World Journal of Gastrointestinal Pathophysiology

World Journal of 

Gastrointestinal Pathophysiology 

World J Gastrointest Pathophysiol 2011 October 15; 2(5): 65-87 

www.wjgnet.com 

ISSN 2150-5330 (online)

Contents Bimonthly Volume 2 Number 5 October 15, 2011 

EDITORIAL 

REVIEW 

AUTOBIOGRAPHY OF 

EDITOPIAL BOARD 

MEMBERS 

65 �� 

��d �� 

De la Roca-Chiapas JM, Cordova-Fraga T 

72 ��d��d ��d��d �� 

�� 

d��d�� 

Akiho H, Ihara E, Motomura Y, Nakamura K 

82 �� d ��d �� d ��d �� 

��b��d �� d�� 

Vinken M 

WJGP|www.wjgnet.com I 

October 15, 2011|Volume 2|Issue 5|

Contents 

ACKNOWLEDGMENTS 

APPENDIX 

ABOUT COVER 

AIM AND SCOPE 

FLYLEAF 

EDITORS FOR 

THIS ISSUE 

NAME OF JOU�NAL 

World Journal of Gastrointestinal Pathophysiology 

LAUN�H DATE 

April 15, 2010 

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Volume 2 Number 5 October 15, 2011 

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World Journal of Gastrointestinal Pathophysiology (World J Gastrointest Pathophysiol, WJGP, online 

ISSN 2150-5330, DOI: 10.4291), is a bimonthly, open-access, peer-reviewed journal 

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WJGP specifically covers growth and development, digestion, secretion, absorption, 

metabolism and motility relative to the gastrointestinal organs, as well as immune and 

inflammatory processes, and neural, endocrine and circulatory control mechanisms 

that affect these organs. This journal will also report new methods and techniques in 

gastrointestinal pathophysiological research. 

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doi:10.4291/wjgp.v2.i5.65 



© 2011 Baishideng. All rights reserved. 

Biomagnetic techniques for evaluating gastric emptying, 

peristaltic contraction and transit time 

Jose María De la Roca-Chiapas, �eo�oro �eo�oro Cor�o�a-�ra�a 

Cor�o�a-�ra�a 

Jose María De la Roca-Chiapas, Division of Health Sciences, 

Department of Psychology, University of Guanajuato, Campus 

Leon, C.P. 37670, Leon, Guanajuato, Mexico 

�eo�oro Cor�o�a-�ra�a, Department of Physical Engineering, 

University of Guanajuato, Campus Leon, 37150 Leon, Guanajuato, 

Mexico 

Author contributions: De la Roca-Chiapas JM and Cordova- 

Fraga T designed the study, wrote the manuscript, conducted 

research and assisted with data analysis. 

Supporte� by PROMEP Grant Ugto-PTC-183 and Ugto-CA-37 

Correspon�ence to: Jose María De la Roca-Chiapas, �hD, �hD, 

Division of Health Sciences, Department of Psychology, University 

of Guanajuato, Blvd. Puente Milenio 1001, Fraccion del 

Predio San Carlos, C.P. 37670, Leon, Guanajuato, 

Mexico. josema_delaroca@yahoo.com.mx 

�elephone: +52-477-2674900-3664 �ax: +52-477-2674900-3664 

Recei�e�: March 3, 2011 Re�ise�: August 31, 2011 

Accepte�: September 7, 2011 

�ublishe� online: October 15, 2011 

Abstract 

Bioma�netic techniques were use� to measure motility 

in �arious parts of the �astrointestinal (GI) tract, particularly 

a new technique for �etectin� ma�netic markers 

an� tracers. A coil was use� to enhance the si�nal from 

a ma�netic tracer in the GI tract an� the si�nal was 

detected using a fluxgate magnetometer or a magnetoresistor 

in an unshiel�e� room. Estimates of esopha- 

�eal transit time were affecte� by the position of the 

subject. �he repro�ucibility of estimates �eri�e� usin� 

the new bioma�netic technique was �reater than 85% 

an� it yiel�e� estimates similar to those obtaine� usin� 

scinti�raphy. �his technique is suitable for stu�yin� the 

effect of emotional state on GI physiolo�y an� for measurin� 

GI transit time. �he bioma�netic technique can 

be use� to e�aluate �i�esta transit time in the esopha- 

�us, stomach an� colon, peristaltic frequency an� �astric 

emptyin� an� is easy to use in the hospital settin�. 

© 2011 Baishi�en�. All ri�hts reser�e�. 

WJGP|www.wjgnet.com 

Key words: Bioma�netic techniques; Ma�neto�astro�raphy; 

Gastric emptyin�; Scinti�raphy; �eristaltic contractions 

Peer reviewers: Daniel Keszthelyi, Dr., Institute of Maastricht, 

PO Box 5800, Maastricht 6202 AZ, The Netherlands; Stelios F 

Assimakopoulos, Dr., Department of Internal Medicine, University 

Hospital of Patras, Patras 26504, Greece; Angelo Izzo, Professor, 

Department of Experimental Pharmacology, University of 

Naples Federico II, via D Montesano 49, 80131 Naples, Italy 

De la Roca-Chiapas JM, Cordova-Fraga T. Biomagnetic techniques 

for evaluating gastric emptying, peristaltic contraction and 

transit time. World J Gastrointest Pathophysiol 2011; 2(5): 65-71 

Available from: URL: http://www.wjgnet.com/2150-5330/full/ 

v2/i5/65.htm DOI: http://dx.doi.org/10.4291/wjgp.v2.i5.65 

INTRODUCTION 

EDITORIAL 

Gastrointestinal (GI) diseases include gastritis [1] , gastroesophageal 

reflux [2,3] , dyspepsia [4-6] , irritable bowel syndrome 

[4,7-9] and gastritis associated with cancer [10] , inflammation 

[11] , emotional state [12] , obstruction [13] , Helicobacter 

pylori infection [14,15] and gastroenteritis [1,16] . If people are 

susceptible to these diseases and dysfunctions [17] , there is 

a high probability that they will undergo clinical diagnosis 

for GI disease at least once during their lifetime. 

The search for ways to diagnose GI diseases and 

define normal gastric activity has generated a variety of 

techniques, some of which are invasive or expose the 

patient to a high dose of ionizing radiation. Nevertheless, 

it is important to point out that they have been used to 

monitor diseases such as diabetic gastroparesis. One of 

these traditional techniques, scintigraphy, is considered 

the gold standard for GI tract disease diagnosis [6,18] . However, 

alternative noninvasive techniques such as the 13C 

octanoic acid [19,20] , superficial electrogastrography [21] , ultrasound 

[22] and biomagnetism are available [12,23-28] . 

65 October 15, 2011|Volume 2|Issue 5|

De la Roca-Chiapas JM et al . Bioma�netic assessment of �astrointestinal tract motility 

The gold standard technique for evaluation and diagnosis 

of diseases of the GI system is scintigraphy [28,29] . 

This is an excellent technique and generates information 

quickly and almost directly. However, it involves ionizing 

radiation. Although exposure to ionizing radiation does 

not have adverse effects if administered in controlled 

doses, it does limit the frequency with which chronic 

patients such as those with diabetes concomitant with 

gastroparesis can be monitored [30] . 

On the other hand, studies on the anatomy and physiology 

of the GI tract indicate that more information is 

required to understand fully this system. In particular, it 

is known that food is propelled down the esophagus by 

peristalsis. Furthermore, the GI system consists of accessory 

organs and the digestive tract that the lumen content 

of the GI tract passes through. The lumen of the GI 

tract passes through the mouth, pharynx, esophagus, 

stomach, small and large intestine, sigmoid colon, rectum 

and anus. The content of the lumen is transported 

through the digestive tract by peristaltic activity [31-33] . The 

GI system is an autonomous system in which the myenteric 

nervous system controls peristaltic activity. Problems 

arise when transit time is impeded in any part of the tract 

by conditions such as diabetes or surgical intervention. 

Biomagnetic assessment of the GI system can be 

conducted using either of two methods. In one, the 

magnetic field generated by the electrical activity of the 

myenteric nervous system is measured. This can be performed 

on any segment of the digestive tract in which 

peristaltic activity is present. In the second method, a 

magnetic tracer or marker is introduced into the GI 

tract and its magnetic field is monitored using an external 

sensor. In the first method, the signal generated is 

in the femtotesla range, detection of which requires a 

magnetometer superconducting quantum interference 

device and a magnetically shielded room [34] . In the second 

method, the markers generate magnetic signal variation in 

the nano- to microtesla range, which can be detected using 

a magnetometer at room temperature. A digital fluxgate 

magnetometer or a magnetoresistor can be used to 

detect the signal and a shielded room is not necessary [34] . 

Recordings obtained using these techniques are similar or 

equivalent to GI system logs obtained using scintigraphy, 

the gold standard. 

As far as we are aware, the first GI system assessments 

were made in the late 1950s and early 1960s [35,36] . However, 

biomagnetic studies on different parts of the body 

only began to proliferate after 1970. It is important to 

note that these early studies involved one of three different 

biomagnetic sources: (1) a magnetic field generated 

generated 

by the movement of ions�� (2) �� a a a magnetic magnetic magnetic field field field created 

created 

created 

by the accumulation of ferromagnetic material in some 

organs of the body�� and (3) �3�� 3�� (3) tracers tracers and and magnetic magnetic mark- mark� mark� mark- 

ers [34-42] . Progress continued using these techniques until 

early 2000. 

Herein, we present a detailed description of how to 

measure the transit time of digesta through the esophagus, 

stomach and colon, and the frequency of peristalsis 


using a biomagnetic technique in which signals from 

magnetic markers or tracers are recorded using a fluxgate 

magnetometer or a magnetoresistor in an unshielded 

laboratory. 

PROCEDURES 

For all the aforementioned measurements, an approximation 

must be made to measure the magnetic dipole, 

which is assumed to be produced by a small magnetic 

source distant from the observer, who is located near to 

the magnetic sensor. The induced magnetic field (B) is 

calculated as follows: 

0 ⎡3r(r ⋅m) 

m ⎤ 

B = 

⎢ 

- 5 3 

4 ⎣ r r ⎥ 

⎦ 

where µ0 is the magnetic permeability, r is the distance 

from source to magnetic sensor, and m is the magnetic 

moment of the magnetic marker. 

It is important to point out that with this biomagnetic 

modality, it is possible to perform the measurements out 

of a magnetic shielding room. This particularity is an additional 

advantage for this technique to be implemented 

in hospitals with a low cost. 

Esophagus 

The human esophagus has an average length of �5 cm 

in adults. The top of the esophagus is connected to the 

pharynx and the bottom of the esophagus is connected 

to the stomach at the cardia. Peristalsis begins in the 

middle of the esophagus, the position at which food arrives 

when it is propelled from the mouth. To our knowledge, 

Daghastanli et al [24] �1998�� were the first to evaluate 

esophageal transit time with biomagnetic techniques�� they 

used food containing tracers and magnetic coils that were 

placed over each end of the esophagus. The standard test 

is nuclear medicine, so they hey also correlated measurements 

using radiotracers and reported that there was a strong 

correlation between measurements made using radiotracers 

and magnetic tracers. Later, Córdova�Fraga et al [25] used 

a cylindrical magnetic marker 3 mm in diameter and 4 mm 

in length and a pair of fluxgate magnetometers 25 cm 

apart �just above the ends of the esophagus�� Figure 1��. 

