute to the diversity of gut microflora and likely represent a
mechanism by which the gut microbiome affects host metabolism. Thus, feeding pattern and
time of harvest, in addition to diet, are important parameters when assessing the
microbiome's contribution to host metabolism.
ALTERATIONS OF THE MICROBIOME FROM DIET
ALTERATIONS OF THE MICROBIOME FROM DIET
Interactions between the diet and the gut microbiota dictate the production of short-chain fatty acids
Nature 535, 56–64 (07 July 2016) doi:10.1038/nature18846
Nutrition Journal Volume 13, Number 61, doi: 10.1186/1475-2891-13-61
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5/16/2017
Summary of diet-induced dysbiosis.
Diet Bacteria Altered Effect on Bacteria References
High-fat Bifidobacteria spp. Decreased (absent) [45]
High-fat and high-sugar
Clostridium
innocuum, Catenibacteriu
Increased [18]
m mitsuokai and
Enterococcus spp.
Bacteroides spp. Decreased [18]
Brown K, DeCoffe D, Molcan E, Gibson DL.
Diet-Induced Dysbiosis of the Intestinal
Microbiota and the Effects on Immunity and
Disease. Nutrients. 2012;4(8):1095-1119.
doi:10.3390/nu4081095.
Carbohydrate-reduced Bacteroidetes Increased [49]
Clostridium
coccoides, Lactobacillus s Decreased (growth
Calorie-restricted
[48]
pp.
prevented)
and Bifidobacteria spp.
Mycobacterium avium
subspecies
Complex carbohydrates
Decreased [49]
paratuberculosis and
Enterobacteriaceae
B.
longum subspecies longu
Increased [53]
m, B.breve and B.
thetaiotaomicron
C. difficile and C.
Refined sugars
Increased [54,55]
perfringens
Vegetarian E. coli Decreased [56]
High n-6 PUFA from
Bacteroidetes Decreased [59,60]
safflower oil
Firmicutes, Actinobacteria
Increased [59,60]
and Proteobacteria
δ-Proteobacteria Increased [61]
Animal milk fat δ-Proteobacteria Increased [62]
STRAINS STUDIED FOR IMMUNE EFFECTS
Bifidobacterium infantis 35624
Improves symptoms of IBS
THE IMPORTANCE OF ENVIROMENTAL BACTERIA
‣ Distinct Distal Gut Microbiome Diversity and Composition in Healthy Children from
Bangladesh and the United States
Audrie Lin, et al 2013
Bifidobacterium lactis Bb-13
Lactobacillus Casei DN 114001
Lactobacillus rhamnosus GG
Lactobacillus reuteri DSM17938
Lactobacillus GR-1
immune stimulation measured by
cytokine changes
Lessens duration of cold and flus,
diarrhea in children
Infant diarrhea treatment – mucin
expression change
Infant Colic and antibiotic associated
diarrhea
Improved vaginal health
“The distal gut of Bangladeshi children harbored significantly greater bacterial diversity than
that of U.S. children, including novel lineages from several bacterial phyla.”
‣ Human gut microbiota community structures in urban and rural populations in Russia
Alexander V, et al 2013
“the original microbial community structures occurred in hosts from urban populations 2.6-fold
less frequently than in the rural hosts, which implies that the rural population’s microbiota
community was the healthy original”
‣ Comparison of fecal microflora of elderly persons in rural and urban areas of Japan.
Benno Y, et al 1989
‘found significant rural-urban disparities in microbiota composition. Rural populations had much
higher bifidobacteria levels…”
THE IMPORTANCE OF ENVIROMENTAL BACTERIA
REQUIRED FEATURES OF NATURE’S PROBIOTIC
STUDIES ON THE HAZDA TRIBE OF TANZANIA
‣ Some of the last hunter-gatherer
people on earth
‣ They live an ancient, ancestral life.
‣ Their environment hasn’t
changed for 1000s of years.
‣ Massive exposure to ancestral
microbial community
‣ Vastly different microbiota
compared to westernized
populations
‣ Virtually no common digestive
diseases such as Crohn’s, UC,
Colon Cancer, Reflux, etc.
‣Naturally survive the harsh gastric environment
‣Be of a strain that is found in the microbiota – It has to have
a binding site and belong in the gut.
‣Must have evolutionary significance
‣Must be a facultative anaerobe
‣Must have a bi-phasic life cycle
‣Must have clinical demonstration of safety and efficacy
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5/16/2017
Bacterial Spores!
• In particular Bacillus spores as they are the most widely studied and
most widely used probiotics outside of the supplement market.
• Bacillus spores were the first commercial probiotics. Were also the
first prescription probiotics starting in 1958:
• Enterogermina® (Italy)
• Bacti-Subtil® (France)
• Used extensively in agriculture and aquaculture
• AlCare®, BioGrow®, BioPlus ®2B, NeoFerm BS10, LiquaLife®, etc.
• Most widely used and well studied strains in humans are:
‣Bacillus Subtilis
‣Bacillus Licheniformis
‣Bacillus Coagulans
‣Bacillus Clausii
‣Bacillus Indicus HU36
Key Features of Bacterial Spores
• They form robust endospore and can withstand harsh temps, desiccation, low pH, gastric
barriers, antibiotics, UV radiation, solvents, enzymes and even high pressures.
• They are found all over the environment (soil, vegetation, dust, rocks, aquaenvironments,
digestive systems of insects, marine life, mammals, etc.
• Spores Remain dormant for over 50 million years
• Found all over the ancient environment: ice-core studies
• They colonize very effectively in the Human GIT and have been found to colonize very
effectively in the GIT of several different animals.
• Are found as part of the normal human commensal flora.
• LONG history of use in industries where efficacy is closely measured (pharma,
agricultural)
• Extremely safe
• Its use as a probiotic is evolutionarily supported – true commensal organism.
Casula, G., & Cutting, S. (2002). Bacillus probiotics: Spore germination in the gastrointestinal tract. Applied &
Environmental Microbiology 68(5):2344-2352.
Cutting, S. (n.d.). Bacillus probiotics-Mechanism of action and use. Protexin Healthcare.
Dong, T., Van, P., & Cutting, S. (2009). Bacillus probiotics. Nutra Foods 8(2):7-14.
Probiotic function of spores
FUNCTION OF SPORES IN THE HUMAN SYSTEM
Microbiota Balance
Spores produce at least 24 potent antibiotics that control
bacterial over-growth in the GIT.
Examples: Coagulin, Subtilisin, Amicoumacin, Surfactin,
Iturins A, and Bacilysin
• Spores conduct competitive exclusion (CE) of pathogenic organisms
to help maintain microbiota balance.
Accomplished by competition for space, nutrients and/or eliciting host
response
Causes host elimination of invading species
• Spores have the ability to increase the numbers of the important
GIT commensals, such as lactobacillus.
Example: the capacity of B. subtilis to produce catalase and subtilisin has been reported
to promote growth of Lactobacillus species.
When co-cultured, Bacillus subtilis enhanced the growth and viability of L. reuteri, L.
acidophilus and L. murinus (Hosoi. T et al 2000)
FUNCTION OF SPORES IN THE HUMAN SYSTEM
Immunomodulation
Mesenteric glands – sites of amplification
The intestines posses the largest amount
of lymphoid tissue in the human body
GALT – Gut Associated Lymphoid Tissue
Peyer’s Patches – found in the ileum of the small
intestines. Maximum numbers found around age 15-
24. Gut bacteria is a major player in development.
Plays a major role in pathogen defense and selfrecognition.
PPs favor a Th1 response via INF-g, TNF-a and IL-2
Immune sampling occurs in the lumen – an immune response is generated in
the mucosa and then amplified in the mesenteric glands
Probiotic function of spores
FUNCTION OF SPORES IN THE HUMAN SYSTEM
ImmunoModulation: Bacillus Spores
• Critical in the development of the GALT itself by cooperation of Bacteriodes Fragilis
sp. (largest population in the GIT)
• Produce potent activation and proliferation of lymphocytes in the Peyer’s patch –
Promotes Th1 shift – Oral tolerance/mucosal tolerance of food proteins and nonpathogenic
microbes. PP dysfunction linked to hypersensitivity, chronic Th2
activation and inflammatory conditions (celiac).
• Cause the production of important immune cytokines in mesenteric lymph nodes
(MLN) (IL-1a, IL-5, IL-6, IFN-g and TNF-a) and in the spleen (IFN-g and TNF-a)
• Interacts with Toll-like receptors(TLR). Vegetative cells of B. subtilis & other Bacillus
sp. up-regulate expression of TLR2 and TLR4
• Leads to amplified innate immune response via macrophages, monocytes,
B-cells and Dendritic cells. Then push to Adaptive Immunity. Dendritic
activation, important to create link between innate and adaptive immunity
Probiotic function of spores
FUNCTION OF SPORES IN THE HUMAN SYSTEM
Immune Modulation: Bacillus Spores
Autoimmune – Bacillus has been shown to improve adaptive immunity via PP activation and
TLR pattern recognition – important self/non-self mechanism.
• Over active innate linked to autoimmune conditions – need for TLR expression to make
adaptive switch.
• Viral mimicry of self proteins invade our immune system (innoculum, vaccines antibodies, etc).
• Vulnerable from 0-7 years during immune development, loss of recognition of self partially
responsible for low TLR activity during PP development.
• Damage to the MHC allows pathogens loose inside the cell to attack (centromeres, DNA, RNA,
and other cell products, tissue, mucous membranes etc.)
Allergies, Psoriasis, Eczema - direct correlation with GIT, especially helpful with babies born by
C-Section
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Probiotic function of spores
FUNCTION OF SPORES IN THE HUMAN SYSTEM
Short Chain Fatty Acids and Immune Modulation
Food Intolerance and Th1/Th2 Shift :
Bacillus Spores
• Innate immunity (first line of defense) vs. adaptive
• Needs push to adaptive to avoid chronic inflammatory state and damage to
self tissue by NK cells and complement system.
• Done via TLRs – stimulated by bacillus probiotics.
• Immune system of GIT is supposed to recognize food and create an adaptive
response to decrease immune reactions – (function of Peyer’s Patches M-Cells via
antigen specific suppressor T-lymphocytes).
• PP development and activation --- key to the function of this mechanism
• Latent viral (CMV, HHV-6, EBV, etc.) and bacterial infections maintain Th2
activation via IL10 mimic
• Causes B-Cell class shift to IgE. This inhibits Th1 and allows for yeast growth.
• Bacillus spores stimulate chemokine receptor CCR5 in GALT to turn on Th1. T-
bet transcriptional factors are up-regulated which promotes TH1 and
suppresses GATA3 (the pro-TH2 factor). Secretion of IL-12, TNF-g and INF-g
also push Th1 shift – all stimulated by bacillus spores.
GUT PERMEABILITY – CHRONIC INFLAMMATION
Stress induces endotoxemia and increasing barrier
permeability
Karin de Punder* and Leo Pruimboom
Frontiers in Immunology published: 15 May 2015
“Chronic non-communicable diseases (NCDs) are the leading causes of work
absence, disability, and mortality worldwide. Most of these diseases are
associated with low-grade inflammation.”
Probiotic function A SOLUTION of spores FOR LEAKY GUT
• Post-prandial Endotoxemia
“In combination with modern life-style factors, the increase in bacteria/bacterial
toxin translocation arising from a more permeable intestinal wall causes a lowgrade
inflammatory state. We support this hypothesis with numerous studies
finding associations with NCDs and markers of endotoxemia, suggesting that this
process plays a pivotal and perhaps even a causal role in the development of lowgrade
inflammation and its related diseases.”
GROUND ZERO OF MOST HEALTH DISORDERS
Pediatr Res. 2015 Jan;77(1-
2):236-44. doi:
10.1038/pr.2014.170. Epub
2014 Oct 14.
A SOLUTION FOR LEAKY GUT
J Interferon Cytokine Res. 2016 Feb;36(2):Effects of Bacillus subtilis on Epithelial Tight
Junctions of Mice with Inflammatory Bowel Disease.
Gong Y 1 , Li H 1 , Li Y 1 .
“B. subtilis intake upregulated expression of TJ proteins(claudin-1, occludin, JAM-A, and
ZO-1), for improved barrier function, and downregulated cytokine expression (IL-6, IL-
17, IL-23, and TNF-α) to reduce intestinal epithelial damage.”
Comp Biochem Physiol A Mol Integr Physiol. 2002 Sep;133(1):95-104.
Histological alterations of intestinal villi in chickens fed dried Bacillus subtilis var. natto.
Samanya M 1 , Yamauchi KE.
“These birds had a tendency to display greater growth performance and intestinal
histologies, such as villus height, cell area and cell mitosis, than the controls. ”
Bacillus subtilis Protects Porcine Intestinal Barrier from Deoxynivalenol via Improved
Zonula Occludens-1 Expression
Min Jeong Gua, Sun Kwang Songa, Sung Moo Park
“B. subtilis may have potential to enhance epithelial barrier function and to prevent
the cells from DON-induced barrier dysfunction.”
Endotoxin (U/L)
3000
2500
2000
1500
1000
500
The effect of 30-days of probiotic supplementation
on post-prandial responses to a high-fat meal: Pilot Study
0
Principal Investigator: Brian K. McFarlin, PhD, FACSM, FTOS
University of North Texas
0 3 5
Feeding Time (H)
Baseline
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Endotoxin (U/L)
3000
2500
2000
1500
1000
500
The effect of 30-days of probiotic supplementation
on post-prandial responses to a high-fat meal: Pilot Study
0
Principal Investigator: Brian K. McFarlin, PhD, FACSM, FTOS
University of North Texas
0 3 5
Feeding Time (H)
Baseline
Post-Probiotic
Ghrelin (pg/ml)
14.5
14.0
13.5
13.0
12.5
12.0
11.5
11.0
10.5
IFN-gamma (pg/ml)
50.0
40.0
30.0
20.0
10.0
0.0
0 3 5
Feeding Time (H)
0 3 5
Feeding Time (H)
Baseline
Insulin (pg/ml)
GLucagon (pg/ml)
40.0
30.0
20.0
10.0
0.0
2000.0
1500.0
Post-
Probiotic
1000.0
Baseline
500.0
Post- 0.0
Probiotic
0 3 5
Feeding Time (H)
0 3 5
Feeding Time (H)
Baseline
Post-
Probiotic
Baseline
Post-
Probiotic
The effect of 30-days of probiotic supplementation
on post-prandial responses to a high-fat meal: An Expanded
Pilot Study
16.0
Principal Investigator: Brian K. McFarlin, PhD, FACSM, FTOS
University of North Texas
The effect of 30-days of probiotic supplementation
on post-prandial responses to a high-fat meal: An Expanded Pilot
Study
Principal Investigator: Brian K. McFarlin, PhD, FACSM, FTOS
University of North Texas
14.0
SNEAK PREVIEW
SNEAK PREVIEW
Change in Serum Endotoxin
12.0
10.0
8.0
6.0
4.0
Placebo
Spores
Spores
2.0
0.0
Baseline
Time
Post-Supplement
The effect of 30-days of probiotic supplementation
on post-prandial responses to a high-fat meal: An Expanded Pilot Study
Principal Investigator: Brian K. McFarlin, PhD, FACSM, FTOS
University of North Texas
Change in Serum Triglycerides
The effect of 30-days of probiotic supplementation
on post-prandial responses to a high-fat meal: An Expanded Pilot Study
Principal Investigator: Brian K. McFarlin, PhD, FACSM, FTOS
University of North Texas
180.0
SNEAK PREVIEW
160.0
140.0
120.0
100.0
80.0
Spores Megaspore
Placebo
60.0
40.0
20.0
0.0
Baseline
Time
Post-Supplement
50
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The effect of 30-days of probiotic supplementation
on post-prandial responses to a high-fat meal: An Expanded Pilot Study
Principal Investigator: Brian K. McFarlin, PhD, FACSM, FTOS
University of North Texas
250.00
SNEAK PREVIEW
200.00
MCP-1 (pg/mL)
150.00
100.00
Megaspore
Placebo
50.00
0.00
1-OH 1-3H 1-5H 2-0H 2-3H 2-5H
Time
Condition
Delivery
Route
Protection
SUMMARY – MICROBIOME AND THE IMMUNE SYSTEM
SporeVax ®
Tetanus Oral √
Nasal
√
Clostridium perfringens
Anthrax
Influenza
Clostridium difficile
Oral
Nasal
Nasal
Nasal
Oral
Sub-lingual
•Bacillus spores carry a natural adjuvant property that enhances the body’s natural immune
responses. Typically, they produce balanced Th1 and Th2 responses as well as stimulating the
innate immune system, an important primer for long-term immunity.
√
√
√
√
√
√
NOT ENOUGH sIgA
• Low microbiota diversity, low microbial exposure, low antigenic species in our environment leads to low
levels of IgA production and actually higher IgE production!
IMBALANCE RESPONSE
• Poor microbiota and low diversity leads to fewer mast cells in the gut and more in circulation – one mode of action
for increasing allergies.
• A weak microbiome leads to Th1/Th2 imbalance and typically leans towards Th2
• The microbiota is responsible for stimulation and maturation of Tregs, when the microbiota is weak we see
increased colitis risk. We find a low level of colonic Treg cells and so T-cells in the colon attack the tissue and
commensals.
POOR TOLERANCE AND FIRST LINE OF DEFENSE
• The microbiome helps APC cells by expressing something called Toll-like receptors (TLRs) – These TLRs neutralizes
immune response to offer “tolerance”.
• The microbiome also goes as far as producing ATP (energy) to help these cells differentiate and function.
• Neutrophils are dependent on the microbiota to stimulate their expression and even to equip them with the tools
to perform their killing function – nitric oxide, super oxides, etc.
• The microbiota effects the potency of NK cells.
BREAKDOWN OF THE CROSS-TALK AND COMMENSAL REGULATION
• The microbiota stimulates the IEC to release key antimicrobials and chemical messengers.
INCREASE DIVERSITY
• Time restricted feeding
• Methodical fiber increase
• Macronutrient Diversity
WHAT CAN WE DO??
CHANGE EXPOSURE
• Get Dirty!
• Eliminate chlorine cleaners
• Eliminate antimicrobial products
• Get a dog
• Protect from EMFs
IMPROVE MUCIN PRODUCTION
• Key Supplements are: L-threonine, L-serine,
L-proline, and L-cysteine. 95% increase in
mucin2 production in male rats treated with
DSS (dextran sulfate sodium)
• Increase butyrate
• Increase autophagosomes by autophagy
INCREASE sIgA
• Supplements that help: essential fatty acids,
glutathione, glycine, glutamine,
phosphatidylcholine, Vitamin C and Zinc
• Colostrum
• Bacillus spores and saccharomyces – possibly
pediococcus
• Address the adrenals
• Stress reduction
RESOLVE LEAKY GUT
• Spore based probiotic
• L-glutamine
• Reduce saturated and oxidized fats
• Lactoferrin
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Subverted Enteroendocrine System in
Obesity, Infection, and Inflammation
Dr. Mi Jung Lee, ND, LAc
www.tahomaclinic.com
The enteroendocrine system not only connects the gut with all of the other organs in the body,
but this system also plays an important role in regulating the fundamentals of metabolism. Hormones
that are produced in the gut provide signals to the brain to integrate nutrients and determine
neuronal phenotypes. This mechanism appears to be subverted in obesity, infection, and inflammation.
Understanding the regulatory peptides involved in the enteroendocrine system not only provides
a validation for traditional therapeutics to gastrointestinal conditions but can pave new ways
to develop effective and safe naturopathic treatments.
Biography
Dr. Mi-Jung Lee, ND, LAc practices integrative medicine at Tahoma Clinic, researches and consults
functional medical testing methods at Meridian Valley Laboratory. In her practice, she incorporates
traditional Asian herbal medicine and restorative acupuncture along with clinical nutrition
and conventional medicine to optimize health. As a physician consultant, she reviews, reports and
recommends functional test results for practitioners. Prior to joining Tahoma Clinic and Meridian
Valley Laboratory in 2012, Dr. Lee practiced in Los Angeles, California with psychiatrist and internist,
helping professionals suffering with mental disorders from depression and anxiety to ADHD with
naturopathic medicine and acupuncture. In that period, Dr. Lee learned the importance of normalizing
gastrointestinal health in order to effectively address mental health issue. She also has assisted
patients with concerns related to menopause and andropause, and helped seniors enhance their
health and vigor with Asian tonic medicines passed down to her from her herbalist mother and midwife
grandmother in Korea. With her extensive training and practice in hormone replacement past
5 years, Dr. Lee has been exploring her research to the area of enteroendocrine system in order to
find the causes and treatments for chronic metabolic conditions.
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5/16/2017
Gut Hormones;
overview, their imbalances
and therapeutics
Mi-Jung Lee, ND, LAc, OMD
CNDAMM19
‣
Outline of presentation
Enteroendocrine system at glance
Meet your gut hormones
Gut Hormone Imbalance
Inflammation
obesity
more
Therapeutics
Old Fashion GI
In a marketplace
Enteroendocrine System
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Enteroendocrine System
Enteroendocrine Cells (EECs)
‣ Forms the largest endocrine organ in the body
‣Provides the foundation of digestive physiology
‣Secretes an array of gut hormones: more than 30 different gut hormones!
‣Via gut hormones, modulates multiple physiological responses
‣ GI infection
‣ Inflammation
‣ Metabolism
‣ Motility
‣ Plays a key role in the orchestration of host defense mechanism
Intestinal Epithelial Cells
Subtypes of EEC and their hormones
Chief Cell: Gastric hormones (Stomach)
P Cell: Leptin (Stomach)
D Cell: Somatostatin
G Cell: Gastrin
A Cell: Ghrelin
Orexigenic Gut
Hormones?
L Cell: GLP-1 (jejunum, ileum and colon), GLP-2, PYY (distal ileum and colon), ILSN5
(Colon)
I Cell: CCK (duodenum and jejunum)
K Cell: GIP (duodenum)
General features of EECs
EECs as neuro-endocrine complex
Restricted to the mucosa, within its deeper half
Comprise only small minority of 1 % of the overall epithelial cell population
Lying isolated from one another interspersed by non-endocrine epithelial cells
EEC population along the gastrointestinal tract varies.
Characterized by the presence of secretary vesicles, either large dense-core vesicles
(LDCVs) or the smaller synaptic-like micro-vesicles(SLMVs), similar to those found in
neurons!
Contains amine transporters! Chromogranin A: catecholamine transporter just as in
adrenal gland!
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Enteroendocrine communication and
the ENS
Conventional endocrine manner by entering the systemic circulation
Paracrine fashion on the adjacent neighboring epithelial cells and other EECs
Neurocine fashion by activating neural pathways
Extrinsic afferent pathway
Intrinsic afferent neurons in the ENS
“neuropod”, a dendrites-like-process
ENS receives hormonal input from CCK, GLP-1, and GLP-2 from EECs
The gut connectome: built for sensing food!
L Cells
Occurs from the duodenum to the rectum
Produces
proglucagon-derived peptides from proglucagon
peptides YY from pro-pancreatic polypeptites such as
GLP-1, GLP-2, Glicentin, PYY, OXM
The Vagus Nerve
CURR OPIN PHARMACOL. 2007 DEC; 7(6): 570–574.
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5/16/2017
5-HT
Increase in gastric and pancreatic secretion
Increase intestinal motility
Accelerate intestinal transit
Regulate appetite
Stimulate insulin release
Meet Your Gut Hormones
Secreted from Enterochromaffin cells, 95% of body content!
Highest in Rectum; neurally regulated-one relevant signaling molecule
between the gut and the CNS
5-HT production in EC cells
5-HT and Peristaltic wave form
Stimulated by
Beta-adrenalgic
PA-CAP receptor
Mucosal stroking
Chemical stimulant such SCFAs
Inhibited by
GABA A
Cholinergic receptor
Bi directional interaction between EC cells and the enteric nervous system:
5-HT from EC cells
5-HT receptor on Nerve terminals
Excitatory neurons in smooth muscle: contract
Direct effect on smooth muscles is inhibitory .
5-HT in IBD
IBD
5-HT level is high in IBD
High colonic hyper-secretion
Increased colonic motility
CONSTIPATION
Lower EC cell number in
constipation
5-HT and Visceral Pain
5-HT is involved in the perception of colorectal distension.
In experiments, it relieves visceral pain
However, visceral sensation is difficult to determine whether mediated by the EC cellderived
or neurally derived 5-HT.
Increased EC cells number has been
observed in IBD.
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Two important hormones from L-Cell
PYY
GLP-1
GLP-2
Anorexigenic !
Anti-Diabetics!
Levels peaked 20 min after having an oral glucose load
in healthy human volunteers: duodenum L cell-neural
regulation-colon L cell
Peptide YY (PYY)
Inhibits gastric emptying
Inhibits motility
Inhibits exocrine function
Suppresses appetite
Stimulates mucosal enterocyte proliferation!
PYY Secretagogues
Via Chemosensing Mechanism
Carbohydrates
Long-Chain Fatty Acid
Especially, Protein-rich meal
PYY levels increases within 30 min after a meal and remain elevated for up to 6hr.
In obesity, serum PYY levels is low.
PYY infusion lowers appetite, and lowers ghrelin levels during and 3 h after infusion
During mid-puberty, PYY levels decrease to stimulate food intake in both gender.
“ Ileo-Colonic Brake “
In healthy human, IV infusion of PYY have demonstrated
reduced intestinal and colonic transit
reduced gastric emptying
reduced gastric acid and pancreatic exocrine secretion.
Unabsorbed nutrients in the distal intestine and colon trigger the inhibition of motility
and secretion upstream.
Reduced PYY in IBD may result in gastric emptying, intestinal motility and intestinal
secretions.
Glucagon-Like-Peptide – 1 (GLP-1)
a 30-amino acid PGDP secreted from gut endocrine cells; Secreted by L Cells in
response to carbohydrates, fat and protein meals.
Regulates glucose homeostasis and augment β-cell and Inhibit α-cell function in
pancreas
Stimulates somatostain release and inhibits glucagon secretion.
Increase satiety and inhibit gastric emptying
increase gastric accommodation: reducing hunger during fasting
GLP-1 Receptor expressed in; pancrese islets, brain, enteric nervous system, heart,
kidney, small and large intestine and stomach => interaction with centers in the brain,
afferent neural pathways and peripheral neural mechanism!
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Endocr Rev. 2012 Apr;33(2):187-215.
Incretin Effect
Gut hormones stimulate pancreatic insulin release in response to ingested glucose in a dosedependent
manner.
Effect is much greater in oral glucose load than IV glucose.
Interaction between GLP-1, and its receptor on beta cells of the pancreatic islets stimulate
insulin transcription, biosynthesis and release
Beta cell differentiation and proliferation!
important target in T2DM therapeutics
GLP1 Secretagogues and degradation
Dietary nutrients especially fat
Intestinal somatostatin such as GRP-gastric releasing peptide
Gamma-aminobutyric acid
A-and B adrenergic agonists
Leptin
GLP1 on B-cell
Modulates pancreatic B-cell proliferation
increases B-cell mass by enhancing
proliferation, inhibiting apoptosis and
stimulating differentiation of stem cells.
Dipeptidyl peptidase-IV (DPP-IV): very potent making its half-life 1-2 min
Glucagon-Like-Peptide – 2 (GLP2)
Co-secreted with GLP-1 by L cell
Key gut hormone to host defense mechanism in the gut
Protect mucosa membrane by stimulating mucosal epithelial proliferation: synergism
with IGF-1!
Increase absorptive capacity: regulate energy absorption
NO effect on glucose homeostasis
GLP-1 R expressed in: stomach, small bowel and hypothalamus; promising
therapeutic for small bowel syndrome
Pharmaceuticals
Liraglutide: GLP-1 agonist (Half-life: 13 hours)
Teduglutide: GLP-2 agonist (Half-life: 3-5 hours)
With increased resistance to DPP-IV
DPP-IV inhibitors: Saxagliptin, sitaglitin and linagliptin
Adverse effects: N/V, pancreatitis (increased risk in obesity and co-administration of
sulfonylurea)
Small bowel is more sensitive to GLP-2 proliferative effect than large bowel
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Alimentary Pharmacology & TherapeuticsVolume 37, Issue 1,
Version of Record online: 5 NOV 2012
Gut Hormone Imbalance
Ominous Octet
EECs and GI Immune
High Lipolysis
Low Insulin
Bacterial Pathogens TLRs Chemokines Defencins
Neurotransmitter
dysfunction
Low Incretin
High Renal
glucose
reabsorption
High Hepatic
glucose
production
High Glucagon
CCK Appetite Contraction Emptying the distal SI
During GI infection
Increased CCK in the blood stream
Decrease food intake
EECs express TLR and IL-6, sense inflammatory mediators
LPS is a TLR agonist: evoke CCK secretion and pro-inflammatory cascade
Are capable of detecting bacterial antigens
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JC virus and mis-folded prion proteins
EEC
intrinsic
nerve
EECs
Infection
Vagal
Nerve
Brain
Subtype of EECs in the colon and the rectum
Enterochromaffin Cell
D cell
L cell
Obesity and PGDPs
Dose dependent inhibitory effect on energy intake by acting directly on the arcuate
nucleus of the hypothalamus
Studies demonstrate
Postgrandual secretion of GLP-1 to be impaired in morbidly obese patients, but the
satiety response to IV administrated GLP-1 remain intact.
This offers potential in the future treatment of obesity.
Therapeutics
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Gut Chemosesing
5 basic tastes: sweet*, sour, bitter*, salty and unami*
G-protein-coupled receptors (GPCRs)
The majority of these luminal chemo-sensors are expressed on the
enteroendocinrecells that releases gut hormones with ligand activation
French gastronome Jean Brillat-Savarin in 1826
Non-lingual GCPR expressing tissues: small bowel, liver, skeletal muscle, brain and
central nerve system; they are involved in hormone release.
Chemo-Sensing
Mechanisms
Glucose, fat, and amino acid sensing by EECs.(A) Glucose
sensing by EECs involves a number of mechanisms. A
critical component of glucose sensing in the gut is Na + -
coupled glucose uptake by SGLT1, which generates small
currents that trigger depolarization and voltage-gated
Ca 2+ entry. Glucose metabolism, involving glucokinase and
the closure of ATP-sensitive (K ATP) channels, and
basolateral/plasma glucose concentration may also play a
role in glucose-stimulated gut hormone release. (B) There
are several pathways by which fatty acids and amino acids
are sensed by EECs. Fatty acids activate nutrient-sensing
GPCRs, which include FFAR1 (GPR40) and FFAR4 (GPR120)
for MCFAs and LCFAs and FFAR2 (GPR43) for SCFAs,
leading to an increase in intracellular Ca 2+ . Activation of
GPR119 by oleoylethanolamide and monoacylglycerols
stimulates gut hormone secretion via an increase in
intracellular cAMP. Similarly, amino acids and
oligopeptides can also activate GPCRs such as the CaSR. In
addition, electrogenic uptake of certain amino acids and
dipeptides and tripeptides can also trigger membrane
depolarization and gut hormone release.
Effects of Carbohydrates
Under research
TAS1R2/TAS1R3
Activation of the sweet tastes receptors has been shown to stimulate gut hormone secretion
such as GLP-1, PYY, GIP, ghrelin and CCK
Artificial sweeteners, NNS-non-nutritive sweeteners, are high-affinity ligands for
TAS1R2/TAS1R3. long-term ingestion progresses insulin resistance and development of
T2DM.
Moderation with complex carbohydrates
Avoid Artificial Sweeteners
J Clin Invest. 2015 Mar 2;125(3):908-17
Effects of High Protein Meals
Increases plasma PYY levels and enhanced satiety
L-Glutamine raises GLP-1 levels in healthy, obese, and diabetic subjects
Umami taste receptor
Protein Sensing gut hormones
CCK
GIP
GLP-1
PYY
Associated with increased feeling of fullness and satiety
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Effects of Fatty Acids (FA)
Hydrolyzed fat in the small intestine is a strong stimulus of gut hormones; activates a
multitude of sensory pathways in EEC.
Enteroendocrine cells expresses FA receptors.
FA1(GPR40) and FA4(GPR120) sense long chain FAs.
FA2(GPR43) and FA3(GPR41) detect short-chain FAs.
GPR40 is expressed on pancreas B-cells; its agonist can be beneficial for T2DM.
Medium- and long-chain fatty acids
FFAR1 and FFAR4
Stimulates GIP and GLP-1 secretion
Increased LCFA mediated CCK release
Fatty acid receptor in the mouth stimulate Ghrelin and increase appetite vs. in the
small intestine reduces appetites.
A-Linoleic acid triggers CCK release via FFAR4 vs. Oleic acid triggers GLP-1
FFAR4: a-linoleic acid, palmitoleic acid and docosahexaenoic acid
Agonism of FFAR4 decrease ghrelin secretion
Short Chain Fatty Acids (SCFAs)
Acetate
Propionate
Butyrate
Key candidate for microbiota-hosting signaling
SCFAs supplementation increased luminal concentration of SCFAs was associated
with an increase in colonic regulatory T cells and expression of the key antiinflammatory
cytokines IL-10.
Caution! Diseases like irritable bowel syndrome and functional dyspepsia are
associated with small intestinal bacterial overgrowth, which increases the amount of
intraluminal SCFAs.; 5HT antagonists
Acetate vs. Butyrate vs. Propionate
GPR43 sensing of acetate has the potential to prime and amplify acute inflammatory arthritis
driven by the NLRP3 inflammasome; butyrate inhibited the capacity of a combination of urate
crystals and the long chain fatty acid palmitate (C16.0) to induce pro-inflammatory responses
in unfractionated human peripheral blood mononuclear cells
Butyrate reversed stress-induced dysmotility (SID) in the colon
Propionate reduced SID in both small and large intestine.
Beneficial neuroactive bacteria can function within seconds or minutes in the host to alter
neurally dependent peristaltic reflexes via exopolysaccarides, microvesicles or
neurotransmitters produced by microbes.
ARTHRITIS RHEUMATOL. 2015 JUN; 67(6): 1419–1423.
Potent effects of Butyrate
Maintaining gut epithelium
Integrate gut
Reduce inflammation
Reduce visceral hyper-analgesia
Therapeutic effect of Rifaximin in irritable bowel syndrome is accompanied by an
increased in Lactobacilli in the ileum.
Neuo-active microbes
B longum
B bifidum
B breve
B infantis
L helveticus
L rhamnosus
L acidophilus
L casei
L plantarum strain PS128
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Metabolites of microbes
Secondary Bile Acids
Phenols
Choline metabolites
Indole derivatives
Vitamins
Neurotransmitters
Neurotransmitter precursors
Bioactive lipids
Bile Acids
Critical in lipid digestion
Plays important role in glucose metabolism by releasing incretin hormones via the G-
coupled receptor GPBAR1 which is enriched in L cells in the distal intestine
Stimulate L-Cell: increase GLP1 levels (dose dependent)and improves glucose
homeostasis
Following Bariatric bypass, increased plasma bile acids and enhanced bile acid
delivery to the distal gut may contributed to the elevated GLP1 and PYY levels
BA levels are elevated in T2DM compared to normal subject in a small cohort study;
consequence of elevated glucose-stimulator for CYP7A1; compensatory mechanism
to improve GLP-1.
Conjugated Bile acids, TGR5 and H.Pylori
TGR5 : antagonizing NF-κB signaling pathway; TGR5 overexpression with ligand
treatment inhibited gene expression of interferon-inducible protein 10 (IP-10), TNF-α,
and chemoattractant protein-1 (MCP-1) induced by LPS.
UDCA (ursodeoxycholic acid) scavenged the reactive oxygen species (ROS), increased
the membrane potential, and inhibited apoptosis in AGS cells exposed to H(2)O(2) in
vitro through the mitochondria-mediated pathway.
TGR5
Taurine and glycine-conjugated and unconjugated bile acids receptor on EECs
In duodenum, TGR5 ligands activate GLP-2 pathway and increases the rate of
duodenal bicarbonate secretion, hence, protect mucosal lining.
Also, decreased the release of many pro-inflammatory cytokines in response to
lipopolysaccharide (LPS) via inverse modulation of the NF- K B signaling pathway.
Highly soluble and acid stable UDCA formula: 300 mg TID
FRONT PHARMACOL.
Bile Acid BioChem Review
Cholesterol via 7a-hydroxylase (CYP7A1)-rate limiting enzyme
Primary bile acid, cholic acid, Chenodeoxycholic acid
Conjugation of BA with either glycine (75%) or taurine (25%)
Fat and protein rich foods -> CCK release -> primary BA release ->in colon, anaerobic
bacteria forms the secondary conjugated BA; deoxy cholic acid, lithocholic acid and
ursodeoxycholic acid -> in terminal ileum, 95% reabsorbed back to liver
ZINC
GPR39 : cation sensing receptor on EECs
G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction.
GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin
release and glucose control.
Zinc is stored and released together with insulin from the Beta-cells.
Zinc also has a general anti-apoptotic effect and has been shown to specifically protect
against streptozotocin-induced diabetes.
Zinc is the only known physiological stimulator of GPR39 activity.
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Vinegar
Mechanism of Vinegar
Human intervention trials showed that vinegar consumptionseems more effective in
modulating glycemic control in normal glucose-tolerant individuals than in either type
2 diabetics or in those with impaired glucose tolerance.
Apple Cider Vinegar
Balsamic Vinegar
Brown rice Vinegar
Persimmon Vinegar
Activation of the free
fatty acid receptor 2
Increased GLP-1
secretion
Increase satiety and
lower food intake
Increase AMPK
(adenosine
monophosphateactivated
protein kinase)
Increase blood flow to
the peripheral tissues
Increase fatty acid
oxidation and decrease
hepatic gluconeogenesis
Lowers circulating fatty
acids and improve
insulin sensitivity
Bitters: T2Rs on EECs
EEC expresses T2Rs!
Inducing vomiting before exiting the stomach
Epithelial defense mechanism
Release PYY, GLP-1 and CCK
Enter the circulation
Activate neuronal pathways
Extrinsic to CNS
Intrinsic to ENS
Bitter study: NW vs. OW/OB
Male and Female age from 18 to 55, healthy without GI condition in Los Angels
35 total: 20 OW/OB and 15 NW
Colonic Mucosa Biopsy, RNA extraction and quantitative RT-PCR,
Immunohistochemistry
Results: Marked increased T2R38 mRNA in OW/OB: 2 folds
PLOS ONE
Gentiana Scabra, Long Dan Cao
Root
Iridoid glycosides: loganic acid, gentiopicrin, trifloroside, rindoside
Dose-dependant GLP-1 secreting effect on EECs
Lower serum glucose and frequently prescribed in TAM
Dose: 3 g per day
Capsaicin
Pungent principle in chill peppers
Induce satiety and reduce caloric intake
Experiment, placebo-controlled crossover study
Infra-duodenal infusion of capsaicin (1.5 mg pure capsaicin) via nasoduodenal
catheter-> measured hunger, satiety and GI symptoms and blood sample.
GLP-1 and PYY were not significantly different.
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Mean ± SEM VAS scores (0–100 mm) for hunger and satiety and AUC scores during intraduodenal capsaicin and
placebo infusions, respectively (n = 12).
Correlation of pain and satiety scores (n = 12).
Mark van Avesaat et al. Am J Clin Nutr 2016;103:305-313
Mark van Avesaat et al. Am J Clin Nutr 2016;103:305-313
©2016 by American Society for Nutrition
©2016 by American Society for Nutrition
Fibers
Impact on satiety: > 5g: decreased hunger, and prolonged satiation
Plasma peptide YY and GLP-1 were significantly increased by the ingestion of meals
with fiber >10g.
Stress and the gut EECs
MC4R
Setmelanotide
POMC mutation
Environmental stress evokes compensatory response in the organism, dys-regulates
the bacteria-gut-brain axis and autonomic nervous system
Impact on the intestinal motility
Alters mucosal permeability, epithelial secretion, blood flow, and visceral sensory
Adrenal Supports
Panthotenic Acid: 500 mg TID
Sodium Ascorbate: up to bowel tolerance
Chromium: 6,000mcg
Lactobacillus helveticus: decreases ACTH and corticosterone, restore 5-HT, norepinephrine
(NE) and brain-derived neurotrophic factor (BDNF)
Oligosaccgarides
Xiao Yao San
Bu Zhong Yi Qi Tang
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Progesterone
Progesterone increased levels of proglucagon mRNA transcripts and directly increased
GLP-1 secretion from GLUTag cells in vitro.