A particularity of these studies was that transit time was 

measured with the subject in four different positions (0°, 

45°, 90° and 85°) [27] . The transit times so measured were 

consistent with those reported by Daghastanli et al [24] , in 

particular those measured when the subject was at 90° 

�in the vertical position��. Previous work showed that estimates 

of transit time through the esophagus are accurate 

when biomagnetism is used with contrast or magnetic 

markers and sensors at room temperature. 

The advantage of using magnetic markers to measure 

esophageal transit time is that the signal does not have 

to be filtered because the high intensity of the magnetic 

field produced by the magnet results in an excellent signal�to�noise 

ratio. A typical magnetometer configuration 

is shown in Figure 1. In this configuration, two signals are 


Ma�netometer 1 

Ma�netometer 2 

Figure 1 Position of magnetometers used for measuring esophageal transit 

time. 

evident, each associated with magnetometers located at 

the extremities of the esophagus and separated by a predetermined 

distance. As the position from which a signal 

originates can be calculated, the transit time of luminal 

contents through the esophagus can be calculated. We 

demonstrated that esophageal transit times assessed in the 

upright, Fowler’s and the supine positions (90°, 45° and 

0°, respectively�� differed significantly �5.� ± 1.1 s, 6.1 ± 

1.5 s and 23.6 ± 9.� s, respectively�� ANOVA with Tukey’s 

post hoc test). 

Stomach 

The human stomach is a hollow organ in the form of 

a J and is located between the esophagus and the small 

intestine. The former attaches to the stomach at the 

esophageal sphincter in the cardia and the latter attaches 

to the stomach at the pylorus. The average volume of 

the stomach is 150 mL at baseline, reference study in the 

same experiment, and can expand to a volume of 1.5 L 

without causing discomfort. From a physiological standpoint, 

the human stomach is divided into two segments, 

the proximal (upper) and distal (lower) portions. Anatomically, 

it has three sections, the bottom, the body and the 

antrum. When food is ingested and enters the stomach, 

it is stored at the fundus and is mixed by contractions 

initiated by action potentials generated in the pacemaker 

area in the middle of the body. The rings of contraction 

travel down the stomach to the pyloric sphincter 

and force some of the luminal contents at the fundus 

up to the antrum, where it encounters a shock wave that 

contributes to the reduction in particle size necessary 

for it to pass into the duodenum. The rate of passage of 

food from the stomach to the duodenum is a function 

of two processes: peristalsis, which is directly related to 

the frequency of contraction generated by the pacemaker 

area, and gastric emptying, the average time taken for the 

stomach to empty half of the contents of the lumen. 

Both processes are altered by diabetes. 

Both processes can be measured using magnetic tracers 

and a vehicle to deposit them in the gastric segment. 

This can be achieved by diluting � to 5 g of magnetite 

(Fe3O4) powder in 200 mL of yogurt [42,43] or by incorpo- 



Bank of 

capacitors 

�lux�ates 

Figure 2 Magnetic stimulator prototype. 

Electronic 

circuit box 

rating magnetite into a pancake by mixing it with flour [28] . 

When these preparations are consumed, it is assumed 

that the magnetite becomes distributed throughout the 

space occupied by the food in the stomach and that it has 

a random magnetic alignment. Consequently, there is no 

net magnetic signal at this stage and the particles must be 

magnetized to obtain a signal. For this purpose, we recommend 

using a device consisting of two identical coils 

assembled as an array of Helmholtz coils (Figure 2). This 

configuration requires the coils to be on parallel planes 

that share the same axis and to be separated by a distance 

equal to their radius. These coils consist of 60 turns of 

4-gauge (6 mm diameter) copper wire (6 mm diameter). 

The coils are supported by two aluminum pulleys. 

In order to break out the induced electric current, each 

contains two cuts to eliminate the induction of a field 

opposite to that produced by the field generated by the 

coils. Each of the coils contains five 1��turn layers and 

their diameters are the same. When the two coils are 

connected in parallel, they have an equivalent resistance 

of 260 mΩ and an equivalent inductance of 0.93 mH. 

To generate the magnetic pulse, a bank of capacitors 

with an equivalent capacitance of 46 mF is connected in 

parallel. 

This bank of capacitors is connected to a ��0 V electrical 

source and the voltage is rectified before it reaches 

the bank of capacitors, which are then loaded to maximum 

capacity before closing the circuit (Figure 2) and 

produce a discharge within 17 µs. This discharge is sufficient 

to generate peak current in the coils and a magnetic 

intensity of the order of 32 mT. This generates a magnetic 

intensity in the tracers of 100 to 300 nT, which can 

be detected by a fluxgate magnetometer or a magnetoresistor 

�Figure ��. Several studies have described validation 

procedures for such systems [26,28,34,40,41] . 

On the other hand, it is important to point out that the 

procedure for measuring gastric emptying is standardized 

by scintigraphy tests, as is that for the measurement of 

peristalsis, in that they both involve digital signal analysis 

of spectral density (in our method, the dominant frequency 

coordinates are determined). On the other hand, magnetic 

tracers have been diluted in semisolid [26] and solid 

meals [28] for consumption by healthy subjects and patients. 

The results of all studies performed by our group were 

compared with the results of techniques such as scintigraphy 

and we have carried out reproducibility studies [28] . 

Magnetic markers are harmless to the human digestive 

tube as they are inert in gastric pH. 

67 October 15, 2011|Volume 2|Issue 5| 

�C

Scinti�raphy - z1 Scinti�raphy - y1 Scinti�raphy - x1 Scinti�raphy - �1 


40 

30 

20 

10 

0 

-10 

-20 

-30 

-40 

-50 

50 

30 

10 

-10 

-30 

-50 

-70 

55 

45 

35 

25 

15 

5 

-5 

-15 

-25 

-35 

40 

30 

20 

10 

0 

-10 

-20 

-30 

-40 

-50 

Figure 3 Bland Altman analysis for different vectors. 

REPRODUCIBILITY AND SENSITIVITY 

Several studies have been conducted to evaluate magnetogastrography 

for use in clinical settings. Reproduc- 


+ 1.96 SD 

26.4 

mean 

-9.2 

- 1.96 SD 

-44.7 

30 40 50 60 70 80 90 

A�era�e of scinti�raphy an� �1 

+ 1.96 SD 

33.3 

mean 

-13.5 

- 1.96 SD 

-60.2 

30 40 50 60 70 80 90 

A�era�e of scinti�raphy an� x1 

+ 1.96 SD 

40.1 

mean 

6.5 

- 1.96 SD 

-27.1 

20 30 40 50 60 70 80 90 

A�era�e of scinti�raphy an� y1 

+ 1.96 SD 

33.4 

mean 

-2.3 

- 1.96 SD 

-38.1 

20 30 40 50 60 70 80 90 

A�era�e of scinti�raphy an� z1 

Scinti�raphy - �2 

Scinti�raphy - x2 

Scinti�raphy - y2 

Scinti�raphy - z2 

40 

30 

20 

10 

0 

-10 

-20 

-30 

-40 

-50 

35 

25 

15 

5 

-5 

-15 

-25 

-35 

-45 

-55 

70 

60 

50 

40 

30 

20 

10 

0 

-10 

-20 

-30 

-40 

-50 

-60 

40 

30 

20 

10 

0 

-10 

-20 

-30 

-40 

-50 

+ 1.96 SD 

29.1 

mean 

-5.4 

- 1.96 SD 

-40.0 

20 30 40 50 60 70 80 90 

A�era�e of scinti�raphy an� �2 

+ 1.96 SD 

20.2 

mean 

-12.8 

- 1.96 SD 

-45.7 

30 40 50 60 70 80 90 

A�era�e of scinti�raphy an� x2 

+ 1.96 SD 

57.6 

mean 

10.7 

- 1.96 SD 

-36.3 

20 30 40 50 60 70 80 90 

A�era�e of scinti�raphy an� y2 

+ 1.96 SD 

33.3 

mean 

-2.1 

- 1.96 SD 

-37.5 

20 30 40 50 60 70 80 90 

A�era�e of scinti�raphy an� z2 

ibility was greater than 85% [26] and a comparison between 

magnetogastrography and scintigraphy using the Bland- 

Altman test showed that the best estimate of the sensor 

axis was BZ and the results of the two methods were sim- 


ilar. Bland-Altman analysis also showed that differences 

between scintigraphy and magnetogastrography estimates 

of emptying time were similar for each of the magnetization 

components (Figure 3). The mean scintigraphy 

estimate for gastric transit time was (23 23 ± 12.9) ) min min and 

and 

the mean ± SD magnetogastrography estimate was (25.8 

25.8 

± 23) ) min 

min [28] . 

Although this study was performed on young subjects, 

information on its sensitivity and specificity is lacking. 

Such data could be obtained by comparing estimates 

derived using the two techniques for healthy subjects and 

patients with a specific disease. Therefore, further research 

is required before this technology can be released 

for commercial use. 

GASTRIC EMPTYING AND PHYSICAL 

AND EMOTIONAL HEALTH 

Previous studies have demonstrated that stress, anxiety 

and gastric emptying influence the symptoms of functional 

dyspepsia �FD��. Patients with FD have a significantly 

elevated gastric emptying half time �4�.�7 ± 7.4) min 

compared with healthy volunteers �33.8 ± 8) ) min, min, but 

but 

gastric peristaltic frequency does not differ between these 

groups (t = −1.60, P = 0.12) [12] . 

“The biomagnetic technique, in combination with 

other test, can be used for assessing physiological factors 

related to emotional state using people, particularly, 

persons who would be unwilling to undergo invasive or 

isotopic procedures, for this end. In addition, magnetogastrography 

shows that patients with FD have a delayed 

gastric emptying time, which may be associated with this 

kind of symptoms.” Magnetic tracers are particles of 

size from 50 to 125 micrometer, such that cannot be absorbed 

by the microvilli on the villi in the small intestine 

so they are eliminated by the human body naturally. 

Large intestine 

The length of the adult human large intestine is 1.5 m�� 

it consists of the ascending colon, transverse colon, 

descending colon and sigmoid segment and ends at the 

rectum. Unlike other segments of the GI tract, the large 

intestine has three types of motion: mass movement, 

peristaltic reflex and peristaltic frequency. According to 

previous work [25,41] , digesta take about 13 h to reach the 

ascending colon. This means that any study on this segment 

of the GI tract should involve measurements for 

a minimum of 14 h. We believe that any of the three 

movements of the large intestine can be measured using 

a magnetic marker instead of food containing a magnetic 

tracer. If a healthy person ingests a magnetic marker, it 

will reach the large intestine, in particular the ascending 

colon, 13 h later. Using a pair of fluxgate magnetometers 

in a first-order gradiometer array, it is possible to 

determine the position of the magnetic marker with a 

high degree of accuracy (Figure 4). Assuming that it is in 

the same plane as the umbilical scar, this is assumed as 



Figure 4 Magnetic marker positions in the large intestine over time. 

the zero for a virtual Euclide’s plane. Data acquisition is 

completed within a few minutes, during which the subject 

remains motionless. After applying a Fourier transform, 

the data are analyzed using Matlab software. 