Furthermore, enteral, but not parenteral, P4 administration improved glucose
tolerance and enhanced circulating levels of GLP-1 in mice.
Progesterone also directly work on beta-cell pancreas to promote insulin secretion
via PGRMC1 (Progesterone Receptor Membrane Component 1)
“Roux-en-Y” in a pill
The holy grail of harnessing the enteroendocrine system for the treatment of
metabolic disease
To mimic the secretary hormone profile that occurs following Roux-en-Y gastric
surgery.
Problem with the plethora of signaling events
Dose: 30-200 mg
GLP-1 Agonist and Weight Loss: metaanalysis
of 27 trials
were the most successful in terms of weight loss;
exenatide 2 mg/week: -1.62 kg (95% CrI: -2.95 kg, -0.30 kg)
exenatide 20 μg: -1.37 kg (95% CI: -222 kg, -0.52 kg)
liraglutide 1.2 mg: -1.01 kg (95%CrI: -2.41 kg, 0.38 kg)
liraglutide 1.8 mg: -1.51 kg (95% CI: -2.67 kg, -0.37 kg) compared with placebo.
Incretin and
Cardiovascular
Health
There were no differences between the GLP-1 receptor agonists in terms of weight
loss.
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68

Natural Approach to Urology
Dr. Eric Yarnell, ND, RH (AHG)
www.dryarnell.com
The gut flora significantly impacts the urinary tract. Uropathogens, which are organisms specially
evolved to be able to survive in the urinary tract, can colonize the gut and then continually seed
the urinary tract, causing urinary tract infections. Gut flora can have an effect on kidney stone formation
and kidney function as well due to the organism Oxalobacter formigenes and its effect on oxalates
in the urine. Dr. Yarnell will discuss various treatment therapies to address gut flora imbalance,
the role of the gut flora in adding to or reducing the toxic load the kidneys have to process in patients
with chronic kidney disease, and the potential for probiotics and fecal transplant in CKD patients.
Biography
Eric Yarnell, ND, RH(AHG) (Bastyr ’96) is professor of botanical medicine at Bastyr University. He has
been in private practice focusing on herbs, men’s health, urology, nephrology, and gastroenterology
for 20 years. He is former chair of botanical medicine at SCNM and former editor of the Journal
of Naturopathic Medicine. He is author of Natural Approach to Gastroenterology 2nd ed, Natural
Approach to Men’s Health and Urology 2nd ed, and Clinical Botanical Medicine among many other
texts and articles.
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5/17/2017
URINARY TRACT/
GUT FLORA
INTERACTION
SCALE OF THE ISSUE
Human:
~24,000 coding genes
~2,240 cell types
(not including the deer)
Eric Yarnell, ND, RH(AHG)
2017
urologynd@gmail.com
@dryarnell7
Public domain by E. Erbe and C. Pooley
Bacterial flora:
~11,600,000 coding genes
~1,000 cell types
(with ~7,000 strains)
and thousands of viruses,
a couple of Archaea, and some fungi
(Karlsson 2014)
DIVERSITY IS KEY
71 shared
bacterial
species
URINARY
TRACT
MICROBIOME
Millions of unshared genes
Ref: Li 2014,
Karlsson 2014
Public domain by E. Erbe and C. Pooley
ORIGINAL DOGMA
NEW EVIDENCE
If left sealed,
doesn’t become
cloudy
Suprapubic aspirations + DNA testing show that (Wolfe 2012):
Clearly bacteria are present in healthy bladder
Ref: Roberts 1881
If left open
(or tap water added),
becomes cloudy
Conclusion:
urine is sterile
Bypass vaginal flora so no contamination issues
Transurethral catheterization is just as good for sampling
this normal flora (Khasriya 2013)
These microbes can be cultured under the right conditions
(Hilt 2014; Khasriya 2013)
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BLADDER MICROBIOME AND
OVERACTIVE BLADDER
OAB patients have more diverse bladder flora (Pearce 2014)
Fewer, less dominant Lactobacillus particularly notable
OAB patients with more diverse flora respond poorly or not
at all to solifenacin treatment (Thomas-White 2016)
Having more Lactobacillus spp in bladder correlates to
fewer post-catheterization UTIs (Pearce 2015)
GUT FLORA
MIGRATION TO
URINARY TRACT
Public domain by E. Erbe and C. Pooley
FROM GUT TO BLADDER
(Antibiotic use in
food production)
UPEC from
food
Ref: Yamamoto 1997;
Manges 2001; Yarnell 2017
Bowel
colonization
Migration to
vaginal flora
Migration to
periurethral flora
GUT FLORA
AND
URINARY/RENA
L DISEASES
Symptomatic
UTI
Intracellular
biofilm formation
Migration to
bladder
Public domain by E. Erbe and C. Pooley
UPEC = uropathogenic E. coli
INTERSTITIAL CYSTITIS
n=18 women with IC in Illinois (vs. 16 healthy age-matched
controls)
Species missing from gut flora of IC patients vs. controls:
Odoribacter splanchnicus, Faecalibacterium prausnitzii,
Colinsella aerofaciens, Eggerthella sinensis, and
Lachnospiriceae longoviformis
Eggerthella sinensis may be elevated in IC (data not as strong)
IC pt had significantly more GI problems than controls
CHRONIC PROSTATITIS
n=25 chronic prostatitis (CP) vs. 25 healthy American
controls
Overall gut flora less diverse in CP vs. controls
Significantly lower levels of Prevotella in CP vs. controls
Ref: Shoskes 2016
Ref: Braundmeier-Fleming 2016
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CHRONIC PROSTATITIS:
ANTIBIOTIC PROBLEMS
CKD GUT FLORA
Fluoroquinolon
e therapy
Dethlefsen
2008
Temporary
improvement
(due to anti-inflammatory
not antibiotic effects)
Recurrent
symptoms
n=24 adults on hemodialysis (HD) vs. 12 healthy controls in
California
Pseudomonadaceae, Enterobacteriaceae families
overrepresented in HD group
Dysbiosis
Leaky gut
Ref: Bergen 1989;
Taylor 2008; Liu 2009
Other groups most increased in HD group: subphylum Clostridia,
Gammaproteobacteria
Possible causes: diet changes (low fiber, low veg/fruit),
phosphate binder use, frequent antibx use
Ref: Vaziri 2013
CKD GUT FLORA
UREMIC TOXINS FROM GUT
FLORA
Same researchers, same test group found:
Increases in HD in microbes producing urease, uricase, p-
cresol, indole
Tryptophan
Dysbiotic
flora
tryptophanase
P5P
Indole
Hepatic
sulfatase
Indican
(indoxyl
sulfate)
Dysbiotic
flora
Indoxyl
Decreases in HD in microbes producing SCFA
Ref: Wong 2014
Tyrosine
Carnitine,
choline
p-cresol
trimethylamine
N-oxide
Indirubin
Alkaline
urine
TMAO AND CKD
IgA NEPHROPATHY
n=521 American patients with stable CKD stage 3 or worse
Serum TMAO significantly higher in CKD pt than 3,166 non-
CKD pt
Pt with highest quartile TMAO = significantly higher
mortality
Ref: Tang 2015
Most common cause of glomerulonephritis world-wide
Particularly common in people of Asian descent (rare in
those of African descent, intermediate in Europeans)
Relatives of IgAN patients more likely to have microscopic
hematuria, IgA-related immune problems
Leaky gut/IgA against gliadin found in some IgAN pt (Almroth
2006)
Genetic associations (see next slide)
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5/17/2017
IgA NEPHROPATHY: GENES
AND THE GUT
GENE (LOCUS)
VAV3 (1p13)
ITAGM, ITAGX
(6p11)
DEFA1,3,5,6
(9p23)
CARD9 (9q34)
TNFSF13 (17p13)
Ref: Kiryluk 2014
FUNCTION
Guanine nucleotide exchange factors
necessary for colon epithelium differentiation,
IgA production
Integrins αM,αX (regulate intestinal DC
tolerance)
α-Defensins (defenses against microbes)
Intestinal repair, bacterial infxn after intestinal
injury
B-cell-stimulating cytokine induced by gut
flora, regulates IgA class switching
DC = dendritic cell
IgA NEPHROPATHY GUT
FLORA
n=16 progressing, 16 non-progressing IgAN pt vs. 16 healthy Italian
controls
Overall gut flora diversity: health > non-prog. > progressing
Reduced in IgAN pts: Bifidobacterium, Enterococcus, Clostridium,
Lactobacillus, Leuconostoc
Greatly overrepresented in IgAN: Streptococcaceae, Eubacteriaceae
Firmicutes:Bacteroidetes ratio: highest in IgAN, lowest in healthy
Various urine, fecal volatiles increased while SCFA decreased in IgAN
vs. healthy
Ref: De Angelis 2014
IgA NEPHROPATHY
DYSBIOSIS
Dysbiosis T cell activation B cell activation
(via LPS)
TLR4
activation in B
cells
Ref: Qin 2008
IgA1
overproduction
OXALOBACTER FORMIGENES
AND KIDNEY STONES
Cosmc
chaperone
methylation
Galactosyltransferase
activity
reduced
Galactosedeficient
IgA1
form
sciencedaily.com
OXALOBACTER FORMIGENES
Rod-shaped, Gram neg, obligate
anaerobe (so how to
supplement??)
GLOSSARY
Non-glycolytic
Uses electrical gradient from
oxalate/formic acid flow to make
ATP
Pt w/ stones way more likely to lack
this in gut (Kaufman 2008)
Certain antibx (macrolides,
tetracycline, metronidazole, etc.)
correlate to low colonization (Kelly
2011)
Ref: Stewart 2004
CP = chronic prostatitis
DC = dendritic cell
HD = hemodialysis
IC = interstitial cystitis
IgAN = Immunoglobulin A
nephropathy
LPS = lipopolysaccharide
OAB = overactive bladder
SCFA = short-chain fatty acids
TLR = Toll-like receptor
TMAO = trimethylamine N-
oxide
UPEC = uropathogenic
Escherichia coli
UTI = urinary tract infection
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REFERENCES
Almroth G, Axelsson T, Müssener E, et al. (2006) Increased prevalence of anti-gliadin IgA-antibodies with
aberrant duodenal histopathological findings in patients with IgA-nephropathy and related disorders. Upsala J
Med Sci 111(3):339–352.
Bergen B, Wedren H, Holm SE (1989) Long-term antibiotic treatment of chronic bacterial prostatitis. Effect on
bacterial flora. Br J Urol 63(5):503–7.
Braundmeier-Fleming A, Russell NT, Yang WB, et al. (2016) Stool-based biomarkers of interstitial
cystitis/bladder pain syndrome. Sci Rep 6:26083.
De Angelis M, Montemurno E, Piccolo M, et al. (2014) Microbiota and metabolome associated with
immunoglobulin A nephropathy (IgAN). PLoS ONE 9(6):e99006.
Dethlefsen L, Huse S, Sogin ML, Relman DA (2008) The pervasive effects of an antibiotic on the human gut
microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 6(11):e280.
Hilt EE, McKinley K, Pearce MM, et al. (2014) Urine is not sterile: use of enhanced urine culture techniques to
detect resident bacterial flora in the adult female bladder. J Clin Microbiol 52(3):871–6.
Karlsson FH, Nookaew I, Nielsen J (2014). Metagenomic data utilization and analysis (MEDUSA)
and construction of a global gut microbial gene catalogue. PLoS Comp Biol 10(7):e1003706.
Kaufman DW, Kelly JP, Curhan GC, et al. (2008) Oxalobacter formigenes may reduce the risk of
calcium oxalate kidney stones. J Am Soc Nephrol 19:1197-203.
Kelly JP, Curhan GC, Cave DR, et al. (2011) Factors related to colonization with Oxalobacter
formigenes in US adults. J Endourol 25(4): 673–679.
Khasriya R, Sathiananthamoorthy S, Ismail S, et al. (2013) Spectrum of bacterial colonization
associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin
Microbiol 51(7):2054–62.
Kiryluk K, Li Y, Scolari F, et al. (2014) Discovery of new risk loci for IgA nephropathy implicates
genes involved in immunity against intestinal pathogens. Nature Genet 46(11):1187–96.
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79

80

The Clinical Impact of Gut & Microbiome
on Skin Disease
Dr. Michael Traub, ND, DHANP, FABNO
www.michaeltraubnd.com
Helicobacter pylori, SIBO, IBD and other GI disorders can have direct correlations in patients with
acne, rosacea, atopic dermatitis, psoriasis, urticaria, and systemic sclerosis. Learn treatment
protocols that will include both naturopathic and pharmacologic options. Examine the mechanisms
of how the gut and skin microbiomes may increase or decrease the risk of certain cancers, and how
the gut microbiome may directly impact the risk of cancer in the skin and other organs by promoting
systemic inflammation. The skin microbiome itself is as diverse as the gut microbiome, but research
has just begun to unravel its influence on the host. Like the gut microbiome, the skin microbiome
affects the risk for several diseases, including cancer. By using health promoting strains from the
microbiome in oral or topical probiotics, it may be possible to reduce the risk of skin cancer and
perhaps increase the likelihood of successful treatment.
Biography
Dr. Traub completed pre-med studies at the University of California at Irvine. He graduated from
National College of Naturopathic Medicine in 1981 and completed a residency there in Family Practice
and Homeopathy. Dr. Traub was recognized for his many years of service in the American Association
of Naturopathic Physicians, including President from 2001-2003, when he was honored with
the 2006 Physician of the Year Award. His father was a dermatologist, and this inspired Dr. Traub to
undertake extra study in this subject and become the leading expert in dermatology in the naturopathic
profession. He has taught dermatology at five of the seven accredited naturopathic medical
schools in North America and is the author of “Essentials of Dermatologic Diagnosis and Integrative
Therapeutics.” He has been medical director of Lokahi Health Center in Kailua Kona, Hawaii for the
past 32 years. Dr. Traub is a fellow of the American Board of Naturopathic Oncology. He has been
actively engaged in clinical research throughout most of his career. His most recent publication is
“Impact of Vitamin D3 Dietary Supplement Matrix on Clinical Response” (JCEM 2013). He is currently
a co-investigator in The Canadian/US Integrative Oncology Study.
81

5/17/2017
Disclosures
Gut Microbiome
and Skin Diseases
June 11, 2017
CNDA MM19
Michael Traub ND, DHANP, FABNO
• Kamedis - Chair Naturopathic Scientific
Advisory Board (paid consultant)
• Dermveda – Advisory Board Member
• Grant and/or research support:
– Nordic Naturals - Advisory Board Member
– Gaia Herbs - Scientific Advisory Board Member
– Nutritional Fundamentals for Health - Medical
Consultancy Group
Microbiome, SIBO, and Skin Disorders
• Acne
• Atopic dermatitis
• Psoriasis
• Urticaria
• Systemic sclerosis
• Skin cancer
• Rosacea
Potential Pathways of the
Gut-Brain-Skin Axis in Acne
Hygiene Hypothesis
‘everything has been thought of
before, but the difficulty is to
think of it again’
Goethe
A lack of early childhood exposure to infectious
agents, symbiotic microorganisms (decreased
diversity of intestinal microbes and probiotics),
and parasites increases susceptibility to allergic
diseases by suppressing the natural
development of the immune system
Strachan 1989
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Small Intestinal Bacterial Overgrowth
• SIBO is common and thought to cause the
majority (60% average) of IBS cases
• SIBO is an accumulation (≥ 10 5 CFU/ml) of
bacteria in the small intestine
• Symptom severity varies and covers the full
range of digestive complaints, along with
systemic symptoms
• Absent or impaired Migrating Motor Complex
is the most common underlying cause
SIBO Risk factors/causes:
– Food poisoning
– Hypochlorhydria (PPIs)
– Antibiotic therapy
– Adhesions
– Carbohydrate malabsorption via bacterial
fermentation is the 1° pathophysiology
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Diagnosis of SIBO
Management of SIBO
• The large list of conditions that can cause IBS symptoms makes
testing for and properly diagnosing SIBO, very important
• The Hydrogen and Methane Breath Test using glucose or lactulose
(LBT) is the standard lab test
• LBT is useful in the diagnosis of carbohydrate maldigestion,
methane-associated constipation, and evaluation of bloating/gas
but not in the assessment of oro-cecal transit
• A rise in hydrogen of ≥20 p.p.m. by 90 min during LBT for SIBO is
considered positive
• Methane levels ≥10 p.p.m. is considered methane-positive
• Rezaie A et al. Hydrogen and Methane-Based Breath Testing in
Gastrointestinal Disorders: The North American Consensus. Am J
Gastroenterol. 2017 Mar 21.
• SIBO is chronic/relapsing in 2/3 of cases requiring
ongoing management
• Treatment algorithm: retest within 2 weeks post-tx; if
not 90% better, multiple treatment rounds are often
needed
• Treatments include: diet along with antibiotics,
herbal antimicrobials, Elemental Diet and prokinetics
• Antibiotics, herbal antimicrobials and Elemental Diet
are equally effective
Acne and hypochlorhydria
• 13,000 adolescents with acne: increased
prevalence of halitosis, GERD, bloating and
constipation
• Hypochlorhydria as risk factor for SIBO
• SIBO detected on HBT in 50% of patients on long
term PPI
– Zhang H et al. Risk factors for sebaceous gland diseases and their relationship
to gastrointestinal dysfunction in Han adolescents. J Dermatol 2008, 35:555-61
– Lombardo L, et al. Increased incidence of small intestinal bacterial overgrowth
during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010, 8:504-
8
Probiotics for Acne
• 45 females randomized to 1 of 3 arms in open-label study
– Grp A probiotic (“Trenev Trio,” Natren: L.acidoph, L.bugaricus, B.
bifidum)
– Grp B minocycline
– Grp C probiotic + minocycline
• At 8- and 12-week follow-up, grp C had significant decrease
in total lesion count versus grp A (p < .001) and B (p < .01)
– Jung GW et al. Prospective, randomized, open-label trial
comparing the safety, efficacy, and tolerability of an acne
treatment regimen with and without a probiotic supplement
and minocycline in subjects with mild to moderate acne. J Cutan
Med Surg. 2013 Mar-Apr;17(2):114-22.
Probiotics for Acne
• Staphylococcus epidermidis in the human
skin microbiome mediates fermentation to
inhibit the growth of Propionibacterium
acnes: implications of probiotics in acne
vulgaris.
– Wang Y et al. Appl Microbiol Biotechnol. 2014
Jan;98(1):411-24.
Probiotics for Acne
• RDBCT 20 adults given L. rhamnosus SP1 or placebo x 12 wk
• Bx at baseline and at 12 wk
• Probiotic group had 32% (P

5/17/2017
SIBO and Psoriasis
• 60% psoriasis pts (33/55) had malabsorption vs.
3% controls based on D-xylose screening test
• 21% had SIBO based on LBT
• Rx with metronidazole or rifaximin successfully
eradicated SIBO, normalized absorption and
improved skin lesions of these pts
• Celiac disease was diagnosed in 3% of the pts in
this study. GF diet improved their skin lesions
Ojetti et al. Malabsorption in psoriatic patients: cause or
consequence?. Scand J Gastroenterol. 2006;41:1267-71.
Bifidobacterium infantis and psoriasis
• B. Infantis 35624 (1 x 1010 CFU) sig. decreased
CRP, TNF-alfa and IL-6 in 9/12 mild-mod. psoriasis
pts. x 8 wks vs. placebo (maltodextran) in RDBPCT
• Did not measure change in Psoriasis Area Severity
Index (PASI)
• Groeger et al. Bifidobacterium infantis 35624 modulates
host inflammatory processes beyond the gut. Gut
Microbes 4:4, 325–339
Urticaria
• 48 pts with chronic spontaneous urticaria (CSU)
• Scored for urticaria activity and QOL
• H. p. in 11 and SIBO in 13; SIBO pts had worse CSU
• Rx x 1 wk and evaluated before and 4 wks after the
eradication Rx
• Rx of H.p. led to improvement in CSU (p< 0.002)
• Rx of SIBO – no improvement in CSU
• What else could explain this – worse CSU to start,
1 wk not enough gut lesions of SIBO (incomplete
resolution of leaky gut), mast cells continue in gut
and skin, memory T cells continue to circulate and
activate skin mast cells
Urticaria
Role of allergy and mast cells
• Food allergies – lead to IgE elevation
• Mast cell activation syndrome: 700 MCAS
patients had 36 sx: fatigue, muscle pain, near
syncope, headache, itching, urticaria, and
nausea occurred in the top 57%
Campanati et al. Acta Derm Venereol 2013;93:161–164
Afrin LB et al. Am J Med Sci. 2017;353:207-215.