If this process is repeated every � h, one can estimate 

transit time through the large intestine and the peristaltic 

frequency at the position at which the magnetic marker is 

located at the time of measurement. Such an estimate of 

point to point is determined in each recording. The above 

is used in order to estimate the dynamics of this part of 

the GI tract. For example, we could monitor colon transit 

time at various phases of the menstrual cycle and determine 

the effects of stress on colonic transit time. 

CONCLUSION 

It has been shown that the biomagnetic technique is versatile 

when used with oral contrast material. It is possible 

to perform studies using a magnetic sensor that functions 

at room temperature and a shielded magnetic room is not 

necessary. It is easy to assess peristalsis in the esophagus, 

stomach and large intestine with this method. Moreover, 

it represents an alternative to procedures based on ionizing 

radiation for determining gastric emptying. 

Nevertheless, more studies should be performed on 

hospital patients to define the best diagnostic protocols 

for various GI diseases. The age and sex of the patients 

should be considered in such protocols. The oral contrast 

medium should also be taken into account when magnetic 

tracers or markers are used. 

Because the biomagnetic technique enables measurement 

of average gastric emptying time for medical diagnostic 

purposes and associated emotional states, it could 

be used to develop a comprehensive health model. 

With small modifications, this new biomagnetic technique 

could be used in hospitals throughout the world for 

diverse GI applications. Furthermore, it does not involve 

ionizing radiation, is not invasive and does not cause discomfort, 

which makes it appropriate for monitoring the 

effects of therapy in chronic diseases such as gastroparesis, 

colon constipation and FD [12] . 

It is still a lab prototype but nevertheless, its individual 

price of productions is around US$3000.00 and each 



human evaluation or human study is around US$10.00. 

REFERENCES 

1 O’Brien SJ, Halder SL. GI Epidemiology: infection epidemiology 

and acute gastrointestinal infections. Aliment Pharmacol 

Ther 2007; 25: 669-674 

2 Cho YK, Kim GH, Kim JH, Jung HY, Lee JS, Kim NY. [Diagnosis 

of gastroesophageal reflux disease: a systematic review]. 

Korean J Gastroenterol 2010; 55: 279-295 

3 Ierardi E, Rosania R, Zotti M, Principe S, Laonigro G, Giorgio 

F, de Francesco V, Panella C. Metabolic syndrome and 

gastro-esophageal reflux: A link towards a growing interest 

in developed countries. World J Gastrointest Pathophysiol 2010; 

1: 91-96 

4 Chang L. Review article: epidemiology and quality of life in 

functional gastrointestinal disorders. Aliment Pharmacol Ther 

2004; 20 Suppl 7: 31-39 

5 Wang A, Liao X, Xiong L, Peng S, Xiao Y, Liu S, Hu P, Chen 

M. The clinical overlap between functional dyspepsia and 

irritable bowel syndrome based on Rome III criteria. BMC 

Gastroenterol 2008; 8: 43 

6 Brun R, Kuo B. Functional dyspepsia. Therap Adv Gastroenterol 

2010; 3: 145-164 

7 Jung HK, Keum BR, Jo YJ, Jee SR, Rhee PL, Kang YW. [Diagnosis 

of functional dyspepsia: a systematic review]. Korean J 

Gastroenterol 2010; 55: 296-307 

8 Camacho S, Bernal F, Abdo M, Awad RA. Endoscopic and 

symptoms analysis in Mexican patients with irritable Bowel 

syndrome, dyspepsia, and gastroesophageal reflux disease. 

An Acad Bras Cienc 2010; 82: 953-962 

9 Lee V, Guthrie E, Robinson A, Kennedy A, Tomenson B, 

Rogers A, Thompson D. Functional bowel disorders in primary 

care: factors associated with health-related quality of 

life and doctor consultation. J Psychosom Res 2008; 64: 129-138 

10 Massironi S, Sciola V, Spampatti MP, Peracchi M, Conte D. 

Gastric carcinoids: between underestimation and overtreatment. 

World J Gastroenterol 2009; 15: 2177-2183 

11 Akiho H, Ihara E, Nakamura K. Low-grade inflammation 

plays a pivotal role in gastrointestinal dysfunction in irritable 

bowel syndrome. World J Gastrointest Pathophysiol 2010; 

1: 97-105 

12 De la Roca-Chiapas JM, Solís-Ortiz S, Fajardo-Araujo M, 

Sosa M, Córdova-Fraga T, Rosa-Zarate A. Stress profile, 

coping style, anxiety, depression, and gastric emptying as 

predictors of functional dyspepsia: a case-control study. J 

Psychosom Res 2010; 68: 73-81 

13 Kim JH, Song HY, Shin JH. Malignant gastric outlet obstructions: 

treatment with self-expandable metallic stents. Gut 

Liver 2010; 4 Suppl 1: S32-S38 

14 Porter CK, Gormley R, Tribble DR, Cash BD, Riddle MS. The 

Incidence and gastrointestinal infectious risk of functional 

gastrointestinal disorders in a healthy US adult population. 

Am J Gastroenterol 2011; 106: 130-138 

15 Saha A, Hammond CE, Beeson C, Peek RM, Smolka AJ. 

Helicobacter pylori represses proton pump expression and 

inhibits acid secretion in human gastric mucosa. Gut 2010; 

59: 874-881 

16 Festini F, Cocchi P, Mambretti D, Tagliabue B, Carotti M, 

Ciofi D, Biermann KP, Schiatti R, Ruggeri FM, De Benedictis 

FM, Plebani A, Guarino A, de Martino M. Nosocomial Rotavirus 

Gastroenteritis in pediatric patients: a multi-center 

prospective cohort study. BMC Infect Dis 2010; 10: 235 

17 Parkman HP, Yates K, Hasler WL, Nguyen L, Pasricha PJ, 

Snape WJ, Farrugia G, Koch KL, Abell TL, McCallum RW, 

Lee L, Unalp-Arida A, Tonascia J, Hamilton F. Clinical features 

of idiopathic gastroparesis vary with sex, body mass, 

symptom onset, delay in gastric emptying, and gastroparesis 

severity. Gastroenterology 2011; 140: 101-115 


18 Bortolotti M. Gastric electrical stimulation for gastroparesis: 

a goal greatly pursued, but not yet attained. World J Gastroenterol 

2011; 17: 273-282 

19 Bluck LJ, Jackson SJ, Vlasakakis G, Mander A. Bayesian hierarchical 

methods to interpret the (13)C-octanoic acid breath 

test for gastric emptying. Digestion 2011; 83: 96-107 

20 Sanaka M, Yamamoto T, Kuyama Y. Retention, fixation, and 

loss of the [13C] label: a review for the understanding of gastric 

emptying breath tests. Dig Dis Sci 2008; 53: 1747-1756 

21 Kudara N, Chiba T, Suzuki K. Gastric emptying and electrogastrography 

in reflux esophagitis: results in patients showing 

endoscopically erosive esophagitis under proton pump 

inhibitor therapy. Hepatogastroenterology 2010; 57: 772-776 

22 Stevens JE, Gilja OH, Gentilcore D, Hausken T, Horowitz M, 

Jones KL. Measurement of gastric emptying of a high-nutrihigh-nutrient liquid by 3D ultrasonography in diabetic gastroparesis. 

Neurogastroenterol Motil 2011; 23: 220-225, 225, 5, e113-e114 

23 Cordova-Fraga T, Bernal-Alvarado JJ, Gutierrez-Juarez G, 

Sosa M, Vargas-Luna M. Gastric activity studies using a 

magnetic tracer. Physiol Meas 2004; 25: 1261-1270 

24 Daghastanli NA, Braga FJ, Oliveira RB, Baffa O. Oesophageal 

transit time evaluated by a biomagnetic method. Physiol 

Meas 1998; 19: 413-420 

25 Córdova-Fraga T, Carneiro AA, de Araujo DB, Oliveira RB, 

Sosa M, Baffa O. Spatiotemporal evaluation of human colon 

motility using three-axis fluxgates and magnetic markers. 

Med Biol Eng Comput 2005; 43: 712-715 

26 de la Roca-Chiapas JM, Cordova T, Hernandez E, Solorio 

S, Solis S, Sosa M. Magnetogastrography (MGG) reproducibility 

assessments of gastric emptying on healthy subjects. 

Physiol Meas 2007; 28: 175-183 

27 Cordova-Fraga T, Sosa M, Wiechers C, De la Roca-Chiapas 

JM, Maldonado Moreles A, Bernal-Alvarado J, Huerta-Franco 

R. Effects of anatomical position on esophageal transit 

time: a biomagnetic diagnostic technique. World J Gastroenterol 

2008; 14: 5707-5711 

28 De la Roca-Chiapas JM, Córdova-Fraga T, Reynaga G, Solorio 

S, Sosa M, Rivera-Cisneros AE, Bernal JJ, Vargas-Luna M. 

Scintigraphy vs. mechanical magnetogastrography: gastric 

emptying analysis. Med Biol Eng Comput 2010; 48: 727-729 

29 Smout AJ, Mundt MW. Gastrointestinal motility testing. Best 

Pract Res Clin Gastroenterol 2009; 23: 287-298 

30 Ma J, Rayner CK, Jones KL, Horowitz M. Diabetic gastroparesis: 

diagnosis and management. Drugs 2009; 69: 971-986 

31 Vander A, Sherman J, Luciano D. Human physiology the 

mechanism of body function. 8th ed. New York: McGraw 

Hill, 2001: 553 

32 Kutchai H, Motility of the gastrointestinal tract. In: Berne 

RM, Levy NM. Principles of Physiology. 3rd ed. St. Louis, 

MO: Mosby, 2000: 354 

33 Heuman DM, Scott Mills A, Hunter H, McGuire JR. Gastroenterology. 

Elsevier Science: Philadelphia, 1997: 1 

34 Williamson SJ, Kaufman L. Biomagnetism. J Magn Magn 

Mater 1981; 22: 129-201 

35 Wenger MA, Engel BT, Clemens TL, Cullen TD. Stomach 

motility in man as recorded by the magnetometer method. 

Gastroenterology 1961; 41: 479-485 

36 Wenger MA, Henderson EB, Dinning JS. Magnetometer 

method for recording gastric motility. Science 1957; 125: 

990-991 

37 Cohen D. Ferromagnetic contamination in the lungs and 

other organs of the human body. Science 1973; 180: 745-748 

38 Cohen D. Detection and analysis of magnetic fields produced 

by bioelectric currents in humans. J AppL Phys 1969; 

40: 1046-1048 

39 Cohen D, Edelsack EA, Zimmerman JE. Magnetocardiograms 

taken inside a shielded room with a superconducting 

point-contact magnetometer. Appl Phys Lett 1970; 16: 278-280 

40 Benmair Y, Dreyfuss F, Fischel B, Frei EH, Gilat T. Study of 

gastric emptying using a ferromagnetic tracer. Gastroenterol- 


ogy 1977; 73: 1041-1045 

41 Benmair Y, Fischel B, Frei EH, Gilat T. Evaluation of a magnetic 

method for the measurement of small intestinal transit 

time. Am J Gastroenterol 1977; 68: 470-475 

42 Frei E, Benmair Y, Yerushalmi S, Dreyfuss F. Measurements 

of the emptying of the stomach with a magnetic tracer. IEEE 



Trans Mag 1970; 6: 348-349 

43 Córdova-Fraga T, De la Roca-Chiapas JM, Solís S, Sosa M, 

Bernal-Alvarado J, Hernández E, Hernández-González M. 