Systemic Sclerosis (SSc)
• Malabsorption and pseudo-obstruction can
occur in 44-88% of those affected leading to
malnutrition
• Nutritional deficiencies - common cause of
morbity and mortality
• Malabsorption: 50% mortality rate at 8.5 yrs
• SIBO in SSc: 30% - 63% of pts w GI Sx
SIBO in SSc
• Eradication of SIBO achieved in 52% of 22 pts
with significant improvement of intestinal Sx
Marie et al. Rheumatology 2009;48:1314-1319
• Enteral and parenteral nutrition may be used
to reverse severe nutritional deficiencies
• Consider new elemental diet formulation
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5/17/2017
SSc: Fecal Calprotectin (FC) and SIBO
• 125 consecutive pts tested for FC and SIBO
• 93 pts had abnl levels of FC (>50 μg/g); 68 of
these pts had high levels of FC (>200 μg/g)
• Global Sx score of digestive Sx: esophageal
and gastric dysfx correlated w elevated FC
• Strong assoc between elevated FC and
presence of SIBO on LBT
– Higher significant correlation when level ≥275
μg/g
SSc, FC, and SIBO
• FC level ≥275 μg/g and risk of SIBO: sensitivity
0.93, specificity 0.95
• Eradication of SIBO was obtained in 52% pts,
yielding sig improvement of intestinal Sx
• 3 mo rotating antibiotics: norfloxacin and
metronidazole, eradication of SIBO was
associated with sig decrease of FC
Marie et al. Autoimmun Rev. 2015;14:547-54
SSc pt with Rosacea
4 wks after 2 wks Xifaxan and
metronidazole (failed doxycyline)
Rosacea: nose and cheeks much better
RLS: completely better
Pruritis in SSc: role for LDN
• SSc = autoimmune disease causes fibrosis and
vasculopathy in skin, lung, and GI tract
• Pilot trials of low-dose naltrexone
hydrochloride (LDN) for pruritus, pain, and
quality of life (QOL) in other GIT diseases have
been successful
• 3 pt case series - sig improvement in pruritus
and total GIT Sx by 10-pt faces scale and UCLA
SCTC GIT 2.0 questionnaire
Fresh, et al. Int J Rheumatol. 2011:8042956
The Take Away
• Test for SIBO in acne, atopic dermatitis,
psoriasis, and scleroderma
• SIBO is not the whole answer
• Altered immunity is critical – Rx all possible
(not just the SIBO)
• Publish your case series
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What do these two have in common?
Hx of Gut and Rosacea
• Alcohol & obesity – 13 th century (Chaucer)
• Dyspepsia – 1895
• Food intolerance/allergies – 1926-1966
• Achlorhydria – 1935, 1941
• Gastritis – 1941
• Celiac and jejunal diseases – 1965, 1970
• Chronic pancreatitis – 1982
• H. pylori – 1990’s
• Ulcerative colitis - 1989
• Crohn’s - 2000, 2011
• SIBO - 2008, 2011, 2016
• GI disease risk - 2016
Rosacea and Risk of GI disorders
Nationwide Denmark Cohort Study
Rosacea N = 49,475
Controls N = 4,312,213
Cox regression analysis to obtain hazard
ratios of the risk of new-onset Celiac, CD,
UC, HP, SIBO and IBS in rosacea pts
Egeberg A, Weinstock LB, Thyssen EP, et al. Br J Dermatol 2016
Rosacea and Risk of GI disorders
Significant assoc developing:
- CeD (HR 1.46)
- CD (HR 1.45)
- UC (HR 1.19)
- IBS (HR 1.34)
Not H.p. (HR 1.04) or SIBO (HR 0.71)
Rosacea and Risk of GI disorders
CONCLUSIONS
GI complaints in pts with rosacea warrant
clinical suspicion of diseases
**************************************************
• Opposite not studied – did GI disease
cause rosacea
• SIBO and H.p. testing not performed
Egeberg A, Weinstock LB, Thyssen EP, et al. Br J Dermatol 2016
Egeberg A, Weinstock LB, Thyssen EP, et al. Br J Dermatol 2016
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5/17/2017
Crohn’s disease and Rosacea
Incidence of 5/60 consecutive CD clinic pts
– 3 active rosacea: treated with rifaximin:
1 partial and 2 complete response
– 2 not currently active (for both)
Crohn’s disease and Rosacea
Response to therapy in active cases
• 60 y.o. female w 40 yr ileitis on no Rx
Crohn’s flares assoc w nasal rosacea
– Rifaximin Rx – cleared both
• 46 y.o. male 26 yr Crohn’s s/p bowel resection
on 6-MP; CD flares assoc w facial rosacea
– Rifaximin Rx – cleared both
Weinstock. J Clin Gastroenterol 2011; 45:295-297.
• 32 y.o. WF severe Crohn’s colitis and rosacea
– See next
Weinstock. J Clin Gastroenterol 2011; 45:295-297.
32 y.o. WF with CD and Rosacea
32 y.o. WF with
CD failing Rx.
Off all meds.
Effect after 2 wks
Rifaximin
1200/mg/d/10 d
Subsequent effect of 8 wks
biologic Rx w adalimulab
SIBO in Rosacea: Prevalence
False positive LBT: Controls
• Genoa: 46% 113 pt in Rosacea Clinic
• St. Louis: 51% of 63 pts (Weinstock)
• St. Louis: 66% of 176 pts (incl. CH4+)
• Genoa, Italy: 3/60 age matched controls
• St. Louis, MO: 3/30 healthy controls
(Lactulose gets to colon faster causes FP)
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.
Weinstock. EMR review of records 2008-2013.
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.
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Rifaximin for rosacea: Italy
• N=113 pts seen in Rosacea Clinic
• 83 F, 31 M, age 52
• 52/113 (46%) LBT+
• 24/113 H.p.+ (7 had SIBO)
• 7 pts Rx for H.p. 1 mo p SIBO Rx
(clin. response occurred with SIBO Rx)
• GI sx response analyzed
Rifaximin for Rosacea
• N = 52 LBT+ (H2 excretion)
• Rifaximin 1200 mg/d/10d vs. Placebo
• Randomized, blinded only to pts
• IGA scoring
• 2 dermatologists (Kappa = 0.97)
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Randomized study results
Before & 1 mo after 1200 mg/d/10d rifaximin
• Rifaximin normalized LBT in 28/32
• 71% cleared rosacea (GA score 0)
• 21% marked impr. (GA score 1)
• Placebo 2/20 worsened, rest unchg.
• GI sx sig. decreased with rifaximin
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Courtesy of V. Savarino:
Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-6.
Before & 1 mo after 1200 mg/d/10d rifaximin
Note periocular and cheek improvement
Courtesy of V. Savarino:
Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-64. Rifaximin 1200 mg/d/10d
Parodi et al. Am J Gastroenterol 2008;6:759-764.
(N=32)
(N=20)
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5/17/2017
Rifaximin for Rosacea: St. Louis
Improvement in 28 pts
% Responders
50
• N=63 pts
• ETR in 50, PP in 9, refract. ocular in 4 (3 E)
45
40
35
46%
71% marked-moderate responders
• Most did not have GI sx
• 51% LBT+ vs. 10% controls (RR, 5.0; 95%
CI, 1.7-15.1; P

5/17/2017
Before & 1 mo after rifaximin 1200 mg/d/10d**
Before & 1 mo after rifaximin 1650/mg/d/14d
**Pi-IBS and rosacea (worsened after colon cancer resection)
Subsequent experience
Ocular Rosacea: SIBO Study
Higher dose to match IBS studies
and additional Rx for complex pts:
• Rifaximin 550 mg TID for 14 days
• Comprehensive post-SIBO Rx for
complex patients
• Low dose naltrexone
• N=24 (21F/3M), age 59
• Refractory ocular rosacea pts referred
by ophthalmologists
• Facial rosacea in 4
• LBT+ in 9/24 (38%)
• GI sx in 63% LBT+ vs. 33% LBT-
Weinstock. Int J Clin Exp Derm 2016
Methods
Ocular Rosacea
SIBO Study
100
90
Improvement in 8 pts
• Open-label, rifaximin 1650-mg/d/10-14 d in
LBT+ pts
• Global assessment 10 d & 20 d after ending
rifaximin: marked, moderate, mild
improvement, or unchanged
Weinstock. Int J Clin Exp Derm 2016
80
70
60
50
40
30
20
10
0
75% marked-moderate responders
50%
25%
12.5%
Marked Moderate Mild
Weinstock. Int J Clin Exp Derm 2016
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5/17/2017
Rifaximin 1200-mg/day/10d: Day 0 & Day 30 Rifaximin 1650/mg/day/14d: Day 0 & Day 14
Less edema, redness and foreign body symptoms after Rx
Rifaximin 1650/mg/day/14d: Day 0 & Day 14
Rifaximin for Ocular Rosacea
Conclusions
• Rifaximin led to improvement in this
small open-label study
• Dysregulation of innate immune system d/t
GI inflammation could increase systemic
cytokines and microbial antigens/antibodies
affecting eyelids and meimobian glands
Less injection of conjunctiva, decreased lid margin inflm, no symptoms
Keep in mind DDx SIBO
Naltrexone & OGFr
Animal studies:
Activated OGFr
Decreased T-
and B-cell
activity and less
permeability
(Decreased
neovascularity in
cornea – rats)
Jejunal Diverticulosis
Zagon. Arch Ophthalmol 2008;126:501-6.
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Rosacea and LDN Rx
Stages of truth
Arthur Schopenhauer, 1788-1860
• First it is ridiculed
• Second it is violently opposed
• Third it is accepted as self-evident
Barry Marshall, MD
Mark Pimentel, MD
Herbal therapy is equivalent to
rifaximin for the treatment of SIBO
• 104 pts who tested positive for newly diagnosed
SIBO by LBT were offered rifaximin 1200 mg daily
or herbal therapy for 4 wks with repeat LBT posttx
• 37 pts had herbal tx; 17 (46%) had neg. F/U LBT
compared to 23/67 (34%) of rifaximin pts
• 14 /44 (31.8%) rifaximin “non-responders” had
herbal “rescue therapy”, with 8/14 (57%) having
a negative LBT
• 10 non-responders to rifaximin had triple
antibiotics and 6 responded (60%)
Herbal Therapy in the Study:
• Dysbiocide & FC Cidal (Biotics) or
• Candibactin AR & BR (Metagenics)
– Dose: 2 caps of each BID x 4 wk
Dysbiocide
• Dill (Anethum graveolens) (seed), Stemona
(Stemona sessilifolia) (root) (powder and extract),
Wormwood (Artemisia absinthium) (shoot & leaf)
(extract), Java Brucea (Brucea javanica) (fruit)
(powder & extract), Chinese Pulsatilla (Pulsatilla
chinensis) (rhizome) (powder & extract), Jamaica
Quassia (Picrasma excelsa) (bark) (extract), Cutch
Tree (Acacia catechu) (heartwood & bark)
(powder & extract), Hedyotis (Hedyotis diffusa)
(aerial part) (powder & extract), Yarrow (Achillea
millefolium) (leaf & flower) (extract).
FC Cidal
• French Tarragon (Artemisia dracunculus) (leaf)
Indian Tinospora (Tinospora cordifolia) (stem &
root)
Horsetail (Equisetum arvense) (whole herb)
Thyme (Thymus vulgaris) (leaf)
Pau D’ Arco (Tabebuia impetiginosa) (inner bark)
Stinging Nettle Extract (Urtica dioica) (root)
Olive (Olea europaea) (leaf)
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5/17/2017
Candibactin AR & BR
• Candibactin AR: oregano oil, thyme oil, sage, and
lemon balm
• Candibactin BR: berberine and proprietary blend
of Coptis (Coptis chinensis) Root & Rhizome,
Chinese Skullcap (Scutellaria baicalensis) Root,
Phellodendron (Phellodendron chinense) Bark,
Ginger (Zingiber officinale) Rhizome, Chinese
Licorice (Glycyrrhiza uralensis) Root, Chinese
Rhubarb (Rheum officinale) Root & Rhizome)
Other common herbal options
• Allimed (garlic) 1 twice daily and Apex H-PLR
(Berberine + Oregano) 3 pills 3 times daily
• Berberine and Neem for hydrogen-producing
bacteria that cause constipation
• Garlic (Allicin) and Neem or Oregano and
Neem for methane-producing bacteria that
cause diarrhea
• Explain equivalence
Rifaximin or Herbs?
• Patient preference
• Most patients require more than one round of
treatment and end up using both
• Choice of herbs depends on whether LBT
reveals high H2 or CH4 or both
Rifaximin
• Dose: 550 mg TID x 2 wk
• If constipation, can prescribe with:
– Neomycin
– Metronidazole
Rifaximin
– not systemically absorbed (

5/17/2017
SIBO dietary guidelines
Prokinetics
• Many diets can be used for SIBO- they all target & reduce
carbohydrates
• Overarching Diet Tips for active SIBO include:
– Avoid raw food/salad & beans
– Caution with whole grains, nuts/seeds, winter squash
– Choose low FODMAP fruit and veg (see LFD App)
– Starch may be tolerated: white rice, white potato, white wheat (if
gluten is tolerated); often one of these is tolerated but not another
– Lactose free dairy, sugar, clover honey & cocoa are often tolerated
– Amount matters- small amounts of individual foods may be tolerated
when larger amounts aren’t
– Experimentation & customization is necessary for best success
• used between treatment rounds and after
eradication to prevent relapse by stimulating
the migrating motor complex
• Common prokinetics used include: Low Dose
Erythromycin, Low Dose Prucalopride, Low
Dose Naltrexone, Iberogast, Motil Pro, Ginger
Preventing Relapse of SIBO
• Diet
• Meal spacing (4-5 hrs apart/12 hr overnight
fast to allow MMC)
• Decrease stress (worry and hurry)
• Visceral manipulation/body work
Probiotics and SIBO
• In practice, probiotics may either benefit
patients with SIBO or aggravate their
symptoms
• 53 pts with chronic liver disease randomized
to either probiotic therapy or placebo:
– 6 bacterial species were used: Bifidobacterium
bifidum, Bifidobacterium lactis, Bifidobacterium
longum, Lactobacillus acidophilus, Lactobacillus
rhamnosus, and Streptococcus thermophilus.
Results of probiotic and SIBO trial:
• After 4 weeks, 3/6 probiotic species (B. lactis, L.
rhamnosus, and L. acidophilus) increased in the feces of the
probiotic therapy group (P

5/17/2017
Key Points for Successful Treatment of
SIBO
– Breath Test: hydrogen and methane
– Successive treatment rounds needed
– Methane &/or constipation cases are harder to cure
– Different treatment needed for methane &/or
constipation
– Die off is common
– Vary treatment method as needed (Abx, HAbx, ED:
often 1or 2 don’t work)
– Re-test to assess results
– Both prokinetic & diet for prevention
– Customize diet to the individual
Take-Aways for Rosacea and SIBO
• Evidence connects GI disease with rosacea, including
observational research and isolated case reports of positive
patient response to rifaximin
• Evidence from Europe suggests SIBO may be present in ~50%
of rosacea patients.
• Randomized trial results suggest gut lumen-targeted
antimicrobial treatment leads to marked improvement in
~93% of patients (30 of 32), with greater response in those
testing positive for SIBO based on LBT
Take-Away for rosacea and SIBO (cont).
• These findings are supported by additional
findings in a small trial of 63 patients with
rosacea in which rifaximin led to moderate or
greater improvement in rosacea symptoms,
including lesion count and severity.
• Isolated case report examples also support a
potential role for SIBO-targeted antimicrobial
treatment in ocular rosacea, with an expected
response rate of 33%.
Mahalo!
• mtraubnd@me.com
• 808-329-2114
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15

Meet your Inner Ecosystem; Your key to
Rebalancing Immune Dysfunction
Dr. Laura Stuve, PhD, Biochemist
www.quantumbodytalk.com
Imbalances in microbiome biodiversity and ecosystem structure can underlie a very diverse set of
health issues including: chronic eye, bladder or vaginal infections, colitis, inflammatory conditions,
leaky gut, anxiety, depression, mood disorders, obesity, food intolerances, asthma, autoimmune disease
and chronic pain. The presentation will focus on an overview of the latest scientific understanding
of the human microbiomes (gut, respiratory, ocular, urogenital, skin, and oral), with a focus on
the best-characterized microbiome of the gut. Learn on the roles of specific beneficial gut microbe
species in maintaining optimal health and ways to promote microbiome biodiversity, rebalance microbiomes
after antibiotics, and understand the role and limitations of probiotics.
Biography
Dr. Laura Stuve, is a PhD molecular biologist and an advanced instructor and practitioner of Body-
Talk Mind-Body medicine. She spent 26 years doing research on the molecular genetics of human
disease in academia and the biotechnology industry. Laura got her PhD at UCSF in biochemistry and
then did a postdoctoral fellowship at Stanford working on the Human Genome Project. She was a
Senior Director of Research and Development at two California biotech companies before changing
careers in 2008. Laura moved into full time practice, research and teaching of a healthcare system
that dramatically changed her own health. She has been teaching BodyTalk and courses of her own
design in science-based mind-body medicine for alternative healthcare practitioners for 8 years.
Her focus is to bring the latest paradigm-changing scientific discoveries into the hands of healthcare
practitioners to make a difference in clinical treatment of chronic disease. Laura developed a 4-day
workshop presenting the latest scientific understanding of the microbiome and immune disease,
together with new BodyTalk clinical treatment strategies in this area. She has been teaching this
course and lecturing in this field for the past 3 years.
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5/17/2017
Meet your Inner Ecosystem:
Your Key to Rebalancing Immune
Dysfunction
Dr. Laura Stuve
PhD Molecular Biologist
Advanced Certified BodyTalk Instructor and
Practitioner
CNDA June 11, 2017
Overview
• Germ Theory of Disease…the History
– Immune Paradigm Change = Clinical Mindset
Change
• Your Microbiome – Your Partner in Health
• Gut-Brain Communication
• Deforestation and Its Impacts
• Take Home Perspectives for your Clinic
My Story
• Academic and Scientific training
– 26 years in scientific research in genetic and
epigenetic basis of disease
• PhD molecular biology – UCSF
• Post-Doc at Stanford Human Genome Project
• Biotechnology Research Director
• BodyTalk Mind Body Medicine
– Practitioner for 12 years, Instructor for 8 years
– Directed the first clinical research study
• Published April 2015: Journal of Pain Management
• Science-Based Mind Body Medicine Course
Development and Instruction
– BodyEcology: new science of the microbiome and
immune imbalance for healthcare practitioners,
– Evolve Epigenetics: latest science of epigenetics
for healthcare practitioners
Branching Out
2013 Members Conference
Skyrocketing Immune Disease
?
Bach, J-F 2002 New England Journal of Medicine 347: 911-920.
A Healthy Immune System
Balance of
Powers
The Immune System in 2017
Innate Immunity
NK Cells
Helper Ts
Killer Ts
?
Peacekeepers
T-Reg
B-Reg
WARRIORS
Peacekeepers
WARRIORS
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5/17/2017
A Bacterial Dominated Planet
Origin of Earth
4.5B
Bacteria
3.8B
Multicellular
Organisms
2.1B
Eukaryotes
1.5B
Age of Bacteria
Homo sapiens
0.2M
• Bacteria…
– Their diversity is mind-boggling!
– Consider that we are more similar to corn than any two
different bacterial species in the gut…
• This means they’ve figured out the physiology to
survive on planet Earth.
The Age of Parasites
200,000 – 10,000 years ago
• Immune system kept in balance
• Daily parasites, viruses, bacteria
without modern sanitation
• High fiber diet
• Low stress! With an occasional threat
• Hunter-gathers in small bands of
dozens of people
– Pathogens couldn’t travel the miles
between settlements
– Viruses, bacteria, parasites were
rewarded for kinder, gentler impacts,
latency
The Age of Plagues/Epidemics
10,000 BCE – 1920s
• Bacterial: Black plague, typhoid,
cholera, tuberculosis, dysentery
(or amoebic)
• Viral: flu, smallpox, measles
• Easy spread of pathogens with
crowding, poor sanitations in cities
• Epidemics killing millions
– US Civil War and WWI: more
soldiers died of typhoid and
dysentery than combat
– 1918-1919: Great Spanish Flu
infected ¼ of the world’s population
(over 500 million), 20-40 million people
died, primarily from bacterial pneumonia.