Gender difference in the gastric emptying measured by 

magnetogastrography using a semi-solid test meal. Acta Gastroenterol 

Latinoam 2008; 38: 240-245 

S- Editor Wu X L- Editor Roemmele A E- Editor Zheng XM 




doi:10.4291/wjgp.v2.i5.72 




Cytokine-induced alterations of gastrointestinal motility in 

gastrointestinal disorders 

Hirotada Akiho, Eikichi Ihara, Yasuaki Motomura, Kazuhiko Nakamura 

Hirotada Akiho, Eikichi Ihara, Yasuaki Motomura, Kazuhiko 

Nakamura, Department of Medicine and Bioregulatory Science, 

Graduate School of Medical Sciences, Kyushu University, 

Fukuoka 812-8582, Japan 

Author contributions: All authors contributed extensively in 

preparing this manuscript; Akiho H provided a significant editorial 

and literature contribution; Nakamura K and Motomura Y 

performed the literature review; Ihara E provided literature related 

comments and review. 

Correspondence to: Hirotada Akiho, M�, M�, �h�, �h�, Department 

of Medicine and Bioregulatory Science, Graduate School of 

Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, 

Fukuoka 812-8582, 

Japan. akiho@intmed3.med.kyushu-u.ac.jp 

Telephone: +81-92-6425286 Fax: +81-92-6425287 

Received: March 31, 2011 Revised: August 12, 2011 

Accepted: August 19, 2011 

�ublished online: October 15, 2011 

Abstract 

Inflammation and immune activation in the gut are usually 

accompanied by alteration of gastrointestinal (GI) 

motility. In infection, changes in motor function have 

been linked to host defense by enhancing the expulsion 

of the infectious agents. In this review, we describe the 

evidence for inflammation and immune activation in GI 

infection, inflammatory bowel disease, ileus, achalasia, 

eosinophilic esophagitis, microscopic colitis, celiac disease, 

pseudo-obstruction and functional GI disorders. 

We also describe the possible mechanisms by which 

inflammation and immune activation in the gut affect 

GI motility. GI motility disorder is a broad spectrum 

disturbance of GI physiology. Although several systems 

including central nerves, enteric nerves, interstitial cells 

of Cajal and smooth muscles contribute to a coordinated 

regulation of GI motility, smooth muscle probably 

plays the most important role. Thus, we focus on the 

relationship between activation of cytokines induced by 

adaptive immune response and alteration of GI smooth 

muscle contractility. Accumulated evidence has shown 


that Th1 and Th2 cytokines cause hypocontractility and 

hypercontractility of inflamed intestinal smooth muscle. 

Th1 cytokines downregulate CPI-17 and L-type Ca 2+ 

channels and upregulate regulators of G protein signaling 

4, which contributes to hypocontractility of inflamed 

intestinal smooth muscle. Conversely, Th2 cytokines 

cause hypercontractilty via signal transducer and activator 

of transcription 6 or mitogen-activated protein 

kinase signaling pathways. Th1 and Th2 cytokines have 

opposing effects on intestinal smooth muscle contraction 

via 5-hydroxytryptamine signaling. Understanding 

the immunological basis of altered GI motor function 

could lead to new therapeutic strategies for GI functional 

and inflammatory disorders. 


Key words: Cytokine; Motility; Inflammation; Immunology 

Peer reviewers: Zhao-Xiang Bian, Professor, School of Chinese 

Medicine, Hong Kong Baptist University, Hong Kong, China; 

Shi Liu, Professor, Union Hospital of Tongji Medical College, 

Department of Gastroenterology, Huazhong University of Science 

and Technology, 1277 Jie Fang Road, Wuhan 430022, Hubei 

Province, China 

Akiho H, Ihara E, Motomura Y, Nakamura K. Cytokine-induced 

alterations of gastrointestinal motility in gastrointestinal disorders. 

World J Gastrointest Pathophysiol 2011; 2(5): 72-81 

Available from: URL: http://www.wjgnet.com/2150-5330/full/ 

v2/i5/72.htm DOI: http://dx.doi.org/10.4291/wjgp.v2.i5.72 

INTRODUCTION 

REVIEW 

Intestinal inflammation and immune activation are accompanied 

by alteration of gastrointestinal (GI) motility, 

associated with altered function of enteric nerves, intestinal 

cell of Cajal (ICCs) or smooth muscles. Changes 

in motor function have been described in experimental 


Akiho H et al . Cytokine-induced gastrointestinal dismotility 

models following a variety of inflammatory stimuli, including 

infection [1,2] , chemical irritation [3,4] and immune 

activation [5,6] . In the context of infection, changes in motor 

function have been linked to host defense by enhancing 

the expulsion of the infectious agent. Also, evidence 

has emerged in animal studies that low-grade inflammation 

in the gut could alter GI motor function [6,7] . 

From a clinical viewpoint, some motility disorders 

have been associated with evidence of immune activation, 

such as inflammatory bowel disease (IBD), ileus, 

achalasia, functional GI disease (FGID), or life-threatening 

intestinal pseudo-obstruction [8] . An understanding of 

the mechanisms that underlie immune-mediated changes 

in gut motor function is therefore critical, not only in understanding 

the pathophysiology of, but also in devising 

new therapeutic strategies for, these disorders. 

This review describes the evidence for immune activation 

in GI inflammation, infection and FGID, with 

a particular focus on cytokine-induced alteration of GI 

motility. 

CLINICAL POINT OF VIEW 

Common symptoms of GI diseases are abdominal pain 

or discomfort, diarrhea, constipation, fullness and bloating. 

A mechanical approach to constipation consists of 

poor intake of fluid or fiber, slow colonic transit, and 

outlet dysfunction in the anorectal area. Diarrhea is an 

increase in the volume of stool or frequency of defecation, 

and is categorized into osmotic, secretory, exudative, 

and altered intestinal motility. Acute diarrhea that lasts 

for < 14 d is usually related to a bacterial, viral, or parasitic 

infection and poses the risk of dehydration. Chronic 

diarrhea that lasts at least 4 wk is more likely to be due 

to alterations in GI motility and rapid transit than to a 

secretory component [9] . The symptoms of GI disorders 

reflect a broad spectrum of disturbance of GI physiology, 

including altered epithelial, muscle, intestinal and 

enteric neural function and are also, at least in part, due 

to immune activation. 

Infections 

Several types of bacteria, including: Campylobacter, Salmonella, 

Shigella and Escherichia coli; viruses, including: Rotavirus, 

Norwalk virus, Cytomegalovirus and herpes simplex virus 

(HSV); and parasites, including: Giardia lamblia, Entamoeba 

histolytica and Cryptosporidium cause diarrhea. Different 

pathogens such as enterotoxin invade the host and cause 

infectious diarrhea. 

In bacterial infection, Salmonella is a leading cause of 

GI disease worldwide. Ma et al [10] have reported that tumor 

necrosis factor (TNF)-α modulates the expression 

of Salmonella typhimurium effector proteins and enhances 

interleukin (IL)-8 secretions in intestinal epithelial cells. 

Other studies have shown that IL-6 may play an important 

role in triggering systemic immune response against 

Salmonella [11,12] . Campylobacter jejuni infection, which induces 

a number of cytokines and chemokines including IL-8 


and IL-10 [13] , is also a common cause of human acute 

bacterial gastroenteritis. 

Inflammatory bowel disease 

In IBD such as Crohn’s disease (CD) and ulcerative colitis 

(UC), there are longstanding observations of altered 

motility and intestinal muscle contractility [14,15] . 

Crohn’s disease 

Traditionally, CD has been associated with a T helper 

(Th)1 cytokine profile. Recent studies have indicated that 

Th17 cells as well as Th1 cells play a major role in the 

pathogenesis of CD. Th17 cells express the IL-23 receptor 

(IL-23R) on their surface. Other studies have identified 

IL-23R and other genes involved in the differentiation 

of Th17 cells as IBD susceptibility genes [16-20] . 

Th17 cells produce IL-17, IL-17F and IL-22, thereby 

inducing a massive tissue reaction, owing to the broad 

distribution of IL-17R and IL-22R. Th17 cells also secrete 

IL-21 to communicate with cells of the immune 

system. Differentiation factors [transforming growth factor 

(TGF)β plus IL-6 or IL-21], growth and stabilization 

factor IL-23 and transcription factors [signal transducer 

and activator of transcription (STAT)3, retinoid-related 

orphan receptor (ROR)γt and RORα] have recently 

been identified as involved in the development of Th17 

cells [21] . 

Some studies have shown delays in gastric and intestinal 

transit that cannot be accounted for on the basis of 

mechanical obstruction, and are therefore likely due to 

inflammation-induced alterations in the motility apparatus 

[22-25] . Conversely, our groups have shown previously 

that contractility of intestinal smooth muscle strips and 

cells from the inflamed intestine of CD patients exhibit 

increased contractility in vitro after stimulation by carbachol 

[14,26] . Although CD is well recognized as having a 

Th1-dominant cytokine profile, we have demonstrated 

the dominant expression of the Th2 cytokine IL-4, with 

little change in the Th1 cytokine interferon (IFN)γ in the 

muscularis externa of small intestinal segments from CD 

patients. We have found that Th2 cytokines, IL-4 and 

IL-13 enhance muscle cell contractility in humans and 

mice [26,27] , and IL-17 enhances muscle cell contractility in 

mice (unpublished observations), therefore, there is the 

possibility that Th2 or Th17 immune activation alters 

muscle contractility in CD patients. 

Ulcerative colitis 

UC is characterized by an exaggerated Th2-like response 

as demonstrated by increased production of Th2 cytokines 

such as IL-4, IL-5 and IL-13 [28,29] . TNF-α mRNA is 

highly expressed in colon biopsy from UC patients correlating 

with the grade of inflammation [30] . Five genes involved 

in downstream signaling of IL-23R, IL-12B, Janus 

kinase 2, STAT3 and IL-2b mediate susceptibility to UC. 

These findings suggest that Th17 cells are also involved 

in UC pathogenesis [17-19,31] . Kobayashi et al [32] have demonstrated 

significant upregulation of IL-17A in lamina 


propria CD4+ T cells following IL-23 stimulation in UC. 

It has been reported that high expression levels of the 

Th17 cytokines IL-17A, IL-22 and IL-26 are found in the 

inflamed colon of CD patients and in active UC [33-35] . 

Altered colonic motor function in UC has been well 

documented [36-38] . Terry et al [39] reported that melatonin, 

which is an important regulator of GI inflammation and 

motility, might have an ameliorative effect on UC. Ohama 

et al [40,41] have shown that protein kinase C (PKC)-potentiated 

phosphatase inhibitor protein-17 kDa (CPI-17) 

expression is decreased in smooth muscle from UC patients. 