• Science worked feverishly to
combat these germs
• Immune system:
– Warriors busy with
viruses, amoebas,
bacteria, parasites,
fungi…all classes
of pathogens
Louis Pasteur’s
Germ Theory of Disease
Pasteur 1822-1895
• Diseases are caused by the presence
and actions of specific micro-organisms
in the body (Mid 1800s)
– Joseph Lister started washing
instruments, bandages and spraying
phenols to reduce infections in hospitals
– Robert Koch developed rules to show
which microbe caused which disease
Lister 1827-1912
Koch 1843-1910
The Discovery of Penicillin
The Age of Antibiotics: Why Not Use
Them for Everything?
• First Antibiotic
– Specifically kills the main
killer, the bacterial class
of microbes!
• Alexander Fleming:
1920s looking for ways to
kill bacteria accidentally
discovered bacteria dead on
his moldy petri dishes
• Miracle drugs
– WWII and beyond:
Saved people from dying
of the deadly infections
of earlier wars
• Use primarily for issues
that are viral in origin
– While only 20% of
earaches, bronchial
infections, etc are
bacterial, doctors
prescribe for all
• OVERUSE TODAY
– 258 million courses
of antibiotics
prescribed in the US
(2010: 833
prescriptions for every
1000 people)
– Highest Rx rate in
kids under 2: 1365
courses per 1000
babies!
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5/17/2017
Fast Forward to 2008
New Tools…
New Research…
New Paradigm…
The New View of
Microbes and Health
• Deadly germs
– Era of Germ Theory of
Disease
– Orientation:
• They’re Deadly - Let’s Kill
Them!
• Friends with
Benefits
– Your body is a jungle!
• Teaming with trillions of
beneficial microbes.
– They’re ESSENTIAL!
Human Microbiome Project
• 5 year multi-million $ research project
funded by the NIH in 2008.
– Results published in Nature in 2012.
• Goal: Census of microorganisms on the human
body in both healthy people and in disease.
– 250 healthy volunteers have been “surveyed” to look at
the bacteria in their guts, skin, urogenital areas,
respiratory systems, mouths and eyes.
– Just starting to characterize fungal, viral, archaea and
bacteriophage components.
– Microbes are visible under the microscope but they are
now being “seen” by their DNA sequence.
Partners in Health
YOUR MICROBIOME
What is your Microbiome and
Why Should YOU Care?
Your Microbiome
An Ecosystem of Microbes
EVERYWHERE on your Body
• Microbes Matter!
– You need to understand their function in your
body and role in your health to make the best
lifestyle and healthcare decisions for yourself
and your patients!
Gut
Lungs
Eyes
Mouth
Bladder
Urogenital
Skin
Mouth
Skin
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5/17/2017
Microbes in the Microbiome
Bacteria
Fungi/Yeast
Where is the Microbiome?
– The borders of the
body with the outside
environment.
Eyes
Nose
Skin
Mouth
Respiratory
Tract
Archaea
• Ancient prokaryote distinct
from bacteria
Viruses
Bacteriophage
• Bacterial viruses
• May be more diverse than
bacteria in the ecosystem
Gut
Urogenital
Tract
What Everyone Should Know About
Their Microbiome - 10 Fun Facts
1. A Healthy Microbiome = A Healthy You
2. Impact your brain function and mood
53
“Earth has always been and always will be a
microbe-dominated world. Microbes existed
for at least 2.5 billion years before the first
multicellular creatures….
If you’re an aspiring multicellular organism
lumbering into this world, do you reinvent the
wheel or do you defer to the masters with
billions of years of experience?
The evidence says we used the experts.”
– M. Velasquez – Manoff
3
We Outsourced our
“Earth has always Physiology! been and always will be a
microbe-dominated world. Microbes existed
for at least 2.5 billion years before the first
multicellular creatures….
If you’re an aspiring multicellular organism
lumbering into this world, do you reinvent the
wheel or do you defer to the masters with
billions of years of experience?
The evidence says we used the experts.”
– M. Velasquez – Manoff
Ancient Binding Contract:
Our Outsourced Physiology
• What do the microbes get?
– “Microbes gain by being able to live a privileged life in your
intestines, which comes with a constant supply of food,
moderate temperatures, and unlimited free travel. They
also gain a free connection to our internal Internet traffic –
the constant flow of information transmitted by hormones,
gut peptides, nerve impulses, and other chemical signals.
• What do we get?
– In exchange, the microbes provide us with essential
vitamins, metabolize digestive compounds called bile
acids, that are produced by our liver, and detoxify foreign
chemicals…digest dietary fiber and complex sugars our
digestive system can’t break down or absorb on its own…”
Emeran Mayer, MD
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4
Mostly Microbe
5
A Healthy Microbiome =
A Healthy Immune System
Balance of Powers
Warriors
Peacekeepers
• We are an ecosystem! Our microbes
outnumber our human cells by about 10:1.
• Multiply a million times more efficiently than
we do.
• Your microbiome is the primary determinant of the balance
between the 2 arms of the immune system...
• Ideally trains:
– Strong warriors primed to fight off invaders AND
– Strong peacekeepers to tolerate the microbiome and keep inflammation,
allergies, auto-immunity low.
6 “Our” Biochemistry
Themes of Microbial Imbalance
7
and Disease
• Our bacterial friends contribution
over 2 million genes to our
wimpy 20,000.
• Most biochemicals floating
around in our bloodstream are
made by our bacteria, not us.
– They produce 100,000s of different
metabolites, many our bodies
don’t make.
– Microbe metabolites account for
40% of the circulating molecules in
OUR BLOOD!
– This is when we don’t have leaky
gut…
1. Wrong place: invasion or leakage through the epithelial wall
2. Wrong amount: ecosystem distortion due to modern lifestyle
factors: antibiotics, meds, stress, diet, c-section, formula-feeding
infants.
3. Wrong context: triggers of neutral and beneficial microbes into
antagonized states
• On Pathogens:
– Most pathogens that cause eye, respiratory, urogenital, gut, bladder
infections were in the catalog of microbes found in the human
microbiome project in the 250 healthy people.
– Most organisms, historically considered to be pathogens, are really
“pathobionts” (neutral or beneficial symbionts causing disease in the
wrong context).
• Local inflammation = global inflammation
– Neutralizing local inflammation = lower inflammation globally
8
How do we get our microbiome?
• Initial seeding from the vagina during birth.
– Vaginal secretions change in late
pregnancy to create an ideal
microbiome for the baby.
• Breastfeeding
– Bifidobacteria from colonies deep within
the mother’s nipples.
– Breast milk has indigestible sugars to
feed their gut microbes.
• Handling by family, friends, pets, contact with all
the things they put in their mouths!
• Multiply to create a very complex
ecosystem by late infancy.
9
Keeping a Happy Microbiome
• Support Biodiversity!
• Feed your Microbes!
– The more diverse your diet, the more
biodiversity in the microbiome.
– The more biodiversity in the microbiome,
the healthier you are.
– The beneficial microbes prefer a breakfast,
lunch, dinner of plant fiber.
– Research suggests that the minimal daily
government requirements for fiber are 10X
lower than the historic human diet of our
hunter/gatherer ancestors.
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5/17/2017
10 Fat or Lean?
Gut Microbiome
• Your microbiome makes the difference!
Gut Microbiome
• Gut lining:100X greater surface area
than the skin, ~ basketball court.
• Most extensive and complex
microbiome:
– Human gut mucosal cells, immune
cells and resident microbes: 1000’s
of species, ~1 kg.
– Influenced by diet, age, genetics, antibiotics, stress, geography.
• Each microbe has distinct nutrient requirements.
– Generate waste products as they dine on the available food in the gut.
– Waste products of one are the food of another, linking all the microbes in
an interconnected web.
– Archaea: Bottom of the food chain, recycle/degrade hydrogen and CO 2 .
Location of the Gut Microbiome
• Microbes inhabit the mucus layer of the
intestine in a biofilm in close contact with the
underlying gut epithelium.
• Structure
• 2 mucus layers in colon
• 1 in the small intestine
• When the biofilm is too thick or too thin,
inflammation can be triggered.
Essential Functions of Gut Microbes
Gut Microbe Numbers
• Nutrient synthesis, including
essential vitamins, B12 and K.
• Maintenance of the gut
epithelia:
• Development
• Growth
• Repair
• Tight fortress
• Angiogenesis
• Nutrient Absorption
• Digestion of complex sugars
and lipids
• Immune support
– Protection from pathogens:
compete for nutrients and
make anti-microbials.
– Educate immune cells in
tolerance; prevent intolerance
to foods and environmental
factors.
• Regulation of energy (fat)
storage.
• Density:
– A billion times more
concentrated in the small
intestine than the stomach
– In this 1cc syringe:
• The stomach would have
100-1000 individual
microbes.
• The small intestine would
have 10 – 100 billion
microbes!
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5/17/2017
Gut Microbes…Super-Communicators,
Set our Rhythms
• Have Rhythm
– The gut microbe’s abundance
and the metabolites they
produce rise and fall in a daily
circadian rhythm.
Bacteroides: B. fragilis
– With the variation in digestive
secretions of the gut lining they
bloom and contract.
– Our intestine and liver’s
physiological rhythms are in
sync with and respond to these
bacterial rhythms.
– Our microbes modulate our
circadian rhythms!
– Our circadian rhythms are key
for overall tuning of hormonal
rhythms, and get out of sync
with aging.
Rhythm and Bacteria
Ashley York
Nature Reviews Microbiology 15, 67 (2017)
• Demands Peace
– 70-80% of us have B. fragilis in our gut.
– Its surface sugar, polysaccharide A, triggers our immune system to
make regulatory T cells, the powerful peacekeepers that produce antiinflammatory
cytokines and ensure tolerance of the microbiome, and B.
fragilis.
– With inadequate T-Regs the immune system is prone to allergic and
self-reactive over-reaction.
• Some probiotics now contain B. fragilis.
– Good choice for patients with auto-immune, allergic and inflammatory
conditions.
Helicobacter pylori (H. pylori)
• Rare bacteria that can survive the high acid
of the stomach.
• Easily eradicated by 1-2 rounds of
antibiotics for routine childhood ear and
bronchial infections.
• Historically classified as a pathogen but has
several mutualist functions:
1. Keeping stomach acid levels at an optimum
level, reducing the incidence of acid reflux.
2. Regulation of our appetite via a hormone
ghrelin.
3. Helps educate tolerance of the immune
system, protecting us from asthma, skin
allergies and hay fever.
• H. pylori is not a pathogen in the stomach
microbiome by a pathobiont, when reintroduced
in adulthood is often not well tolerated.
Clostridia
• Gram-positive, rod-shaped bacteria in the phylum Firmicutes
– Predominant class of gut, especially colon, microbes.
• Mutualist Benefits:
– Colonize the intestines of breastfed newborns within the first
month of life.
– Prevent pathogenic organisms from taking up residence.
– Nourish colonocytes and repair the colon lining. Primary energy
source for the colon is butyrate, the end product of their
fermentation process.
• More on butyrate later.
– Convert inactive dopamine and norepinephrine neurotransmitters
made in the gut to active forms.
• Involved in gut-brain communication.
The Gut Microbiome in Disease
• Poor biodiversity and imbalanced gut ecosystems
have been implicated in…
– Inflammatory Bowel Disease, Ulcerative Colitis,
Crohn’s
– Obesity
– Autism
– Celiac disease
– Rheumatoid arthritis
– Other immune and autoimmune diseases
• Key mutualist species missing or depleted, some
species growing like weeds, pathogens moving
into the ecosystem.
Inter-Kingdom Communication
MICROBE SPEAK
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Microbe-Speak
• “Your gut microbes are engaged in ongoing
conversations with your GI tract, your immune
system, your enteric nervous system and your
brain – as with any cooperative relationship,
healthy communication is essential.
• Recent research reveals that the disturbance of
these conversations can lead to GI diseases,
including IBD, antibiotic-associated diarrhea, and
obesity, with all its deleterious consequences, and
may be involved in the development of many
serious brain diseases, including depression,
Alzheimer’s disease, and autism. “
Emeran Mayer, MD
Communication Between the
Microbiome and the Epithelial Border
• Bidirectional
• Mechanism?
– Hormones and other
small metabolites
– EVs!
EVs = Extracellular Vesicles
• Tiny vesicles bud off of most cells
– Microbes and human cells emit EVs
– A form of inter-kingdom and inter-cell
communication
– Zipcoded and taken up by other cells with the
appropriate zipcode
• Carry important cargo
– Small miRNAs within epigenetically reprogram recipient cells
by blocking translation of specific proteins
• All fluids of the body contain EVs: Blood, lymph,
saliva, urine
Intestinal Epithelial Cells
Communicate with the Microbiome
• 2016 study
– Intestinal epithelial cells
use microRNA
epigenetic strategies to
‘select’ the microbiome
– microRNAs control
bacterial growth and
limit growth of
unfriendly species
– How do the microRNAs
get to the bacteria?
• EVs!!!!
Disease Spotlight on Type II Diabetes:
Microbiome Communicates with our Cells
• New research (2015)
– Commensal gut microbes involved in insulin
resistance for people on high fat diets
– Mechanism elaborated in mouse study
– Bacterial EVs increase from a specific gut
bacteria when host eats a high fat diet.
• Pseudomonas panacis (phylum Proteobacteria)
– These bacterially derived EVs blocked insulin
signals in muscle and fat tissue and caused
typical diabetes symptoms.
• Indication: Bacterial EVs may play a role in
insulin resistance in Type II Diabetes.
Gut – Brain Connection
– Gut Microbes influence functioning of your brain? !!
HOW?
Sleep
Memory
Mood
Happy
Satisfied
Depressed
Anxious
Clarity
Foggy Head
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5/17/2017
Channels of Gut Microbiome -
Brain Communication
• Nervous system
– Stress Channel:
Sympathetic
– Rest and Digest Channel:
Parasympathetic
• Endocrine system:
Human/Microbe hormone talk
– Metabolic Channel: Are
you hungry? Satiated?
What do you want to eat?
• Immune system: Via
cytokine messages
– Inflammation Channel
– Anti-Inflammation
Channel
Endocrine
System
Nervous System
(Stress/Relaxation)
The Gut Microbiome
(EVs and metabolites from
15K – 36K species)
Immune
System
Enteric Nervous System
• Glial cells support
• 500 million neurons
• 40 NTs identified
• Produces
– 50% of all dopamine
– 95% of all serotonin
Gut Microbiome – Brain
Endocrine Talk
• Inter-Kingdom Communication
– Goes both ways
• Microbes secrete hormones and EVs that influence our cells
• Impact our hormone production
• Our hormones influence them – their growth, aggressiveness
• Example:
– Gut bacteria make and respond to these hormones
• Norepinephrine: They get more aggressive when we are
stressed!
• Serotonin
• Dopamine
• GABA
How we effect them…
• Stress
• Exercise
• Diet
• Mood
– Anxiety,
depression
• Health
• Gender
The Nervous System Channel
• STRESS Channel - Sympathetic
– As part of fight or flight,
digestion is put on hold (must
survive mortal peril before digesting
lunch)
– Norepinephrine, Epinephrine
main NTs
– Epithelial fortress gets leaky,
more bacteria and bacterial
products leak in, inflammation
elevates
Stress Channel Impacts on
Gut Microbiome
Stress hormones:
Norepinephrine
Epinephrine
• Bacterial Growth
• Biofilm Growth
• Increased aggressiveness
• Decreased resistance to our
defenses
• RELAXATION Channel
Parasympathetic
– Rest and digest, digestive
secretions, gut motility back on
line when we’re safe
– Acetylcholine NT
– Main parasympathetic nerve is
vagus nerve
90% of traffic from gut to brain
10% from brain to gut
Norepinephrine
• Stimulates growth of bacterial pathogens
• Activates genes in pathogens
• Increases their aggressiveness
• Some gut microbes can modify
norepinephrine to give it superpowers with
even greater impacts
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5/17/2017
Stress Channel in Pregnancy
Other Hormone Channels
Impact the Microbiome
Stress hormones:
Norepinephrine
Epinephrine
Cortisol
• Vaginal microbiome
• During pregnancy key gut
microbes appear in
vaginal microbiome
• Stress reduces these
important lactobacillus needed
for newborns gut microbiome
• Deficiencies in newborn gut
ecology
Dopamine
Estradiol
Progesterone
Bacterial Growth
Biofilm Growth
Female sex hormones
Bacterial Growth
Estradiol
Estriol
Female sex hormones:
Decreased Virulence and
aggressiveness
Immunity
Microbiome Impacts on Us
Metabolism/
Appetite
Stress & Anxiety
Gender-Specific
Hormone and Nervous System
Channel Gatekeeper: NE Cells
• The pathway: (1) Gut microbiome metabolites
– (2) NE Cells – (3) bloodstream – (4) travel
anywhere in the body
– 100,000s of microbial metabolites in the
bloodstream
• Receptors: Neuroendocrine cells in the gut
epithelia
– Studded with receptors for these metabolites,
sense:
• Bile acid metabolites
• SCFAs such as butyrate (short chain fatty acids)
– Have taste receptors and olfactory (smell)
receptors, just like your tongue and nose.
• For example, they sense 28 different types of bitter!
Likely they sense different microbe products.
– What they sense impacts how you feel…after
eating a healthy meal vs a meal of fried chicken
and greasy potato chips
The NeuroEndocrine Hub
Modulation of
Microbe Behavior
Serotonin,
Other
Hormones
Microbe
Metabolites
NE
Cells
Serotonin,
Other
Hormones
Neuroendocrine Cells
• Integrate nervous, endocrine,
immune and microbiome
systems
• Receive input from nerves and
secrete hormones in response
• Clustered in the epithelial
borders of the lungs, gut,
prostate, eye
• Regulate growth and
differentiation, etc.
• Implicated in diarrhea, constipation,
cancers: (prostate, lung, pancreatic)
Pulmonary NE Cells (pink)
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Gut NE Cells
Gut-Brain Communication – Autism
• Gut = Largest endocrine system
in the body
– Make 30+ different hormones
– 3 different subtypes of NE gut
cells that produce different
hormones (EC, L and D cells)
– Secrete
• Serotonin: influences mood,
diarrhea, constipation, intestinal
motility
• Somatostatin: modulates intestinal
absorption
• Metabolic hormones: impact
metabolic rate, insulin levels in
blood, appetite
– Imbalanced in food intolerances,
constipation, diarrhea, weight
and metabolism, very rare
cancers
Small Intestine, Duodenum, NE Cell, X3500
• GI issues, often severe, go hand in hand with autistic behavioral
symptoms
• Microbiome differences in autistic children: less biodiversity vs
normal siblings
• Significant percentage of individuals with autism have had an
extensive history of antibiotic use in first 3 years of life
• Gut microbiome bacterial strains commonly associated with autism
– Sarcina ventriculi, Barnesiella intestihominis, Clostridium
bartlettii, and Clostridium bolteae
– Haemophilus parainfluenzae bacteria was found to correlate with GI
pain and self-injurious behavior in an autism case study
• Mouse study 2016
– Adding back a single species of gut bacteria, Lactobacillus reuteri,
restored normal social behavior in a mouse model of autism
• Fecal transplant study 2017 in autistic children ages 7-16
– Fecal transplant significantly improved diarrhea and stomach pain as
well as autism related social symptoms evaluated by a questionnaire of
parents (social skills, irritability, hyperactivity, communication)
The Gut-Brain Communicators
Serotonin
• BDNF
• Butyrate
• Dopamine
• Epinephrine
• GABA
• Norepinephrine
• Serotonin
• Creates: Well being,
happiness, memory,
learning, appetite, gut
motility, impacts sleep
and pain sensitivity
– 90% made in the gut
brain
• Made by the
enterochromaffin cells
of the intestinal lining
– A specialized type of
neuroendocrine cell
• Serotonin
– NT via the vagus nerve to
the brain
– Hormone via bloodstream
• Some bacteria make their
own serotonin which adds to
that we make to keep
serotonin balanced in our
nervous system and gut.