CPI-17 is downregulated by IL-1β and might contribute 

to the decreased motor function. 

Ileus 

Ileus occurs as a result of hypomotility of the GI tract in 

the absence of mechanical bowel obstruction. Presumably, 

the muscle of the bowel wall is transiently impaired 

and fails to transport intestinal contents. This lack of coordinated 

propulsive action leads to the accumulation of 

gas and fluids within the bowel. Many factors cause ileus, 

such as sepsis, drugs, trauma and GI inflammation, and 

most cases of ileus occur after abdominal surgery. The 

mechanisms underlying the development of postoperative 

ileus are complex, and involve central neural reflexes, 

hormonal influences, local molecular inflammatory responses 

and the recruitment into the intestinal muscularis 

of activated immune cells [42-46] . Immune activation is involved 

in ileus as well as IBD. Serum IL-6 and IL-1β are 

increased in patients with ileus [47] . 

Bauer's group [48-51] have shown from animal studies 

that surgical manipulation of the intestine activates the 

dense network of normally quiescent macrophages, as 

demonstrated by phosphorylation of mitogen-activated 

protein kinases (MAPKs) with resultant activation of 

transcription factors, early growth response gene-1, nuclear 

factor κB (NF-κB), IL-6 and STAT3. The translocation 

of the transcription factors to the nucleus ultimately 

induces the secretion of a complex inflammatory milieu 

of proinflammatory cytokines: TNF-α, IL-1β and IL-6, 

and chemokines. Furthermore, NO and prostaglandins 

have the important role of smooth muscle inhibition in 

postoperative ileus. 

Achalasia 

Esophageal achalasia is a motor disorder that is characterized 

by the absence of esophageal peristalsis and by 

incomplete relaxation of the lower esophageal sphincter 

(LES). The failure of LES relaxation is primarily caused 

by the loss of the inhibitory innervation of the esophageal 

myenteric plexus [52] . 

Recent evidence has shown that HSV-1 is involved in 

the pathogenesis of achalasia [53] . Facco et al [54] reported 

that achalasia patients are characterized by significantly 

higher esophageal lymphocyte infiltration, mainly represented 

by CD3+CD8+ T cells than controls. LESinfiltrating 

lymphocytes recognize HSV-1 antigens 

specifically. Facco et al [54] observed that IL-1β, IFNγ and 



IL-2 are increased in achalasia patients. Another group 

has shown that in the immune activation of achalasia patients, 

TNF-α is significantly increased in the LES [55] . 

Eosinophilic esophagitis 

Eosinophilic esophagitis is an important and established 

cause of dysphagia, which is caused by exposure to exogenous 

allergens. Eosinophils and IL-5 produced by 

Th2 cytokines play a crucial role in this disease. Patients 

are exposed to food or air allergens. Antigen presenting 

cells (APCs) process these antigens and present them to 

Th2 cells. Activated Th2 cells produce IL-5, which is crucial 

for the terminal differentiation and proliferation of 

eosinophils. IL-4, also produced by Th2 cells, promotes 

eosinophilic accumulation and IgE production from B 

cells. In addition, Th2 cells and activated mast cells release 

IL-13 and TNF that promote local inflammation. 

GI epithelial cells produce eotaxins, which have essential 

chemokine activity for the recruitment of circulating eosinophils 

to the site of inflammation. As a result, mature 

eosinophils accumulated in the esophagus, are activated, 

degranulate and release multiple cytotoxic agents [56] . 

Microscopic colitis 

Microscopic colitis is a common cause of chronic watery 

diarrhea, especially among older persons. Diagnosis requires 

histological analysis of colon biopsy samples in the 

appropriate clinical setting [57] . Microscopic colitis demonstrates 

a Th1 mucosal cytokine profile with IFNγ as 

the predominantly upregulated cytokine, with concurrent 

induction of NO synthase and downregulation of IFNγrelated 

cell junction proteins [58] . 

Celiac disease 

Celiac disease is a disorder that is characterized by a deregulated 

immune response to ingested wheat gluten and 

related cereal proteins in susceptible individuals [59,60] . The 

characteristic features of celiac disease include nausea, 

bloating and diarrhea in patients presenting with otherwise 

typical irritable bowel syndrome (IBS) [61] . Several studies 

have shown increased concentrations of 5-hydroxytryptamine 

(5-HT) in the duodenal mucosa [62] , increased plasma 

5-HT levels [63] and increased urine excretion of the 5-HT 

metabolite and 5-hydroxyindoleacetic acid [64] . 

It is considered that the onset of celiac disease is mediated 

by a skewed Th1 response [65] . In recent literature it 

has been shown that gliadin-specific Th17 cells are present 

in the mucosa of celiac disease patients. These Th17 

cells have a role in the pathogenesis of the disease as 

they produce pro-inflammatory cytokines (such as IL-17, 

IFNγ and IL-21), mucosa-protective IL-22 and regulatory 

TGFβ, which actively modulates IL-17A production by T 

cells in the celiac mucosa [66] . 

Pseudo-obstruction 

Chronic idiopathic intestinal pseudo-obstruction (CIIP) 

is a rare, progressive and life-threatening syndrome that is 

characterized by severely impaired GI motility. Recurrent 



episodes of abdominal pain and distention are accompanied 

by bloating, nausea and vomiting without evidence 

of mechanical obstruction [67] . CIIP may occur throughout 

the GI tract, but usually involves the small bowel. Several 

neurotropic viruses have the ability to infect the central 

and enteric nervous systems. Selgrad et al [68] and Sanders 

et al [69] have shown that the polyoma virus, JC virus, infects 

the enteric glia of patients with CIIP [68] . JC virus may 

infect ICCs and therefore contribute to ICC loss or to redifferentiation 

to smooth muscle cells. Further investigation 

is needed. 

Functional dyspepsia 

FGIDs are common clinical syndromes worldwide. 

Functional dyspepsia (FD) is characterized by the presence 

of recurrent or chronic upper abdominal symptoms, 

such as epigastric pain, early satiety and fullness, without 

anatomical or biochemical abnormalities [70] . There is increasing 

evidence for involvement of the immune system 

in FD. Kindt et al [71] have reported that, compared to 

controls, stimulated lymphocyte expression of IL-5 and 

IL-13 is enhanced in IBS, FD and non-cardiac chest pain. 

Conversely, stimulated monocytic IL-12 and lymphocytic 

IL-10 expression is reduced in IBS and FD, while IFNγ 

expression is also reduced in FD patients. A shift towards 

a Th2 cytokine profile is present in FGID, while the 

cellular immunophenotype remains largely unchanged. 

Arisawa et al [72] have reported that IL-17F 7488T and 

macrophage migration inhibitory factor -173C alleles are 

significantly associated with the development of FD, particularly 

epigastric pain syndrome, a subgroup of FD, in 

Helicobacter pylori-infected subjects. 

Futagami et al [73] have reported that gastric emptying 

evaluated by T-max values in post-infectious FD patients 

is similar to that in controls. However, the degree of histrogical 

duodenitis in post-infectious FD is significantly 

greater than that in controls. CCR2/CD68-double positive 

cell number in post-infectious FD patients is significantly 

increased. 

Irritable bowel syndrome 

IBS is characterized by the presence of abdominal pain 

or discomfort and an alteration in bowel habits [74] . The 

pathogenesis is considered to be multifactorial and includes 

psychosocial factors, visceral hypersensitivity, infection, 

microbiota and immune activation. Several reports 

have described increased numbers of T cells in various 

lymphoid compartments of the small or large intestine in 

IBS patients [75-78] . Pro-inflammatory cytokines such as IL- 

1β, IL-6 and TNF-α in peripheral blood mononuclear 

cells [79] and IL-6 and IL-8 in serum [80,81] have been reported 

to be increased in IBS patients. 

ROLE OF IMMUNE RESPONSE IN ALTERED 

INTESTINAL MUSCLE FUNCTION 

Innate immune response 

Goblet cells: The mucous layer that coats the GI tract is 


the front line of innate host defense largely because of 

the secretory products of intestinal goblet cells. In most 

intestinal infections, induction of goblet cells and mucin 

synthesis and secretion occur frequently, during the acute 

phase, to expel antigens [82] . 

Macrophages: Macrophages perform a key role in innate 

defense against foreign invaders and produce a 

number of cytokines such as IL-1β, IL-6 and TNF-α. 

Macrophages are not crucial for changes in muscle contraction 

in Trichinella spiralis-infected mice [83] . Innate immune 

response seems not to have a major role in muscle 

function. 

Adaptive immune response: APCs present antigens to 

CD4+ Th cells. Th cell-dependent immune responses are 

divided into four subsets: Th1, Th2, Th17 and T regulatory 

(Treg). Th1 cells produce IFNγ and their primary 

role is protection against intracellular microbes. Th2 cells 

produce IL-4, IL-5 and IL-13 and are involved in allergic 

disorders and protection against extracellular pathogens. 

Th1 differentiation is mainly driven by IL-12 and IFNγ, 

while IL-4 drives Th2 differentiation. Treg cells are 

important in the control of immune responses to selfantigens, 

prevention of autoimmunity and maintenance 

of self-tolerance. In contrast, IL-17-producing Th17 cells 

play a major role in autoimmunity [19] (Figure 1). 

Th1/Th2/5-HT: Recent animal studies have shown that 

Th1 and Th2 immune response is associated with hypocontractility 

or hypercontractility of inflamed intestinal 

smooth muscle, respectively. 

We have previously shown [7] that Th1 and Th1-related 

cytokines cause hypocontractility of inflamed intestinal 

smooth muscle. TNF-α and IL-1β inhibit carbacholinduced 

contraction via downregulation of CPI-17 [84] 

and L-type Ca 2+ channels [85] , respectively. Other groups 

have shown that surgical manipulation suppresses jejunal 

contractions with upregulation of IL-6, TNF-α, cyclooxygenase-2 

and inducible NO synthase [86] . We also have 

shown that incubation of IFNγ with intestinal smooth 

muscle decreases carbachol-induced smooth muscle cell 

contraction [87] . Wells and Blennerhassett have reported a 

decrease in muscle contractions in 2,4,6-trinitrobenzenesulphonic 

acid (TNBS)-inflamed preparations [88] . In a 

Th1-dominant, TNBS-induced colitis model, it has been 

shown that carbachol- and 5-HT-induced contractility of 

rat colonic circular smooth muscle cells is decreased in 

the acute phase, and 5-HT-mediated contraction is still 

impaired by day 36 post-TNBS. 

On the contrary, the Th2 cytokines IL-4 and IL-13 

acting via STAT6 mediate the development of nematode 

T. spiralis-induced intestinal muscle hypercontractility, 

which contributes to worm expulsion [27,89,90] . A model of 

Nippostrongylus brasiliensis infection supports our finding 

that Th2 responses mediate muscle contraction [91,92] . Ihara 

et al [93] have shown that MAPK pathways play crucial 

roles in Th2-cytokine-mediated Ca 2+ sensitization and 


Inducing cytokines 

T-bet 

STAT4 

Th1 

Naive 

CD4+ cell 

IL-12 

IFNγ IL-4 

Effector cytokines 

hypercontractility observed in inflamed colonic circular 

smooth muscle from sodium dextran sulfate-treated mice. 

We evaluated the association of 5-HT with Th1/Th2 

responses. 5-HT influences intestinal homeostasis by 

altering gut physiology, and has been implicated in the 

pathophysiology of various GI disorders such as IBD, 

IBS and GI infection [94-97] . Using the Trichuris murisinfected 

AKR (susceptible to infection with generation 

of a Th1 response), BALB/c (resistant to infection, with 

generation of a Th2 response), STAT4-deficient (impaired 

in Th1 responses) and STAT6-deficient (impaired in Th2 

responses) mice to explore the mechanism of the enterochromaffin 

(EC) cell and 5-HT responses in Th1/Th2dominant 

environments, we found that the EC cell and 

5-HT responses to the same infectious agent were influenced 

by Th1 or Th2 cytokine predominance [98] . 

Furthermore, we evaluated the 5-HT response and 

intestinal motility using T cell-induced enteropathy in 

Th1/Th2-dominant environments [99] . In BALB/c mice, 

carbachol-induced intestinal smooth muscle cell contraction 

was significantly increased at day 7 post anti-CD3 

antibody injection, when the tissue damage returned to its 

normal histological appearance. We observed that 5-HT 

protein in the intestine was significantly increased at day 

7. On the other hand, in AKR mice, carbachol-induced 

muscle cell contraction was significantly decreased and 

5-HT protein in the intestine was also decreased at day 7. 

We showed, in this model, that Th1 and Th2 cytokines 

had opposing effects on intestinal muscle contraction via 

5-HT signaling in the post-inflammation phase. 


GATA-3 

STAT6 

Th2 

Activated 

T cell 

IFNγ 

IL-4 

IL-27 

IL-6 

IL-23 

TGFβ 

RORγt 

STAT3 

Th17 

IFNγ IL-4, IL-5, IL-9, IL-13 IL-17A, IL-17F, IL-21, IL-22 

IL-26, TNFα 

Host defence 

(intracellular pathogens) 

Autoimmunity 

Host defence 

(parasites) 

Allergy 

Asthma 


Host defence 

(extracellular pathogens) 

Inflammation 

Autoimmunity 

TGFβ 

Foxp3 

STAT5 

iTreg 

TGFβ, IL-10 

Antiinflammation 

Figure 1 Development of Th1, Th2, Th17 and induced Treg cells from naïve CD4+ T cells. Cytokines that inhibit the development of Th17 cells are marked in 

red. CD: Crohn’s disease; T-bet: T box expressed in T cells; GATA: GATA-binding protein; ROR: Retinoid-related orphan receptor; Foxp3: Forkhead box P3; STAT: 

Signal transducer and activator of transcription; IL: Interleukin; IFN: Interferon; TGF: Transforming growth factor. 

Th17: Several disorders that were originally considered 

to be Th1-mediated have been reclassified as Th17mediated 

inflammation [100,101] . A recent study has shown 

that Th17 cells are increased during acute infection with 

T. spiralis, and that jejunal smooth muscle strips cultured 

with IL-17 show enhanced contractions, elicited by acetylcholine, 

in a concentration-dependent manner [102] . We 

found that IL-17 protein in the small intestine is upregulated 

in mice injected with an anti-CD3 antibody [103] , and 

that IL-17 incubation with smooth muscle cells enhances 

carbachol-induced smooth muscle cell contraction (unpublished 

observations). IL-17 might be the key cytokine 

to alter GI muscle function. 

HOW DO CYTOKINES AFFECT GI 

MUSCLE FUNCTION? 

As we have mentioned in this review, several cytokines 

are upregulated in GI diseases, and adaptive immune 

systems have a key role in altered muscle function of 

chronic GI diseases such as IBD and FGID. 

Signal transduction pathways in smooth muscle cells 

Motility disorder is a broad spectrum disturbance of GI 

physiology, including altered epithelial, smooth muscle, 

intestinal and enteric neural function and while immune 

activation may contribute, it plays only a limited role 

(Figure 2). GI motility depends on activation and coupling 

of muscarinic receptors at multiple sites including 


It has been reported that IL-1β plays an important 

role in decreased GI smooth muscle contractility in Th1 

cytokines-dominant colitis. It has been shown that IL- 

1β downregulates CPI-17 expression, which contributes 

to decreased GI smooth muscle contractility [40,41,84] . It has 

also been shown that IL-1β upregulates RGS4 expression 

by inhibiting NF-κB activation and RGS4 contributes to 

the inhibitory effect of IL-1β on the GI smooth muscle 

contraction [111,112] . Th2 cytokines may have opposing 

mechanisms to downregulate RGS4 expression. The important 

point is that it has yet to be determined whether 

the activated cytokines indicated above actually contribute 

to alteration of GI motility disorder in humans. However, 

several animal studies have shown that cytokines directly 

affect GI motility [84,87,89,102] . Further investigations should 

be undertaken. 

CONCLUSION 

Understanding the underlying immunological basis of GI 

disease by considering the time course of the disease, cytokine 

profile, and motor function may ultimately lead to 

new therapeutic strategies for GI functional and inflammatory 

disorders. 

REFERENCES 

1 Bercík P, De Giorgio R, Blennerhassett P, Verdú EF, Barbara 

G, Collins SM. Immune-mediated neural dysfunction in a 

murine model of chronic Helicobacter pylori infection. Gastroenterology 

2002; 123: 1205-1215 

2 Vallance BA, Croitoru K, Collins SM. T lymphocyte-dependent 

and -independent intestinal smooth muscle dysfunction 

in the T. spiralis-infected mouse. Am J Physiol 1998; 275: 

G1157-G1165 

3 Myers BS, Dempsey DT, Yasar S, Martin JS, Parkman HP, 

Ryan JP. Acute experimental distal colitis alters colonic transit 

in rats. J Surg Res 1997; 69: 107-112 

4 Krauter EM, Strong DS, Brooks EM, Linden DR, Sharkey 

KA, Mawe GM. Changes in colonic motility and the electrophysiological 

properties of myenteric neurons persist following 

recovery from trinitrobenzene sulfonic acid colitis in the 

guinea pig. Neurogastroenterol Motil 2007; 19: 990-1000 

5 Radojevic N, McKay DM, Merger M, Vallance BA, Collins 

SM, Croitoru K. Characterization of enteric functional 

changes evoked by in vivo anti-CD3 T cell activation. Am J 

Physiol 1999; 276: R715-R723 

6 Mizutani T, Akiho H, Khan WI, Murao H, Ogino H, 

Kanayama K, Nakamura K, Takayanagi R. Persistent gut 

motor dysfunction in a murine model of T-cell-induced enteropathy. 

Neurogastroenterol Motil 2010; 22: 196-203, e65 

7 Akiho H, Ihara E, Nakamura K. Low-grade inflammation 

plays a pivotal role in gastrointestinal dysfunction in irritable 

bowel syndrome. World J Gastrointest Pathophysiol 2010; 

1: 97-105 

8 Di Lorenzo C. Pseudo-obstruction: current approaches. Gastroenterology 

1999; 116: 980-987 

9 Collins SM. Translating symptoms into mechanisms: functional 

GI disorders. Adv Physiol Educ 2007; 31: 329-331 

10 Ma J, Zhang YG, Xia Y, Sun J. The inflammatory cytokine tumor 

necrosis factor modulates the expression of Salmonella 

typhimurium effector proteins. J Inflamm (Lond) 2010; 7: 42 

11 Li Y, Reichenstein K, Ullrich R, Danner T, von Specht BU, 

Hahn HP. Effect of in situ expression of human interleukin-6 

on antibody responses against Salmonella typhimurium an- 



tigens. FEMS Immunol Med Microbiol 2003; 37: 135-145 

12 Lin CH, Hsieh CC, Chen SJ, Wu TC, Chung RL, Tang RB. 

The diagnostic value of serum interleukins 6 and 8 in children 

with acute gastroenteritis. J Pediatr Gastroenterol Nutr 

2006; 43: 25-29 

13 Li YP, Vegge CS, Brøndsted L, Madsen M, Ingmer H, Bang 

DD. �ampylobacter �ampylobacter jejuni in�uces in�uces an anti-inflammatory reresponse in human intestinal epithelial cells through activation 

of phosphatidylinositol 3-kinase/Akt pathway. Vet Microbiol 

2011; 148: 75-83 

14 Vermillion DL, Huizinga JD, Riddell RH, Collins SM. Altered 

small intestinal smooth muscle function in Crohn’s 

disease. Gastroenterology 1993; 104: 1692-1699 

15 Snape WJ, Williams R, Hyman PE. Defect in colonic smooth 

muscle contraction in patients with ulcerative colitis. Am J 

Physiol 1991; 261: G987-G991 

16 Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux 

JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton 

A, Dassopoulos T, Datta LW, Green T, Griffiths AM, 

Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm 

LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor 

C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens 

D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont 

D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon 

LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, 

Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, 

Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfiel� 

J, Jewell D, Satsangi J, Mathew �G, Parkes M, Georges 

M, Daly MJ. Genome-wide association defines more than 

30 distinct susceptibility loci for Crohn’s disease. Nat Genet 

2008; 40: 955-962 

17 Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, 

Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths 

A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, 

Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada 

MM, Rotter JI, Nicolae DL, Cho JH. A genome-wide association 

stu�y i�entifies IL23R as an inflammatory bowel �isease 

gene. Science 2006; 314: 1461-1463 

18 Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling 

M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond 

H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, 

Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, 

Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle 

W, Lewis CM, Lobo A, Sanderson J, Jewell DP, Deloukas P, 

Mansfiel� J�, Mathew �G, Satsangi J, Parkes M. Investigation 

of Crohn’s disease risk loci in ulcerative colitis further 

defines their molecular relationship. Gastroenterology 2009; 

136: 523-529.e3 

19 Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, 

Schuldt D, Nikolaus S, Rosenstiel P, Krawczak M, Schreiber S. 