• Some microbial metabolites
increase serotonin
production in the NE cells
Butyrate
Butyrate and Brain Function
• A SCFA produced by colon
bacteria on high fiber diet,
(they eat, ferment the fiber)
– By Clostridium,
Eubacterium and
Butyrivibio bacteria
– Fiber of choice: whole
grains, legumes,
bananas, onions,
asparagus
• Also found in butter,
highest dietary source (but
the amount the
microbiome makes is
much greater potentially!)
• Improves brain, colon and immune
system health
• Keeps gut epithelial cell tight junctions
tight, prevents microbes, their products
and toxins from leaking in
• A key energy source for colon epithelial
cells
• Anti-inflammatory
• Boosts T-Reg function
• Protects against colon cancer
• Modulates our epigenetics (histone
deacetylase inhibitor, keeps genes on) in
epithelial and brain.
• Improves insulin sensitivity
• Improves mitochondrial function
• Balances metabolism (increases leptin
which lowers appetite).
• Profound effect on
improving learning and
memory
• Promising in mouse
models of Alzheimer’s
and Parkinson’s
• Protective from neuronal
cell death and oxidative
stress
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5/17/2017
Other Communicators in
the Gut - Brain Channel
• Dopamine
– Reward neurotransmitter, feeling
positive, satisfied
– Activated by bacteria in the gut
microbiome
• GABA
– Major inhibitory neurotransmitter
– When GABA signaling is
disturbed, depression or anxiety
can result.
– Gut bacteria (lactobacillus and
bifidobacteria) make GABA
which behaves like Valium in our
brains, calming us down! Make
us less sensitive to negative
emotions
• Brain-Derived Neurotropic
Factor (BDNF)
– “Fertilizer” for neurons,
promotes neuroplasticity
• Linked to memory and
depression
• Lowers risk of dementia
– Stress (cortisol) lowers BDNF
– When BDNF is lower, memory
issues, anxiety and depression
are elevated
– In mice without a microbiome,
with deforested gut
microbiomes or on
antibiotics…BDNF is reduced
• Adding a probiotic back can
bring up BDNF levels!
Microbes and Our Metabolism
• Microbes and their metabolites modulate
– Insulin sensitivity
– Hormones for
• Hunger (Ghrehlin, GLP-1)
• Satiation
• Starvation (Leptin)
– Fat storage in the liver
The Inflammation Channel
Inflammation Channel
• Microbe – Immune System – Brain Speak
• Depends on:
– Biofilm thickness
– Normally tight barriers: Gut leakiness and blood
brain barrier
• When weakened, inflammation can spread systemically
in the body
• Triggers for weakening:
1. Stress
2. Inflammation
3. High fat diet
4. Food additives
1. Via dendritic cell sampling, assessing friend or foe
• Friends generate signals of peace, build peacekeepers
• Foes or perceived foes trigger inflammatory response
2. When microbes get too close…penetrate inner
mucus zone their cells walls (LPS) trigger/activate
immune cells in the GALT, LPS can increase gut
leakiness and therefore exposure of gut microbes to
the immune system, elevating inflammation
3. On high animal fat diet, levels of proteobacteria and
firmicutes increase, chronically triggering
inflammation
Inflammation Channel:
Cytokine-Talk when Immune Cells Engage
• Can cause major gut inflammation (IBD, gastritis)
• Cytokines communicate to the brain by
a) Vagus nerve
– Reduce energy level
– Increase fatigue
– Elevate inflammation in the vagal nerve itself impacting
sensing of satiation (so less sensitivity around whether
you are full)
b) Blood stream
– Once through the blood brain barrier, activate the
brain’s immune cells, microglia (majority of cells in the
brain)
– Implicated in Alzheimer’s and other neurodegenerative
disorders
Anti-Inflammation Channel:
Cytokine-Talk when Immune Cells
Sees Friends
• When dendritic cells sense
bacterial mutualists in the
microbiome
– Trigger body to make more T-Reg
peacekeepers
– Produce anti-inflammatory cytokines
– Microbial metabolites, like butyrate…
• Boost activity of T-Regs
• Help neutralize inflammatory cytokines
• Anti-Inflammatory Cytokines also
communicate to the brain by
a) Vagus nerve
b) Blood stream
– Lower inflammation
systemically
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Role of Peacekeeper Cells in
Allergies
• T and B regs calm down over-reactivity in the immune
system to keep us allergy-free
• If there are allergies, there is either a peacekeeper:
1. Depletion or
2. Dysfunction
Link between your Microbiome and
your Emotions
• Research studies - POOP SWAP
– Possible to swap microbiomes and change emotional profiles
– Anxious mice and fearless mice have distinct gut ecosystems.
• Food allergies:
– A newly discovered specialist T-Reg, pT-Regs (or
peripheral T-Regs in the gut help us tolerate the foreign
substances in our gut
• Appear as we start on solid food as babies
– Research Note: suggests that exposing babies to egg and
peanut at ages 4-6 months actually protects from these
allergies later on by building the pT-Regs
Anxious Mouse
Swap Microbiomes
Fearless Mouse
Your Microbiome Impacts Your
Emotional State
• Research studies on Probiotic Effects
• Probiotics can stabilize and improve the health of your microbiome.
Parasites
Pathogens
Inflammatory Chemicals
Probiotics
Your Microbiome Impacts Your
Stress Sensitivity
• Research studies on Probiotic Effects
• Probiotics can stabilize and improve the health of your microbiome.
Scary and Disturbing Images
Probiotics
Create Anxious Mice
Fearless Mice
Your Microbiome Impacts Your
Perception
– Gut bacteria influence PAIN perception!
– Gut bacteria influence what you are hungry
for!
Microbiomes: Common Features
1. Protection
• Keep pathogens out – occupy real estate.
• Make anti-microbials focused on pathogens.
• Support immune system – Train warriors.
2. Tolerance
• Boost levels and function of Regulatory T
cells (peacekeepers).
• Ensure balance in the immune system.
3. Nourishment/Repair
• Provide nutrients for human epithelial cells.
• Keep epithelial boundary tight and healthy.
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Skin (Cloud) Microbiome
• Different micro-environments: moist,
hairy, dry, oily.
• Present on the epidermal layers, the
surface of the skin, within the glands
and along the hair shaft. And floating
several inches off the body in a “cloud”
around us!
• Impacted by age, genetics, hygiene,
external climate and immune
reactivity.
• Estimated that cm 2 of the skin has a
billion microbes!
– Viruses
– Bacteria
– Fungi
– Small arthropod (demodex mite)
Respiratory Microbiome
– Beneficial functions of complex
ecosystem of microbes in the
respiratory lining
• Occupy real estate and prevent
pathogenic microbes from
colonizing
• Boost T-reg, anti-inflammatory
arm of the immune system
– Resides in mucus biofilm on
respiratory epithelium in nasal,
sinus, trachea, bronchi to
alveoli.
– Imbalances in asthma, COPD,
smoking, emphysema.
• Ocular microbiome
– Resides in mucus on corneal
surface.
– Core set of 12 main bacterial
groups in healthy eyes.
• All known pathogens
causing eye infections are
on the list!
• Delicate balance between
bacterial friends and
antagonized bacteria that
trigger infection.
• Function:
1. Protection from infection:
Keep pathogens out
2. Train warriors.
Other
Microbiomes
• Vaginal microbiome
– Healthiest woman have low diversity
vaginal microbiome. (Opposite to gut)
– Highly dynamic from day to day,
impacted by: age, ethnicity, diet,
hygiene, hormonal changes,
menstruation, sexual intercourse,
pregnancy and antibiotics.
• Low pH and lactobacillidominated
microbiome in
reproductive age women.
• Function - Protection from infection by:
– Occupying real estate, consuming
nutrients
– Creation of an acidic environment
– Production of hydrogen peroxide that
deter pathogens
– Protect from
• Bacterial vaginosis (BV)
• Yeast infections
• UTIs
• HIV infection.
Deforestation and its Impacts
IMMUNE DYSFUNCTION
What has destabilized our
immune system?
• And thrown it into an
inflammatory overreaction???
Microbiome Disruption
• Disruption of microbe
biodiversity with
modernization behind the
spike in “modern
diseases”
• What is disrupting our
microbiomes?
– Our Modern Lifestyles!!
• This disruption is throwing
our immune systems into
inflammatory disarray.
• Allergies
• Autism
• Asthma
• Autoimmunity
• Crohn’s
• Diabetes
• Obesity
• Cancer
• Multiple Sclerosis
Immune cell doing its job
Peanuts as dangerous invaders?
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What is Disrupting our
Microbiome?
5 Key Factors…
Factor #5: C-section Impacts on
Microbiome Biodiversity
• Microbiome more closely resembles a
mother’s skin.
• 6 months: Major deficits in key
mutualist species that educate the
immune system and aid in digestion
• 7+ years: Very different microbe
profile can persist.
5. C-sections
– Increasing prevalence of c-sections.
• US, >30% of all births are by c-section.
• Urban China, Brazil numbers are double that.
– The microbiomes of c-section babies show
major differences to vaginal deliveries, and the
microbial education of their immune system
is different.
Health/Disease Spotlight:
Modern Disturbances
• Vaginal delivery vs
c-section
• C-section often
means antibiotics
– 3 months of
breast feeding
can help repair
antibiotic hit
Factor #4: Family Size Impacts on
Microbiome Biodiversity
4. Family size
– Trend to smaller family sizes means kids
have fewer siblings and are exposed to less
microbes from the families colds and flus
while they grow up.
– Microbial education of the immune system is
different.
Factor #3: Sanitation Impacts
Microbiome Biodiversity
3. Sanitation
– Reforms of the past 100 years: cleaner water,
and MANY anti-microbial cleaner products.
– Cleaner drinking water has saved many from
illness and deadly disease.
– Microbial education of the immune system is
different.
Factor #2: Diet Impacts on
Microbiome Biodiversity
2. Diet: Unprecedented changes in our diet.
– Pre-Industrial revolution: unrefined grains,
tubers, vegetables, dairy and lean meat from
grass-fed animals.
– Today: 75% of our energy, from refined sugars,
grains, vegetables and dairy products.
• Sugar consumption up 10-fold from 1815 to 2000
(154 lbs/year)!
– Microbes that dine on plant-based fiber are
literally starving to death on our modern diets!
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Factor #1: Antibiotics
Antibiotics – They’re Everywhere
• Even if you do not take them yourself, or haven’t
since childhood, other sources of exposure.
• Biggest use in animals, to check infections and
accelerate growth.
– Low doses cause animals to gain weight with less food.
– Antibiotic-tainted meat not uncommon in the US food
supply.
• Use is still increasing TODAY in livestock and dentistry,
despite the latest science on impact on the microbiomes
and OUR health!
– Issue is not USE but OVERUSE: Still needed to save many from
deadly infections
• Does vegetarianism save you from the fate of
antibiotic exposure? Unfortunately not!
– >50% of antibiotics excreted in urine or feces.
– Animal manure and treated human waste used for
fertilizer and food crops readily absorb antibiotics.
• Lettuces, cabbage, carrots, wheat, corn, barley, soybeans and
potatoes soak up antibiotics.
Antibiotic Impacts on the
Microbiome
Oops! We’ve Been Deforesting Our
Ecosystems
• The available data suggests that short-term antibiotic exposure
can:
– Alter microbe physiology, gene expression, ecosystem structure
• Some depleted, eliminated, others grow like weeds.
– Immediate decrease in the stability and biodiversity of the microbial
ecosystems.
– Only partial recovery up to 4 years after antibiotic treatment.
– As the mutualists are cleared out, the microbiome is more susceptible
to pathogens moving in.
• Creates super bugs with genetic adaptations to allow them to
survive antibiotics.
– Growth almost unstoppable by traditional pharmaceutical warfare
strategies.
Antibiotics and Obesity
Health Issue: Obesity
• A correlation…you decide
• Ecosystem disruption
YES, gut microbes different
• Reduced biodiversity
• Elevated inflammation
YES, Lower Bacteroidetes, higher Firmicutes.
• In obesity and high carb diets, Prevotella,
outcompetes its neighbors, dominates
ecosystem.
YES, fat cells elevate inflammation
Microbiome and host (us) shift to get enough
energy our diet when Bacteroidetes reduced.
• Bacteria activate genes that break down carbs
into different substances (short-chain fatty
acids).
• Fatty acids trigger the body to make more fat
cells and store excess calories as fat.
• Our livers also shift their metabolism, and store
more calories as fat.
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Allergic Reactiveness:
• Allergies, Food
Intolerances, Asthma,
Ezcema, Inflammation,
Autoimmune Disease
We’re Too Clean: The Hygiene
Hypothesis
?
• What cells in the
immune system are
going haywire and
why?
Bach, J-F 2002 New England Journal of Medicine 347: 911-920.
Missing our Old Friends
• Graham Rook: Old Friends Hypothesis
– Highlights the simple observation that our
immune system has co-evolved for millions
of years with parasites.
– In their absence, our immune system can
neither develop nor function properly.
– It is missing its ‘old friends’ the parasites,
rewarded for their soft touch during ancient
hunter-gather tribal eras of human
civilization.
The Immune System in Confusion
Eosinophil
FACTORS
1) Confused YANG
– Immune cells whose job it is to
fight off parasites are all involved
in allergic reactiveness today.
• TH2 helper cells
• Eosinophils, Basophils, Mast Cells
• IgE producing Plasma cells
2) Deficient YIN
– Depletion of Regulatory T and B
cells that produce powerful antiinflammatory
cytokines and
balance the over-reactiveness of
the ”warriors” due to microbiome
deforestation.
Basophil
Mast Cell
The Peacekeepers
“In a field built on martial metaphors, regulatory T cells
were notable for what they guaranteed didn’t happen.
They ensured tolerance to one’s tissues;
They helped maintain peace with commensal microbes
in the intestinal tract;
They offered a new way of conceptualizing immunemediated
diseases, such as asthma or inflammatory
bowel disease….they stemmed from a deficiency or
absence of peacekeeping cells.
Not too much yang, but too little yin.”
– Moises Velasquez-Manoff
The Immune System in Confusion
• Allergens come from
about 10,000 different
protein families.
– Half of all allergens found in
only 10/10,000 families, all
from invertebrate
substances that “look” like
parasites to an immune
system hungry to find a
parasite.
– One can imagine confusing
a dust mite for a parasite …
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Unhealthy Microbiome =
A Reactive Immune System
Unhealthy Microbiome =
An Overactive Immune System
STRESS
Depleted
Microbiome
STRESS
Depleted
Microbiome
Peacekeepers
Peacekeepers
WARRIORS
WARRIORS
Allergies, Food Intolerances
Asthma
Autoimmune disease
Inflammation
Re-Wild our Bodies? Parasite Medicine
How to “Fix” the Microbiome…
• Joel Weinstock
– Modern diseases like Crohn’s are not caused
by invading species but by taking species
away.
– Reasoned that if the problem with our guts
today is that they are missing the parasites,
what would happen if they were added back?
• 1999 experiment:
– 25 Crohn’s patients and Gatorade laced with
nematodes,
– By week twelve, 22 of 25 patients better.
– By week 24, all by one patient was better.
• Approach does work for some but isn’t
always reproducible – too simplistic and
everyone can’t tolerate worms.
Fecal Microbiota Transplant (FMT)
• If the healthy, diverse microbiome of the gut prevents inflammation,
can it be transferred to someone with an inflamed colon?
– Common in rodent research studies
– Human studies show it works sometimes with some conditions and
doesn’t have side effects
• FMT or stool transplant:
– Tested in Clostridium difficile infections and ulcerative colitis.
• Resolves about 90% of C. diff infections, most in one treatment.
– Results not as effective with UC.
– 300+ published reports of FMT - no indication of infection risk in the
recipient.
– Newer strategies of purifying the fecal microbiota and serving them in a
colorless, odorless form are more palatable to many and showing
promise.
For You and Your Patients
TAKE HOME PERSPECTIVES
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What does this Mean for
Healthcare Practitioners Today?
• How can we get back to a state of immune
balance???
– Educate
– Intakes should contain: Antibiotics?
– Shift our treatment bias
– Shift our subconscious beliefs embedded in
the age of epidemics and the germ theory of
disease
Leave the Germ Theory of Disease
Behind!
• This is an entrenched
paradigm…
– We all grew up with it.
– We were educated
academically in science
and medical training in
this scientific paradigm.
– Reinforced from other
doctors, nurses,
dentists, healthcare
professionals,
veterinarians, research
publications.
• The REAL Picture:
Microbes and Health!
Friends
(mutualists and commensals)
.
Enemies
(the pathogens)
Pathogen Bias Needs to
Change In…
• Medicine
• Dentistry
• Pharmacology
• Household cleaning
products
• Veterinarian Medicine
• Alternative Healthcare
• The REAL Picture:
Microbes and Health!
Friends
(mutualists and commensals)
.
Enemies
(the pathogens)
Use Natural Antimicrobials
• Essential Oils
– Plant based anti-microbials
prune the ecosystem vs
antibiotics which carpet
bomb and annihilate the
ecosystem
– Research on effectiveness
• Melaleuca (Tea tree)
• Oregano
• Cinnamon
• Thyme
• Colloidal Silver
• Acupuncture and Chinese
herbs
• Avoid antibiotics, where
possible or use for
minimal vs maximal
periods of time
• Rebuild with diet,
probiotics post-antibiotics
: The Key to Health!
Microbiome Re-Balancers
Biodiversity Boosters
• Diet: Diversity of fruits & veggies
• FIBER!!!!
• Get dirty
• Breastfeed babies
Ecosystem Deforesters…
Avoid where possible:
• Antibiotics
• Anti-microbial products
• Diets without greens
• C-sections
Pre and Probiotics:
• Great but only add back a handful
of the thousands of beneficial
microbes.
• Probiotic foods common but newer
supplements only widely available
in the US
• Evidence that oral probiotics can
also influence respiratory system
inflammation
• Things to know about
Probiotics
1. Need to rotate every month
or two
2. Common dietary intake
negates the positive
impacts of probiotics
• Too much sugar
• Alcohol can kill beneficial
bacteria
3. Are very specific – most
people need a refrigerated
complex (>10 bacterial
strains) intestinal probiotic
to repair from antibiotic
ecosystem damage.
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Best Psychobiotics
Microbiome Rebalancers
• Probiotics that help with
depression, anxiety, stress
resilience
• Enriched for gut bacteria that
produce the neuroactive
compounds
– GABA
– Catecholamines
– Serotonin
• Clinical Trial: Some prebiotics also
boost bacteria that regulate mood!
– FOS (fructooligosaccharides)
– B-GOS (bimunogalactooligosaccharides)
– Shown to improve emotional
processing and lower cortisol levels.
• Clinical Trial: depression and
anxiety
– Lactobacillus acidophilus,
Lactobacillus casei, Bifidobacterium
bifidum
– 8 weeks reduced scores on Beck
Depression Inventory, systemic
inflammation, insulin resistance,
increased glutathione
• Clinical Trial: Coping strategies in
healthy people
– Lactobacillus helveticus R0052,
Bifobacterium longum R0175
– Alleviated psychological stress,
anger-hostility, anxiety, depression,
Improved problem solving
• Skin Microbiome
– How to support a healthy skin bacteria
• Mark Sisson
– http://www.marksdailyapple.com/how-to-support-healthy-skinbacteria/#axzz3NUj92hgx
– Throw away all anti-bacterial soaps
– Consider probiotic lotions that add back beneficial
bacteria
• Mother Dirt
– Garden and work in the soil, replaces natural skin
microbes
– Get a dog!
Microbiome Rebalancer: Diet
Microbiome and Immune
Rebalancer: Lower Stress
• Stress adversely impacts the microbiome
• Stress depletes the immune system
• More fiber! More greens!
– Food for the beneficial gut microbes
– Microbe composition changes quickly
(days) with diet changes!
• Less sugar…lowers yeast/fungal
component of microbiome
• Biggest Stressor: Sense of isolation, being alone,
unsupported
• Causes key set of genes to change!