Replication of signals from recent studies of Crohn’s disease 

identifies previously unknown disease loci for ulcerative 

colitis. Nat Genet 2008; 40: 713-715 

20 Brand S. Crohn’s disease: Th1, Th17 or both? The change of 

a paradigm: new immunological and genetic insights implicate 

Th17 cells in the pathogenesis of Crohn’s disease. Gut 

2009; 58: 1152-1167 

21 Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 

Cells. Annu Rev Immunol 2009; 27: 485-517 

22 Annese V, Bassotti G, Napolitano G, Usai P, Andriulli A, 

Vantrappen G. Gastrointestinal motility disorders in patients 

with inactive Crohn’s disease. Scand J Gastroenterol 1997; 32: 

1107-1117 

23 Götze H, Ptok A. Orocaecal transit time in patients with 

Crohn disease. Eur J Pediatr 1993; 152: 193-196 

24 Hyams JS, Fitzgerald JE, Wyzga N, Treem WR, Justinich CJ, 

Kreutzer DL. Characterization of circulating interleukin-1 receptor 

antagonist expression in chil�ren with inflammatory 

bowel disease. Dig Dis Sci 1994; 39: 1893-1899 

25 Kohno N, Nomura M, Okamoto H, Kaji M, Ito S. The use of 



electrogastrography and external ultrasonography to evaluate 

gastric motility in Crohn’s disease. J Med Invest 2006; 53: 

277-284 

26 Akiho H, Lovato P, Deng Y, Ceponis PJ, Blennerhassett P, 

Collins SM. Interleukin-4- and -13-induced hypercontractility 

of human intestinal muscle cells-implication for motility 

changes in Crohn’s disease. Am J Physiol Gastrointest Liver 

Physiol 2005; 288: G609-G615 

27 Akiho H, Blennerhassett P, Deng Y, Collins SM. Role of IL-4, 

IL-13, an� STAT6 in inflammation-in�uce� hypercontractility 

of murine smooth muscle cells. Am J Physiol Gastrointest 

Liver Physiol 2002; 282: G226-G232 

28 Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand 

B, Mankertz J, Gitter AH, Bürgel N, Fromm M, Zeitz M, 

Fuss I, Strober W, Schulzke JD. Interleukin-13 is the key effector 

Th2 cytokine in ulcerative colitis that affects epithelial 

tight junctions, apoptosis, and cell restitution. Gastroenterology 

2005; 129: 550-564 

29 Fuss IJ, Strober W, Dale JK, Fritz S, Pearlstein GR, Puck 

JM, Lenardo MJ, Straus SE. Characteristic T helper 2 T cell 

cytokine abnormalities in autoimmune lymphoproliferative 

syndrome, a syndrome marked by defective apoptosis and 

humoral autoimmunity. J Immunol 1997; 158: 1912-1918 

30 Olsen T, Goll R, Cui G, Husebekk A, Vonen B, Birketvedt 

GS, Florholmen J. Tissue levels of tumor necrosis factoralpha 

correlates with grade of inflammation in untreated 

ulcerative colitis. Scand J Gastroenterol 2007; 42: 1312-1320 

31 Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese 

V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, 

Klei L, Daly MJ, Abraham �, Bayless TM, Bossa F, Griffiths 

AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, 

Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner 

EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor 

KD, Roeder K, Duerr RH. Ulcerative colitis-risk loci on chromosomes 

1p36 and 12q15 found by genome-wide association 

study. Nat Genet 2009; 41: 216-220 

32 Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen 

H, Saito R, Kitazume MT, Nakazawa A, Sugita A, Koganei K, 

Isobe K, Hibi T. IL23 differentially regulates the Th1/Th17 

balance in ulcerative colitis and Crohn’s disease. Gut 2008; 

57: 1682-1689 

33 Dambacher J, Beigel F, Zitzmann K, De Toni EN, Göke B, 

Diepolder HM, Auernhammer CJ, Brand S. The role of the 

novel Th17 cytokine IL-26 in intestinal inflammation. Gut 

2009; 58: 1207-1217 

34 Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte 

JM, Diepolder H, Marquardt A, Jagla W, Popp A, Leclair S, 

Herrmann K, Seiderer J, Ochsenkühn T, Göke B, Auernhammer 

CJ, Dambacher J. IL-22 is increased in active Crohn’s 

�isease an� promotes proinflammatory gene expression an� 

intestinal epithelial cell migration. Am J Physiol Gastrointest 

Liver Physiol 2006; 290: G827-G838 

35 Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, 

Tsujikawa T, Kitoh K, Kim-Mitsuyama S, Takayanagi A, Shimizu 

N, Fujiyama Y. Interleukin-22, a member of the IL-10 

subfamily, in�uces inflammatory responses in colonic subepithelial 

myofibroblasts. Gastroenterology 2005; 129: 969-984 

36 Vrees MD, Pricolo VE, Potenti FM, Cao W. Abnormal motility 

in patients with ulcerative colitis: the role of inflammatory 

cytokines. Arch Surg 2002; 137: 439-445; discussion 445-446 

37 Reddy SN, Bazzocchi G, Chan S, Akashi K, Villanueva- 

Meyer J, Yanni G, Mena I, Snape WJ. Colonic motility and 

transit in health and ulcerative colitis. Gastroenterology 1991; 

101: 1289-1297 

38 Schoen RE, Wald A. Colonic motility in ulcerative colitis: 

muscling in on a mucosal disease? Am J Gastroenterol 1992; 

87: 1674-1675 

39 Terry PD, Villinger F, Bubenik GA, Sitaraman SV. Melatonin 

and ulcerative colitis: evidence, biological mechanisms, and 

future research. Inflamm Bowel Dis 2009; 15: 134-140 


40 Ohama T, Hori M, Fujisawa M, Kiyosue M, Hashimoto M, 

Ikenoue Y, Jinno Y, Miwa H, Matsumoto T, Murata T, Ozaki 

H. Downregulation of CPI-17 contributes to dysfunctional 

motility in chronic intestinal inflammation mo�el mice an� 

ulcerative colitis patients. J Gastroenterol 2008; 43: 858-865 

41 Ohama T, Hori M, Sato K, Ozaki H, Karaki H. Chronic 

treatment with interleukin-1beta attenuates contractions by 

decreasing the activities of CPI-17 and MYPT-1 in intestinal 

smooth muscle. J Biol Chem 2003; 278: 48794-48804 

42 Barquist E, Zinner M, Rivier J, Taché Y. Abdominal surgeryinduced 

delayed gastric emptying in rats: role of CRF and 

sensory neurons. Am J Physiol 1992; 262: G616-G620 

43 Kalff JC, Schraut WH, Simmons RL, Bauer AJ. Surgical manipulation 

of the gut elicits an intestinal muscularis inflammatory 

response resulting in postsurgical ileus. Ann Surg 

1998; 228: 652-663 

44 Kreiss C, Birder LA, Kiss S, VanBibber MM, Bauer AJ. 

�OX-2 �epen�ent inflammation increases spinal Fos expression 

during rodent postoperative ileus. Gut 2003; 52: 527-534 

45 Kreiss C, Toegel S, Bauer AJ. Alpha2-adrenergic regulation 

of NO production alters postoperative intestinal smooth 

muscle dysfunction in rodents. Am J Physiol Gastrointest Liver 

Physiol 2004; 287: G658-G666 

46 Wehner S, Schwarz NT, Hundsdoerfer R, Hierholzer C, 

Tweardy DJ, Billiar TR, Bauer AJ, Kalff JC. Induction of IL-6 

within the rodent intestinal muscularis after intestinal surgical 

stress. Surgery 2005; 137: 436-446 

47 Frasko R, Maruna P, Gurlich R, Trca S. Transcutaneous 

electrogastrography in patients with ileus. Relations to 

interleukin-1beta, interleukin-6, procalcitonin and C-reactive 

protein. Eur Surg Res 2008; 41: 197-202 

48 Moore BA, Albers KM, Davis BM, Grandis JR, Tögel S, 

Bauer AJ. Altere� inflammatory gene expression un�erlies 

increased susceptibility to murine postoperative ileus with 

advancing age. Am J Physiol Gastrointest Liver Physiol 2007; 

292: G1650-G1659 

49 Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative 

ileus. Neurogastroenterol Motil 2004; 16 Suppl 2: 54-60 

50 Kalff JC, Schraut WH, Billiar TR, Simmons RL, Bauer AJ. 

Role of inducible nitric oxide synthase in postoperative intestinal 

smooth muscle dysfunction in rodents. Gastroenterology 

2000; 118: 316-327 

51 Schwarz NT, Kalff JC, Türler A, Engel BM, Watkins SC, 

Billiar TR, Bauer AJ. Prostanoid production via COX-2 as a 

causative mechanism of rodent postoperative ileus. Gastroenterology 

2001; 121: 1354-1371 

52 Mittal RK, Kassab G, Puckett JL, Liu J. Hypertrophy of the 

muscularis propria of the lower esophageal sphincter and 

the body of the esophagus in patients with primary motility 

disorders of the esophagus. Am J Gastroenterol 2003; 98: 

1705-1712 

53 Robertson CS, Martin BA, Atkinson M. Varicella-zoster virus 

DNA in the oesophageal myenteric plexus in achalasia. 

Gut 1993; 34: 299-302 

54 Facco M, Brun P, Baesso I, Costantini M, Rizzetto C, Berto 

A, Baldan N, Palù G, Semenzato G, Castagliuolo I, Zaninotto 

G. T cells in the myenteric plexus of achalasia patients show 

a skewed TCR repertoire and react to HSV-1 antigens. Am J 

Gastroenterol 2008; 103: 1598-1609 

55 Kilic A, Owens SR, Pennathur A, Luketich JD, Landreneau 

RJ, Schuchert MJ. An increase� proportion of inflammatory 

cells express tumor necrosis factor alpha in idiopathic achalasia 

of the esophagus. Dis Esophagus 2009; 22: 382-385 

56 Yan BM, Shaffer EA. Primary eosinophilic disorders of the 

gastrointestinal tract. Gut 2009; 58: 721-732 

57 Pardi DS, Kelly CP. Microscopic colitis. Gastroenterology 

2011; 140: 1155-1165 

58 Tagkalidis PP, Gibson PR, Bhathal PS. Microscopic colitis 

�emonstrates a T helper cell type 1 mucosal cytokine profile. 

J Clin Pathol 2007; 60: 382-387 


59 Green PH, Cellier C. Celiac disease. N Engl J Med 2007; 357: 

1731-1743 

60 Jabri B, Sollid LM. Mechanisms of disease: immunopathogenesis 

of celiac disease. Nat Clin Pract Gastroenterol Hepatol 

2006; 3: 516-525 

61 Spiller R. Recent advances in understanding the role of 

serotonin in gastrointestinal motility in functional bowel disorders: 

alterations in 5-HT signalling and metabolism in human 

disease. Neurogastroenterol Motil 2007; 19 Suppl 2: 25-31 

62 Challacombe DN, Dawkins PD, Baker P. Increased tissue 

concentrations of 5-hydroxytryptamine in the duodenal mucosa 

of patients with coeliac disease. Gut 1977; 18: 882-886 

63 Sjölund K, Nobin A. Increased levels of plasma 5-hydroxytryptamine 

in patients with coeliac disease. Scand J Gastroenterol 

1985; 20: 304-308 

64 Challacombe DN, Brown GA, Black SC, Storrie MH. Increased 

excretion of 5-hydroxyindoleacetic acid in urine of 

children with untreated coeliac disease. Arch Dis Child 1972; 

47: 442-445 

65 Monteleone I, Monteleone G, Del Vecchio Blanco G, Vavassori 

P, Cucchiara S, MacDonald TT, Pallone F. Regulation of 

the T helper cell type 1 transcription factor T-bet in coeliac 

disease mucosa. Gut 2004; 53: 1090-1095 

66 Fernández S, Molina IJ, Romero P, González R, Peña J, Sánchez 

F, Reynoso FR, Pérez-Navero JL, Estevez O, Ortega C, 

Santamaría M. �haracterization of glia�in-specific Th17 cells 

from the mucosa of celiac disease patients. Am J Gastroenterol 

2011; 106: 528-538 

67 Coulie B, Camilleri M. Intestinal pseudo-obstruction. Annu 

Rev Med 1999; 50: 37-55 

68 Selgrad M, De Giorgio R, Fini L, Cogliandro RF, Williams 

S, Stanghellini V, Barbara G, Tonini M, Corinaldesi R, Genta 

RM, Domiati-Saad R, Meyer R, Goel A, Boland CR, Ricciardiello 

L. JC virus infects the enteric glia of patients with 

chronic idiopathic intestinal pseudo-obstruction. Gut 2009; 

58: 25-32 

69 Sanders KM, Ordög T, Ward SM. Physiology and pathophysiology 

of the interstitial cells of Cajal: from bench to 

bedside. IV. Genetic and animal models of GI motility disorders 

caused by loss of interstitial cells of Cajal. Am J Physiol 

Gastrointest Liver Physiol 2002; 282: G747-G756 

70 Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada 

JR, Tytgat GN. Functional gastroduodenal disorders. 