– 131 genes that lower and control inflammation suppressed
– 78 genes that drive inflammation up
• Steve Cole, PhD (UCLA)
Mind-Body Modalities Lower Stress:
BodyTalk, Yoga, Meditation, Martial Arts, etc
STRESS
Nervous System
Immune System
PEACE
Stress Reducing Technique
(BodyTalk System)
• Switching: Resets nervous system and
meridian system out of stress mode
1) 4 reset points
– Ki27 under clavicles
– Pressure on closed eyes
2) Deep long breaths: activation of the
parasympathetic nervous system
3) Light tapping to activate ”brains”
– Head, Heart, Enteric
4) Focus: on reset of nervous system
from sympathetic to parasympathetic
Kidney 27:
Improves mental clarity
Balances the adrenals
Inflammatory
Warriors!
Anti-inflammatory
Peacekeepers
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References – Available
“The biological reality that we are vessels
to a vast microbial ecosystem is radically
altering our basic understanding of
medicine, nutrition, public health and the
very scientific foundation of what makes
us sick.”
– Jeff Leach, Honor Thy Symbionts
Thank You
laura@dnaintuitive.com
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THE ESTROBOLOME:
The Influence of the Microbiome
Upon Estrogen Metabolism and
Estrogenic Cancers
Dr. Nalini Chilkov, LAc, OMD
www.aiiore.com
www.nalinichilkov.com
www.integrativecanceranswers.com
The intestinal microbiome modulates the endogenous metabolism of estrogens. Learn how this
influences a woman’s lifetime exposure to circulating estrogens and how the intestinal microbiota
may contribute to the development of estrogen driven cancers. We will learn to use specific nutraceuticals,
probiotics and botanicals to promote a healthy and protective microbiome that favors
estrogen conjugation and excretion.
Biography
Dr. Nalini Chilkov, L.Ac., O.M.D. is a leading edge authority and pioneer in the field of Integrative
Cancer Care, Cancer Prevention and Immune Enhancement.. She is the Founder of the American Institute
of Integrative Oncology www.aiiore.com and IntegrativeCancerAnswers.com and the author
of the number one best-selling book “32 Ways to Out Smart Cancer: How to Create A Body Where
Cancer Cannot Thrive.” Dr. Chilkov brings over 30 years of clinical experience, combining the best of
Functional Medicine and Oriental Medicine. She has lectured at the School of Medicine at UCLA and
UC Irvine in California and the Medical Academy in London, UK. She is a member of the Scientific
Advisory Board of Mederi Foundation and is a regular contributor to the Healthy Living section of
the Huffington Post. She featured as a cancer expert on TAPIntegrative.com and on NBCTV and has
been recognized as one of the top 10 Online Influencers for Breast Cancer by Dr. Mehmet Oz and
WebMD. Her private practice is in Santa Monica, California.
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5/16/2017
THE ESTROBOLOME
Estrogen | Microbiome | Malignancy
Learning Objectives
Define Estrobolome
Understand how intestinal bacteria influence enterohepatic
circulation of estrogens
Understand how a woman’s lifetime burden of estrogen
exposure may reflect the metabolic functioning of her
estrobolome
Dr. Nalini Chilkov, Founder
American Institute of Integrative Oncology
Understand the link between the estrobolome and gut
microbiota to estrogen driven cancers
Understand how to use nutraceuticals, botanicals and
probiotics to promote estrogen conjugation and excretion and
inhibit reabsorption of free estrogens
The Human Microbiome
Residential Microbes That Colonize Humans
Bacteria Archaea Eukaryotes Viruses
Get to Know Your Microbes
Microbiome Perturbation
Increases
Inflammatory
AutoImmune
Malignant Disease
favoring
Oncogenesis
Tumor Progression
Microbiota effect local, adjacent
and distant neoplasia
Hormonal Intermediates
Metabolites
Immunologic Messengers
Induce Genotoxic Responses
Promote Chronic Inflammation
Alter Microenvironment and
Metabolism
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The tumor microenvironment
contributes
to every aspect of carcinogenesis
Classification of Microbiome-Associated
Human Malignancies
Adapted from Blaser (2008)
Role of
Inflammation-
Associated
Microenvironment in
Tumorigenesis and
Metastasis
Feng Gao, et al
Current Cancer
Drug Targets,
2014, 14, 30-45
Microbiome and Oncology
THE HUMAN
ESTROBOLOME
A functional estrobolome is the
Current Cancer
Drug Targets,
2014, 14, 30-45
aggregate of
enteric bacterial genes
whose products are capable of
metabolizing estrogens
Microbiome and Malignancy Plottel, Claudia S. et al.
Cell Host & Microbe. Volume 10 , Issue 4 , 324 – 335 October 2011
BEYOND THE HUMAN
ESTROBOLOME
Microbiome also influences the metabolism of
phytochemicals that exert epigenetic effects on
• Estrogen receptor binding
• Estrogen signaling
• Estrogen metabolism
• Estrogen driven cancers
THE HUMAN
ESTROBOLOME
The bacterial composition of the Estrobolome
is affected by host factors such as
Age
Ethnicity
Lifetime Environmental Influences
Diet
Alcohol
Antibiotic Use
Biosci Microbiota Food Health. 2016; 35(2): 97–103.
A comparative study of bifidobacteria in human babies and adults
Shadi KHONSARI, et al
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HUMAN ESTROBOLOME
Diversity of Microbiome
& Breast Cancer
Less diverse fecal microbiome in
post menopausal women
newly diagnosed with ER+ breast cancer
JNCI J Natl Cancer Inst (June 2015) 107(8): djv147
Investigation of the Association Between the Fecal
Microbiota and Breast Cancer in Postmenopausal
Women: a Population-Based Case-Control Pilot Study
James J. Goedert, et al
Adiposity, Obesity & Breast Cancer
Adiposity is linked to higher circulating estrogens
and increased risk of breast, ovarian and endometrial cancers
Adiposity induces Insulin Resistance, increases IGF-1 and
Suppresses Hepatic Binding Proteins
Increasing Free Unbound Bioavailable Circulating Estrogens
Insulin is a growth factor for Tumor Cells
Tumor Cells Exhibit More Insulin Receptors Than Normal Cells
Annu Rev Med. 2015;66:297-309.
Obesity and cancer: local and systemic mechanisms.
Iyengar NM1, Hudis CA, Dannenberg AJ.
3 Modifiable Microbial Biotransformations
Influencing Cancer Prevention & Treatment
1. De-Conjugation: Reversal of Liver Detoxification by
Microbial Deglucuronidation Enzyme β-
glucuronidase
2. Production of Toxic Secondary Bile Acids by
Microbial Dehydroxlyation Enzyme 7-α-dehydroxylase
(CYP7A1)
3. Production of Butyrate from Dietary Fiber to
AcetylCoA to Butyrate by Butyrogenic Pathway
(6 microbial enzymes)
Microbiome and Malignancy
Plottel, Claudia S. et al.
Cell Host & Microbe. Volume 10 , Issue 4 , 324 – 335 October 2011
THE ESTROBOLOME and
ITS SWITCH
Cell,Host, Microbe
2011 Oct 20; 10(4):324-335
MICROBIAL
BIOTRANSFORMATION
Deglucuronidation of Estrogens
by beta-glucuronidase enzyme
Reversal of Liver Detoxification
from
Kwa,Plottel,
Blaser,
Adams 2016
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Microbial Transformation
of Estrogen Metabolites
Estrogen Glucuronidation
• Estrogens are metabolized and conjugated in
the liver via glucuronidation resulting in
glucuronides which are not ligands and do not bind
to estrogen receptors
• Estrogens are conjugated with glucuronic acid
and made more hydrophilic to allow excretion
via bile or urine
• Glucuronides are excreted from the liver into the
bile and later from the body in the stool
Reversal of Liver Detoxification
Intestinal Deconjugation by
Bacterial Beta-Glucuronidase
SYSTEMIC ENTERO-HEPATIC CIRCULATION
Glucuronidation
Liver
Conjugation
Small Intestine
De-Glucuronidation
Large Intestine
De-Conjugation
by
b-glucuroindase
• Bacterial beta-glucuronidase enzyme
deconjugates glucuronic acid from estrogen
reversing hepatic detoxification
• Estrogens are now able eligible for re-uptake
and recirculation
• Beta-glucuronidase is produced in increased
amounts with dysbiotic intestinal ecology
Bile
Transport
Bloodstream
Bile
Transport
Glob Adv Health Med. 2014 May; 3(3): 33–43.
Elevated Levels of Circulating Estrogens
• Deconjugation >>>Enterohepatic Recirculation of
Estrogens by bacterial glucuronidase
• Circulating Sex Hormone concentrations are strongly
associated with higher concentrations of circulating
estrogens and established risk factors for breast cancer
• Fecal beta-glucuronidase is inversely correlated to with
fecal total estrogens, both conjugated and unconjugated
• Intestinal microbial richness as well as betaglucuronidase
influence levels of non-ovarian estrogens
via enterohepatic circulation
Enteric Microbes and Enterohepatic
Circulation of Estrogens
• A woman's lifetime burden of estrogen exposure may
reflect the functioning of her estrobolome influencing
development of estrogen driven neoplasms
• An estrobolome rich in genes encoding enzymes
favoring deconjugation promotes reabsorption of
free estrogens that contribute to the hosts total
estrogen burden
• Suppression of deconjugation leads to increased
estrogen excretion
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Hormone-dependent breast,
ovarian, and endometrial cancer
• The gut microbiome modulates estrogen metabolism
and contributes to the proportion of re-circulated and
excreted estrogen and estrogen metabolites
• Reduction in the population of specific gut bacteria in
humans causes increased fecal excretion of conjugated
estrogens and decreases in urinary estrogens
• Deconjugation may result in greater reabsorption of
free estrogens, & development of estrogen-driven
cancers such as breast, ovarian, and endometrial
cancers.
Clin Epigenetics. 2015; 7: 112. Published online 2015 Oct
16. doi: 10.1186/s13148-015-0144-7
PMCID: PMC4609101
Influences of diet and the gut microbiome on epigenetic
modulation in cancer and other diseases
Bidisha Paul, Stephen Barnes, Wendy Demark-Wahnefried,
Casey Morrow, Carolina Salvador, Christine Skibola, and
Trygve O. Tollefsbolcorresponding author
Fundamental changes
in cultural traditions
and socio-economic
status have affected
the nutritional status
of humans worldwide,
altering microbial
communities in
unpredictable and
possibly harmful ways
(Lozupone et al., 2012).
Dysbiosis
Dysbiosis is the disturbed microbiome
ecology secondary to host diseases, medications,
diet and genetic conditions often leading to
abnormalities of the host immune system.
Non-modifiable factors such as age and genetic
mutations disrupt the microbiome
Modifiable factors such as diet and use of
antibiotics and lifestyle may also lead to profound
disruptions
Systemic Effects of Dysbiosis
Initiation of Cancer
Dysbiosis of the microbiota seems to be an
important factor in determining whether the
immune system contributes or protects
against the initiation of cancer.
Cell. 2014 Mar 27; 157(1): 121–141.
Role of the Microbiota in Immunity and inflammation
Yasmine Belkaid and Timothy Hand
Dysbiosis may lower circulating lymphocytes, and
increase neutrophil to lymphocyte ratio, which is
associated with decreased survival in women with breast
cancers. (NLR > 4.0 poor prognosis)
Dysbiosis plays a role in the recycling of estrogens
via the entero-hepatic circulation, increasing
estrogenic potency in the host, which is another leading
cause of breast malignancy.
Dysbiosis causes local and distant increases in
inflammation and inflammatory cytokines
ISRN Oncol. 2013 Sep 25;2013:693920
Evolving concepts: how diet and the intestinal microbiome act as
modulators of breast malignancy. Shapira I, Sultan K, Lee A, Taioli E.
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Dietary
Influences on
Microbiome
Key Nutrient Factors
Vitamin D3
Vitamin A-Retinoic Acid
Folate
Fatty Acids
Phytophenols
Sulphoraphanes
Dietary Fiber
PreBiotics
Probiotics
Dietary Influences on Microbiome
• The diet has a profound and highly dynamic impact
on the composition and function of the microbiota.
• Multi-directional interaction exists between the diet,
immune system and commensal microflora.
• The immune system is not only controlled by its
symbiotic relationship with the microbiota but is also
exquisitely sensitive to the nutritional status of the
host.
Dietary Interventions for
Lowering Beta-Glucuronidase
Plant Based Vegetarian Diet or plant based diet low in
animal proteins. High meat diets increases BG
Vegetarian diets are associated with reduced
concentrations of Clostridial cluster XIVa bacteria
Raw Vegan Diet Change from standard diet rapidly
and significantly reduces BG activity
Avoidance of Heterocyclic Amines from Charred
Grilled Animal Proteins plus ingestion of Lactobacillus
and Bifidobacterium
Lower Incidence of Breast Cancer
in Vegetarian Women
• Vegetarian women excrete 2 to 3 times more
estrogens in feces than do omnivores
• Omnivores have about 50% higher mean plasma level
of unconjugated estrone and estradiol than vegetarians
• In vegetarians a greater amount of the biliary estrogens
escape reabsorption and are excreted with the feces
Cancer Res. 1981 Sep;41(9 Pt 2):3771-3. Effect of diet on excretion of
estrogens in pre- and postmenopausal women. Goldin BR, et al
Dietary Interventions for
Lowering Beta-Glucuronidase
• BG is induced by a high pH which is also a
risk for colorectal cancer
• BG is increased in high fat high protein diets
• BG is decreased in high fiber diets
Daily Dietary Interventions for
Lowering Beta-Glucuronidase
INCLUDE
Cultured or Fermented dairy or non-dairy products
(condiment sized portion 1-2 oz)
Cruciferous Vegetables (1-3 1 cup servings/d)
Foods High in Soluble PreBiotic Fiber (1-3 servings/day)
A Multi-Species Probiotic Supplement with L.GG
(1 -2 caps -10-25 billion colony forming units CFU)
Scutellaria baicalensis Huang Qin Root
rich in BG Inhibitor baicalin (500mg--3 g/day)
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Dietary Interventions for
Lowering Beta-Glucuronidase
Traditional Fermented Foods (condiment)
Sauerkraut, Kim Chee, Cultured Olives
Cultured Goats and Sheeps Milk Products
Probiotic Lactobacillus plantarum plus (1-2 caps)
Prebiotic Fructo-Oligo-Saccharides (FOS) (1 cap)
onion, chicory, garlic, asparagus, banana, artichoke
Black Currant Extract Powder or Concentrate
or "First Leaf" formula 500mg-2g/day
Contains black currant ext.powder, lactoferrin, lutein
Reduces colon ph,
Significantly increases Lactobacilli and Bifidobacteria
Decreases Clostridium and Bacterioides
Dietary Interventions for
Lowering Beta-Glucuronidase
Traditional Fermented Drinks
Rich in Healthy Microbes
¼ - 1 cup/day
Beet Kvaas (Eastern Europe)
Kombucha (East Asia)
Sweet Tea + Kombucha starter
Kanji (India)
Beets, Carrots, Mustard Seed
Kefir (Eastern Europe)
Milk or Milk Substitute + Kefir Grains
Dietary Influences on Microbiome
A Healthy Diet is Crucial to the Establishment and
Proliferation of Healthy Bacteria
Pre-Biotics-Soluble Fibers: Jerusalem artichokes,
chicory, onions, leek, shallots, asparagus, beetroot,
fennel, peas, cabbage, nuts and seeds (3
servings/day)
Breast milk an amazing source of natural prebiotic
substances. Baby picks up bacteria from the
mother's vaginal canal and then gets prebiotics
nourishment for the bacteria from breast milk.
Sulphoraphanes
Glucosinolates
Isothiocyanates
1-3 1 cup servings vegetables daily
500-1000 mg Broccoraphanin/day
200-400 mg Di-Indole-Methane/day
Cancer J. 2014 May-Jun; 20(3): 170–175.
Diet, the Gut Microbiome, and Epigenetics
Meredith A, et al
Microbial metabolism of
glucosinolates to isothiocyanates
• Bacteria play a critical role in converting
glucosinolates to isothiocyanates
• Glucosinolates are converted into isothiocyanates
(ITC) by either the plant myrosinases, or bacterially
produced thioglucosidases.
• Cooking cruciferous vegetables deactivates the plant
myrosinases
Front Nutr. 2016; 3: 24.
Bioavailability of Glucosinolates and Their
Breakdown Products: Impact of Processing
Francisco J. Barba, et al
After ingestion, glucosinolates could be partially absorbed
in their intact form through the gastrointestinal mucosa.
The largest fraction is metabolized in the gut lumen
When cruciferous are cooked before consumption,
myrosinase is inactivated and glucosinolates transit to
the colon where they are hydrolyzed by the intestinal
microbiota in active forms indole-3-carbinol and diindole-methane.
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Carcinogenesis. 2007;28:1485–1490
Cornblatt BS, Ye L, Dinkova-Kostova AT, Erb M, et al.
Preclinical and clinical evaluation of sulforaphane
for chemoprevention in the breast.
In a human study
(women undergoing reduction mammoplasty)
it was shown that after
consumption of 200 μmol SFN (35.5mg)
about 2 pmol/mg (0.355 ng/mg)
SFN was detected in the breast tissue suggesting
its availability at the tumor site
Nutrient deficiencies can also influence
commensal communities
Nutrient
Influences on
Microbiome
Vitamin A-Retinoic Acid
Vitamin D3
Folate
Omega- 3 Fatty Acids
Phytophenols
Fiber
PreBiotics
Probiotics
Downregulation of Th17 cells in the small
intestine by disruption of gut flora in the absence of
retinoic acid. Cha, H.R, et alJ. Immunol. 2010; 184:
6799–6806
Vitamin A
5,000-20,000 iu/d
The essential micronutrient
Vitamin A that is required for the
induction of protective immunity
has also profound effects on the
composition of the microbiota
Tissue-specific factors such as
Vitamin A, contribute to the
regulatory specialization of
mucosal dendritic cells which are
an integral part of local gut
immunity
Vitamin D and
Upper GI Microbiome
2K-10K iu/day
Vitamin D3 supplementation changed the gut
microbiome in the upper GI tract
(gastric corpus, antrum, and duodenum) resulting in a
reduction in opportunistic pathogens and an increase
in bacterial richness.
(at a serum level of 25 OH Vit D3 55.2)
Eur J Nutr. 2016; 55: 1479–1489. Effects of high doses of vitamin D3 on mucosaassociated
gut microbiome vary between regions of the human gastrointestinal
tract, Mina Bashir, et al
Role of the Microbiota in Immunity and Inflammation
Belkaid, Yasmine et al. Cell , Volume 157 , Issue 1 , 121 – 141
March 2014
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Understanding the Impact of
Omega-3 Rich Diet on the Gut Microbiota
600 mg of Omega-3 daily
• Significant changes in the gut
microbiota in bacterial populations
associated with health
• Increases in butyrate-producing
bacteria
Case Rep Med. 2016; 2016: 3089303 Blanca S. Noriega,
Marcos A. Sanchez-Gonzalez * Daria Salyakina and Jonathan Coffman
Eicosapentanoic Acid and
Gut Microbiota
2g-6g/day
Importantly, we found that EPA-FFA
treatment resulted in the
enrichment of Lactobacillus species in
the gut microbiota
Int J Cancer. 2014 Nov 1;135(9):2004-13. Eicosapentaenoic acid free
fatty acid prevents and suppresses colonic neoplasia in colitisassociated
colorectal cancer acting on Notch signaling and gut
microbiota.Piazzi G, et al
Commensal Bifidobacterium
Enhance Anti-Tumor Immunity
BIFIDOBACTERIA
• Commensal Bifidobacterium-derived signals modulate the
activation of Dendritic Cells and support improved effector
function of tumor-specific CD8+ T cells.
• Beneficial effects and alteration of innate immune function
are observed in multiple tumor settings
• Bifidobacterium interact with host cells that are critical for
modulating Dendritic Cells
Science. 2015 Nov 27;350(6264):1084-9, Sivan, A, et al
Commensal Bifidobacterium promotes antitumor immunity and
facilitates anti-PD-L1 efficacy.
Decline in Bifidobacteria with Aging
Front. Microbiol., 19
August 2016 |
Gut Bifidobacteria
Populations in Human
Health and Aging Silvia
Arboleya, et al
FIBER
DIETARY
FIBER
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Fiber Intake and Breast Cancer
A meta-analysis of large prospective cohort
studies (n = 16 848) showed that
high dietary fiber intake is a protective factor
for breast cancer
(RR = = 0.89; 95% CI: 0.83–0.96)
compared with low intake;
every 10-g/d incremental increase in dietary
fiber intake was associated with a 7%
reduction in risk of breast cancer
FIBER
Recommended
Daily Allowance
The RDA of fiber is 25-30 g/day
modern diet is deficient in
whole grains, fruits and vegetables
nuts and seeds
Americans only average about 15 g per day
A combination of fibers derived from fruits, vegetables,
roots, seeds, and tree extracts. • A good balance of soluble
(prebiotic) and insoluble fibers, with emphasis on soluble fiber
(which is very hard to get from common diets)
• Types of fiber: acacia gum, guar gum, cranberry seed powder,
carrot fiber, inulin, citrus fiber, apple pectin, glucomannan, psyllium
husk, flax, prune
• Free of grains (wheat, oat or ricebran) and legumes (peas, beans or
soy fibers)
▶ gluten and lectin free, low allergenicity
▶ free of phytates (phytate fiber is found in grains, binds minerals
-which interferes with their absorption)
• Has significant antioxidant activity high in polyphenols))
• Negligible caloric value: no significant carbohydrate content Free
of toxic contaminants
• Naturally flavored: no artificial sweeteners, flavors, or colors
2 tsp= 4g =3 g soluble + 1g insoluble fibers
2 – 6 tsp/day (4-12g)
Fiber Intake and Breast Cancer
Increased Excretion of Estrogens and
Decreased Plasma Estradiol Concentrations
• High fecal fiber inhibits absorption of estrogens in the gut
reducing the total body pool of estrogen
• Binding of unconjugated estrogens to fiber in the gut
decreases estrogen reabsorption
Contemp Oncol (Pozn). 2016; 20(1): 13–19.
Diet and risk of breast cancer Manas Kotepui
Healthy Microbiome & Dietary Fiber
15-30g per day
Insoluble Fiber which does not dissolve in water
not a substrate or fuel for enteric microbiota
Soluble Fiber does dissolve in water,
substrate and fuel for enteric microbiota
Resistant Starch
Is not digested in stomach or small intestine, fermented by
enteric bacteria, lowers the ph of the colon
Prebiotic Soluble Fiber
substrate and fuel for colonic bacteria
Foods: jerusalem artichoke, chicory root, onions,
whole grains, bananas, garlic, onions, cabbage,
root vegetables, apples,
beans, legumes asparagus, flax seeds
Prebiotic Supplements
Fructo-Oligosaccharides
Inulin Acacia Psyllium
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Healthy Microbiome & Dietary Fiber
Higher Intake of Soluble Dietary Fiber
Reduces Risk of
ER- Breast Cancer in Premenopausal Women
Eur J Nutr. 2013 Feb;52(1):217-23.
Dietary fiber intake and risk of breast cancer by
menopausal and estrogen receptor status. Li Q1,et al
Resistant Starch
not digested in stomach or small intestine
fuel and substrate for enteric bacteria
contributes to production of
short chain fatty acids (SCFA) such as butyrate
Foods: seeds, cashews, unprocessed whole grains, legumes,
raw or cooled potatoes, raw green bananas, raw oats
Resistant Starch Products
Unmodified Potato Starch, Plantain Flour
contributes to insulin sensitivity, satiation,
weight loss and colon health
Effects of
PhytoEstrogens
Polyphenols and Microbiome
Two Way Gut Microbiota Polyphenol Interactions
Dietary polyphenols and their metabolites modulate
gut microbial balance through
stimulation of the growth of beneficial bacteria
including Lactobacillus and Bifidobacterium
and inhibition of pathogen bacteria
exerting pre-biotic like effects
Polyphenols depend upon gut microbiota
for their transformation to active metabolites
which positively influence inflammation, carcinogenesis,
apoptosis, cell proliferation and modulation of enzymes
The Role of the Enteric Microbiome
in Phytochemical Bioactivity
Orally ingested natural products can be biotransformed
to their metabolites by microbiota in the gut.
Intestinal microbiota may play an important role in
mediating the metabolism and bioactivity
Phytochemicals such as ginsenosides, hesperidin,
baicalin, daidzein and glycyrrhizin exert some of their
therapeutic effects through gut microbiota-mediated
bioconversion”
Bio-Activation of Phytoestrogens
The ROLE OF INTESTINAL BACTERIA
Phytoestrogens = Polyphenols
• Similar to human estrogens
• Found in plants or derived from plant precursors
• Structurally similar to endogenous estrogens
• Metabolized by intestinal microbiota to bioavailable forms
• Act like SERMs (Selective Estrogen Receptor Modulators)*
• Both estrogenic and anti-estrogenic activity
• Function as “estrogen mimics” binding to ERa and ERb
work like estrogen at low doses & block estrogen at
high doses
*SERM an agent that activates some estrogen receptors (ER)
and not others, thereby having estrogenic effects on some
target tissues without affecting other tissues with ER
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Bio-Activation of Phytoestrogens
The ROLE OF INTESTINAL BACTERIA
Phytoestrogen Metabolites = Entero-phytoestrogens
Phytoestrogen metabolites are more bioavailable
act as SERMS
Found in high concentrations in:
Soy Isoflavones genistein, daidzein -> Equol
Flax Seed Lignans ->Enterolignans, Enterodiol, Enterolactone
Berry, Nut and Seed Elligitanins, Ellagic Acid -> Urolithins
Phytoestrogen Metabolites Effects
anti-inflammatory anti-oxidant
anti-proliferative pro-apoptotic
Bio-Activation of Phytoestrogens
THE ROLE OF INTESTINAL BACTERIA
DIETARY PHYTOESTROGENS
Bioavailablity Bioactivity Health Effects
Strongly determined by
Intestinal Bacteria of Each Individual
Western Diet: < 1.0 mg/day
Asian Diet: 25-100 mg/day
Lower incidence of
Osteoporosis, Breast Cancer
Menopausal Symptoms
Bio-Activation of Phytoestrogens
The ROLE OF INTESTINAL BACTERIA
Phytoestrogen Metabolites: “Entero-phytoestrogens”
Phytoestrogen metabolites are more bioavailable
Found in high concentrations in:
Soy Isoflavones genistein, daidzein -> Equol
Flax Seed Lignans ->Enterolignans, Enterodiol, Enterolactone
Berry, Nut and Seed Elligitanins, Ellagic Acid -> Urolithins
Phytoestrogen Metabolites Effects
anti-inflammatory anti-oxidant
anti-proliferative pro-apoptotic
Bio-Activation of Phytoestrogens
THE ROLE OF INTESTINAL BACTERIA
EQUOL
Intestinal Metabolite of Daidzein Isoflavone from Soy
• Produced exclusively by intestinal bacteria
• Approximately 1/3 of humans harbor daidzein transforming
microbiota
• Strong affinity for ERa and Erb
• Protective against estrogen mediated disorders of breast
(Low, et al, 2005, Hardy, Abrams, Messina, 2010)
• Androgen antagonist: Protective against 5-a-OH di-hydrotestosterone
mediated prostate disorders (Lund et al, 2011,
Messina et al, 2006)
• Potent lipophilic and hydrophilic anti-oxidant activity
Bio-Activation of
Phytoestrogens
Soy Foods and Breast Cancer
J NUTR. 2010 JULY; 140(7) 1369S-72S REVIEW: EMERGING
RESEARCH ON EQUOL AND CANCER, LAMPE, JW
CURR PROTEIN PEPT SCI 2017 JAN 11 EPUB
MOLECULAR MECHANISMS OF ANTI CANCER EFFECTS OF
PHYTOESTROGENS IN BREAST CANCER. HSIEH, HSU, HUANG,
ET AL
ONCOLOGY 2013 MAY;27(5):430-7.
IT'S TIME FOR CLINICIANS TO RECONSIDER THEIR
PROSCRIPTION AGAINST THE USE OF SOYFOODS BY BREAST
CANCER PATIENTS.
MESSINA M, CAAN BJ, ABRAMS DI, HARDY M, MASKARINEC G.
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Soy Foods and Breast Cancer
• Soy consumption tended to reduce recurrence to a
greater extent in tamoxifen users than in non-users
• Soy intake did not affect the efficacy of tamoxifen
• Soy intake enhanced the efficacy of anastrozole (an
aromatase inhibitor)
Oncology 2013 May;27(5):430-7. It's time for clinicians to reconsider their
proscription against the use of soy foods by breast cancer patients.
Messina M1, Caan BJ, Abrams DI, Hardy M, Maskarinec G
Soy Foods and Breast Cancer
• Lack of human evidence for adverse effects, soyfoods
can be part of a healthy lifestyle for breast cancer
patients and survivors
• Allow soyfood use by patients for whom soyfoods
already represent a normal part of their diet (mainly
vegetarians and patients of Asian ethnicity) and not to
discourage other survivors from moderate
consumption.
• This recommendation is consistent with the position of
the American Cancer Society and the American
Institute for Cancer Research.
Oncology 2013 May;27(5):430-7. It's time for clinicians to reconsider their
proscription against the use of soy foods by breast cancer patients.
Messina M1, Caan BJ, Abrams DI, Hardy M, Maskarinec G.
Soy Foods and Breast Cancer
SOY INTAKE AND THE BREAST CANCER SURVIVOR
An analysis in 9514 breast cancer survivors who were
followed for 7.4 y found that higher post-diagnosis soy
intake was associated with a significant 25%
reduction in tumor recurrence.
Clinical and epidemiologic data indicate that adding soy
foods to the diet can contribute to the health of
breast cancer survivors
Am J Clin Nutr July 2014 vol. 100 no. Supplement 1 423S-430S Soy foods,
isoflavones, and the health of postmenopausal women1,2,3 Mark Messina
Bio-Activation of Phytoestrogens
THE ROLE OF INTESTINAL BACTERIA
ENTERODIOL and ENTEROLACTONE
Intestinal Metabolites of Flax Seed Lignans
Usual dose 5-13 grams flaxseed per day
(also Sesame Lignans)
1-2 Tab/day
• Lipophilic and hydrophilic antioxidant activity
• Bind to and complete with estradol at ERa and ERb
• Act as SERMs by Modulating 17-b-estradiol activity
• Alter estrogen receptor expression (inhibit transcription factors)
• Decrease plasma estradiol and estrone sulfate in post menopausal
women
• Antiproliferative activity
Bio-Activation of Phytoestrogens
THE ROLE OF INTESTINAL BACTERIA
Crit Rev Food Sci Nutr: 2016 56:11 1826-1843 BioActivation of
Phytoestrogens: Intestinal and Bacterial Health, Landete, Arques,
Medina, et al
J Agric Food Chem. 2016 54 1611-1620 Urolithins, Ellagic Acid
Derived Metabolites Produced by Human Colonic Microflora,
Exhibit Estrogenic and Anti-Estrogenic Activities, Larrosa,
Gonzalez, , et al
J. Ethnopharm. 2016 Feb 17: 179:253-64 Could gut microbiota
reconcile oral bioavailability conundrum of traditional herbs? Chen,
Wen, Jiang, et al
Bio-Activation of Phytoestrogens
THE ROLE OF INTESTINAL BACTERIA
UROLITHINS A and B:
Intestinal Metabolites of Elligitanins and Ellagic Acid
from strawberries, raspberries, walnuts, pomegranates,
oak-aged wines
• Anti-Oxidant
• Pro-Apoptotic
• Anti-Proliferative
• Antagonize growth promotion effect of 17-b-estradiol
• Affinity for prostate, breast, colon, intestine
(Gonzalez, Barrio, et al 2005, 2010)
I cup berries, 1-2 oz walnuts
1 cup i
6 oz wine “Reds” Concentrate Powders
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Bio-Activation of
Phytoestrogens
EUR J NUTR. 2017 MAR;56(2):831-841 ANTIPROLIFERATIVE ACTIVITY OF THE
ELLAGIC ACID-DERIVED GUT MICROBIOTA ISO-UROLITHIN A AND
COMPARISON WITH ITS UROLITHIN A ISOMER: THE ROLE OF CELL
METABOLISM. GONZÁLEZ-SARRÍAS, NÚÑEZ-SÁNCHEZ M, GARCÍA-VILLALBA
R, TOMÁS-BARBERÁN FA, ESPÍN JC.
J NAT PROD. 2016 DEC 23;79(12):3022-3030 DIFFERENCES IN METABOLISM
OF ELLAGITANNINS BY HUMAN GUT MICROBIOTA EX VIVO CULTURES.
PIWOWARSKI JP, GRANICA S, STEFAŃSKA J, KISS AK.
POMEGRANATE ELLAGITANNINS. IN: BENZIE IFF, WACHTEL-GALOR S,
EDITORS. HERBAL MEDICINE: BIOMOLECULAR AND CLINICAL ASPECTS.
2ND EDITION. BOCA RATON (FL): CRC PRESS/TAYLOR & FRANCIS; 2011.
CHAPTER 10.HEBER, D.
Effects of
Phytochemicals
Materia
Medica
Inhibition of Glucuronidase
Plant derived Glucuronides inhibit beta-glucuronidase.
Black Currant Extract
Ribes Nigrum
Sources of Glucuronides (500 mg-3 g/day)
Baicalin, Wogonoside (Scutellaria baicalensis Huang
Qin)
Luteolin-3'-glucuronide (Rosmarinus Officinalis
Rosemary)
Glycyrrhizin (Glycyrrhiza glabra Licorice Root Gan Cao)
Other Glucuronide Rich Plants
Perilla
Salvia off Sage spp
Anthemis spp Chamomile
Lycopus lucidus Bugleweed
Phytother Res. 2014 Mar;28(3):416-22. Evaluation of the effect of
blackcurrant products on gut microbiota and on markers of risk for
colon cancer in humans. Molan AL et
Healthy Microbiome & Phytophenols
Curcuminoids (1-6g/day)
are degraded to their active metabolites
by human fecal microbes
Curcumin > tetrahydrocurcumin
Demethoxycurcumin > dihydroferulic acid
Bis-demethoxycurcumin >
1-(4-Hydroxy-3-methoxyphenyl)-2-propanol
Healthy Microbiome & Phytophenols
Curcumin increased bacterial richness, prevented
age-related decrease in alpha diversity, increased
the relative abundance of Lactobacillales
(murine study)
Int J Food Sci Nutr. 2015;66(7):790-6..
The degradation of curcuminoids
in a human faecal fermentation model.
Tan S1,2,3, Calani L4, Bresciani L4, Dall'asta M4, Faccini A5,
Augustin MA1, Gras SL2,3,6, Del Rio D4.
Inflamm Bowel Dis. 2015 Nov;21(11):2483-94. The Role of Curcumin in
Modulating Colonic Microbiota During Colitis and Colon Cancer Prevention.
McFadden RM, et al
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Bio-Activation of Panax Ginseng
THE ROLE OF INTESTINAL BACTERIA
1-3 g/day
Ginsenoside Rg3: an intestinal metabolite of Panax Ginseng root
biotransformed by enteric microbiota demonstrates
Anti-Angiogenic Activity on pulmonary, gastric, ovarian cancers
Int J Pharm 2008 363:1-25 The gastrointestinal microbiota
as a site for biotransformation of drugs Sousa, Paterson, et al
Science 2012 : 336-1253-55 Is it time for a metabologenomic basis of
therapeutics? Haiser, Turnbaugh,et al
J. Ethnopharm. 2016 Feb 17: 179:253-64 Could gut microbiota reconcile oral
bioavailability conundrum of traditional herbs? Chen, Wen, Jiang, et al
Healthy Microbiome & Phytophenols
• Bioavailability and effects of polyphenols greatly depend on
their transformation by components of the gut microbiota.
• Phytochemicals and their metabolic products may also inhibit
pathogenic bacteria while stimulate the growth of beneficial
bacteria, exerting prebiotic-like effects.
• Intestinal microbiota is both a target for nutritional
intervention and a factor influencing the biological activity of
other food compounds acquired orally.
The Reciprocal Interactions between Polyphenols and
Gut Microbiota and Effects on Bioaccessibility.
Ozdal T, Sela DA, Xiao J, Boyacioglu D, Chen F, Capanoglu E.
Nutrients. 2016 Feb 6;8(2):78. doi: 10.3390/nu8020078. Review.
Summary
Summary
• A woman's lifetime burden of estrogen exposure
may reflect the metabolic functioning of her Estrobolome
(the aggregate of enteric bacteria that metabolize
estrogens)
• Enteric Bacteria influence enterohepatic circulation
of estrogens
• The composition of the Estrobolome is linked to
the enteric microbiome and estrogen driven cancers
• Bacterial Beta Glucuronidase deconjugates conjugated
estrogen metabolites reversing liver detoxification and
estrogen metabolite excretion
• Dysbiotic intestinal ecology produces increased amounts of
beta-glucuronidase in the Estrobolome
• Entero-PhytoEstrogens, intestinal metabolites activated by
microbiota, act as SERMS, exerting both estrogenic and
anti-estrogenic effects
Summary - Interventions
from
Kwa,Plottel,
Blaser,
Adams 2016
• Diet Plant Based, Soluble & Insoluble Fiber, Resistant Starch,
Fermented Foods, Cruciferous Vegetables, Garlic, Onions,
Legumes, Beans, Colorful Fruits and Vegetables Rich in
Polyphenols
• Functional Foods Resistant Starch Powder, Flax Seeds,
Psyllium, Greens or Reds Powders (fruit and vegetable
concentrates as a source of polyphenols)
• Supplements Prebiotics, Probiotics, Vitamin D3, Vitamin A,
Methyl-Folate, Omega 3 Fatty Acids
• Nutraceuticals & Botanicals: Scutellaria baicalensis,
Berberine, Black Currant Extract Powder, Curcumin, Rosemary,
Licorice Root, Panax Ginseng
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Primary References
Microbiome and Malignancy
Plottel, Claudia S. et al.
Cell Host & Microbe , Volume 10 , Issue 4 , 324 - 335
Review Article:Evolving Concepts: How Diet and the
Intestinal Microbiome Act as Modulators of Breast Malignancy
Juliana Shapira, Keith Sultan, Annette Lee, and Emanuela Taioli
ISRN Oncology Volume 2013 Article ID 693920 10 pages
The Intestinal Microbiome and Estrogen Receptor-Positive Female
Breast Cancer.
Kwa M, Plottel CS, Blaser MJ, Adams S.
J Natl Cancer Inst. 2016 Apr 22;108(8)
Diet, the Gut Microbiome, and Epigenetics
Meredith A, et al
Cancer J. 2014 May-Jun; 20(3): 170–175.
BIG
IDEA
Host-Microbiome Interaction and Cancer:
Potential Application in Precision Medicine
Front Physiol. 2016 Dec 9;7:606 Contreras AV, et al
THANK YOU!
Nalini Chilkov, L.Ac., O.M.D, Founder
American Institute of Integrative Oncology
and Education
Research
drchilkov@aiiore.com
www.aiiore.com
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ReneeNewberryPhotography.com
310 279 3295
reneenewberryphotography@gmail.com
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Dr. Jennifer Bahr, ND - President
Dr. Dhurga Reddy, ND - Vice President
Dr. Aliza Cicerone, ND, FABNO - Treasurer
Dr. Lilian Au, ND - Secretary
Dr. Heather Barrett, ND
Dr. Laura Enfield, ND
Dr. Teray Garchitorena Kunishi, ND
Dr. Chris Holder, ND
Dr. Sandy Le, ND
Dr. Sarah Murphy, ND
Dr. Ann Marie Nguyen, ND, LAc
Dr. Rachel Rozelle, ND
Dr. Aumatma Shah, ND
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The California Naturopathic Doctors Association (CNDA) is a professional membership
association representing California naturopathic doctors (NDs). The CNDA is incorporated
as a California mutual benefit 501(c)(6) nonprofit corporation.
Vision: A healthy California
Mission: To advance the field of naturopathic medicine and make integrative
healthcare accessible to all Californians.
Objectives:
1. Increase positive visibility and perception of naturopathic medicine.
2. Ensure organizational and financial sustainability and growth.
3. Proactively address relevant legislative and regulatory issues.
4. Support ND’s for successful clinical practice and healthcare leadership.
5. Develop a network of positive relationships.
The CNDA Team
Executive Director
Kathy Konst
executive@calnd.org
Events Coordinator
Karen Berzanski
admin@calnd.org
Membership & Legislative Affairs Coordinator
Frances McAdam
coordinator@calnd.org
www.calnd.org
310-670-8100
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