Gut 1999; 45 Suppl 2: II37-II42 

71 Kindt S, Van Oudenhove L, Broekaert D, Kasran A, Ceuppens 

JL, Bossuyt X, Fischler B, Tack J. Immune dysfunction 

in patients with functional gastrointestinal disorders. Neurogastroenterol 

Motil 2009; 21: 389-398 

72 Arisawa T, Tahara T, Shibata T, Nagasaka M, Nakamura M, 

Kamiya Y, Fujita H, Yoshioka D, Arima Y, Okubo M, Hirata 

I, Nakano H. Genetic polymorphisms of molecules associate� 

with inflammation an� immune response in Japanese 

subjects with functional dyspepsia. Int J Mol Med 2007; 20: 

717-723 

73 Futagami S, Shindo T, Kawagoe T, Horie A, Shimpuku M, 

Gudis K, Iwakiri K, Itoh T, Sakamoto C. Migration of eosinophils 

and CCR2-/CD68-double positive cells into the 

duodenal mucosa of patients with postinfectious functional 

dyspepsia. Am J Gastroenterol 2010; 105: 1835-1842 

74 Longstreth GF, Thompson WG, Chey WD, Houghton LA, 

Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 

2006; 130: 1480-1491 

75 Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, 

Wilson I. Activation of the mucosal immune system in irritable 

bowel syndrome. Gastroenterology 2002; 122: 1778-1783 

76 Törnblom H, Lindberg G, Nyberg B, Veress B. Full-thickness 

biopsy of the jejunum reveals inflammation an� enteric neuropathy 

in irritable bowel syndrome. Gastroenterology 2002; 

123: 1972-1979 

77 Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, 



Skinner M, Neal KR. Increased rectal mucosal enteroendocrine 

cells, T lymphocytes, and increased gut permeability 

following acute Campylobacter enteritis and in post-dysenteric 

irritable bowel syndrome. Gut 2000; 47: 804-811 

78 Ohman L, Isaksson S, Lindmark AC, Posserud I, Stotzer PO, 

Strid H, Sjövall H, Simrén M. T-cell activation in patients 

with irritable bowel syndrome. Am J Gastroenterol 2009; 104: 

1205-1212 

79 Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester 

S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann 

G. Immune activation in patients with irritable bowel syndrome. 


80 Dinan TG, Quigley EM, Ahmed SM, Scully P, O’Brien S, O’ 

Mahony L, O’Mahony S, Shanahan F, Keeling PW. Hypothalamic-pituitary-gut 

axis dysregulation in irritable bowel 

syndrome: plasma cytokines as a potential biomarker? Gastroenterology 

2006; 130: 304-311 

81 Scully P, McKernan DP, Keohane J, Groeger D, Shanahan F, 

Dinan TG, Quigley EM. Plasma cytokine profiles in females 

with irritable bowel syndrome and extra-intestinal co-morbidity. 

Am J Gastroenterol 2010; 105: 2235-2243 

82 Kim YS, Ho SB. Intestinal goblet cells and mucins in health 

and disease: recent insights and progress. Curr Gastroenterol 

Rep 2010; 12: 319-330 

83 Galeazzi F, Haapala EM, van Rooijen N, Vallance BA, 

Collins SM. Inflammation-induced impairment of enteric 

nerve function in nematode-infected mice is macrophage 

dependent. Am J Physiol Gastrointest Liver Physiol 2000; 278: 

G259-G265 

84 Ohama T, Hori M, Momotani E, Iwakura Y, Guo F, Kishi H, 

Kobayashi S, Ozaki H. Intestinal inflammation downregulates 

smooth muscle CPI-17 through induction of TNF-alpha 

and causes motility disorders. Am J Physiol Gastrointest Liver 

Physiol 2007; 292: G1429-G1438 

85 Kinoshita K, Sato K, Hori M, Ozaki H, Karaki H. Decrease 

in activity of smooth muscle L-type Ca2+ channels and its 

reversal by NF-kappaB inhibitors in Crohn’s colitis model. 

Am J Physiol Gastrointest Liver Physiol 2003; 285: G483-G493 

86 Schwarz NT, Kalff JC, Türler A, Speidel N, Grandis JR, 

Billiar TR, Bauer AJ. Selective jejunal manipulation causes 

postoperative pan-enteric inflammation and dysmotility. 


87 Akiho H, Khan WI, Al-Kaabi A, Blennerhassett P, Deng Y, 

Collins SM. Cytokine modulation of muscarinic receptors in 

the murine intestine. Am J Physiol Gastrointest Liver Physiol 

2007; 293: G250-G255 

88 Wells RW, Blennerhassett MG. Persistent and selective effects 

of inflammation on smooth muscle cell contractility in 

rat colitis. Pflugers Arch 2004; 448: 515-524 

89 Akiho H, Deng Y, Blennerhassett P, Kanbayashi H, Collins 

SM. Mechanisms underlying the maintenance of muscle hypercontractility 

in a model of postinfective gut dysfunction. 


90 Khan WI, Vallance BA, Blennerhassett PA, Deng Y, Verdu 

EF, Matthaei KI, Collins SM. Critical role for signal transducer 

and activator of transcription factor 6 in mediating 

intestinal muscle hypercontractility and worm expulsion 

in Trichinella spiralis-infected mice. Infect Immun 2001; 69: 

838-844 

91 Zhao A, Urban JF, Anthony RM, Sun R, Stiltz J, van Rooijen 

N, Wynn TA, Gause WC, Shea-Donohue T. Th2 cytokineinduced 

alterations in intestinal smooth muscle function 

depend on alternatively activated macrophages. Gastroenterology 

2008; 135: 217-225.e1 

92 Zhao A, McDermott J, Urban JF, Gause W, Madden KB, 

Yeung KA, Morris SC, Finkelman FD, Shea-Donohue T. Dependence 

of IL-4, IL-13, and nematode-induced alterations 

in murine small intestinal smooth muscle contractility on 

Stat6 and enteric nerves. J Immunol 2003; 171: 948-954 

93 Ihara E, Beck PL, Chappellaz M, Wong J, Medlicott SA, 



MacDonald JA. Mitogen-activated protein kinase pathways 

contribute to hypercontractility and increased Ca2+ sensitization 

in murine experimental colitis. Mol Pharmacol 2009; 75: 

1031-1041 

94 Camilleri M, Atanasova E, Carlson PJ, Ahmad U, Kim HJ, 

Viramontes BE, McKinzie S, Urrutia R. Serotonin-transporter 

polymorphism pharmacogenetics in diarrhea-predominant 

irritable bowel syndrome. Gastroenterology 2002; 123: 425-432 

95 Crowell MD, Shetzline MA, Moses PL, Mawe GM, Talley 

NJ. Enterochromaffin cells an� 5-HT signaling in the pathophysiology 

of disorders of gastrointestinal function. Curr 

Opin Investig Drugs 2004; 5: 55-60 

96 Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, 

Blaszyk H, Crowell MD, Sharkey KA, Gershon MD, Mawe 

GM, Moses PL. Molecular defects in mucosal serotonin content 

and decreased serotonin reuptake transporter in ulcerative 

colitis and irritable bowel syndrome. Gastroenterology 

2004; 126: 1657-1664 

97 Garvin B, Wiley JW. The role of serotonin in irritable bowel 

syndrome: implications for management. Curr Gastroenterol 

Rep 2008; 10: 363-368 

98 Motomura Y, Ghia JE, Wang H, Akiho H, El-Sharkawy RT, 

Collins M, Wan Y, McLaughlin JT, Khan WI. Enterochromaffin 

cell an� 5-hy�roxytryptamine responses to the same infectious 

agent differ in Th1 and Th2 dominant environments. 

Gut 2008; 57: 475-481 

99 Murao H, Akiho H, Mizutani T, Yamada M, Tokunaga N, 

Aso A, Ogino H, Kanayama K, Sumida Y, Iboshi Y, Itaba S, 

Nakamura K, Takayanagi R, Khan WI. Reciprocal modulation 

of smooth muscle cell contractility in Th1 and Th2 

dominant environments using murine model of early post 

inflammatory gut �ysfunction. (Abstract) T1778 DDW 2009 

100 Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, 

Kakuta S, Sudo K, Iwakura Y. IL-17 plays an important role 

in the development of experimental autoimmune encephalomyelitis. 

J Immunol 2006; 177: 566-573 

101 Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of 

immune induction of collagen-induced arthritis in IL-17- 

�eficient mice. J Immunol 2003; 171: 6173-6177 


102 Fu Y, Wang W, Tong J, Pan Q, Long Y, Qian W, Hou X. 

Th17: a new participant in gut dysfunction in mice infected 

with Trichinella spiralis. Mediators Inflamm 2009; 2009: 517052 

103 Akiho H, Nakamura K. Daikenchuto ameliorates muscle 

hypercontractility in a murine T-cell-mediated persistent gut 

motor dysfunction model. Digestion 2011; 83: 173-179 

104 Huang J, Mahavadi S, Sriwai W, Hu W, Murthy KS. Gicoupled 

receptors mediate phosphorylation of CPI-17 and 

MLC20 via preferential activation of the PI3K/ILK pathway. 

Biochem J 2006; 396: 193-200 

105 Gerthoffer WT. Signal-transduction pathways that regulate 

visceral smooth muscle function. III. Coupling of muscarinic 

receptors to signaling kinases and effector proteins in gastrointestinal 

smooth muscles. Am J Physiol Gastrointest Liver 

Physiol 2005; 288: G849-G853 

106 Somlyo AP, Somlyo AV. Signal transduction and regulation 

in smooth muscle. Nature 1994; 372: 231-236 

107 Somlyo AP, Somlyo AV. Ca2+ sensitivity of smooth muscle 

and nonmuscle myosin II: modulated by G proteins, kinases, 

and myosin phosphatase. Physiol Rev 2003; 83: 1325-1358 

108 Taylor DA, Stull JT. Calcium dependence of myosin light 

chain phosphorylation in smooth muscle cells. J Biol Chem 

1988; 263: 14456-14462 

109 Hartshorne DJ, Ito M, Erdödi F. Role of protein phosphatase 

type 1 in contractile functions: myosin phosphatase. J 

Biol Chem 2004; 279: 37211-37214 

110 Eto M, Ohmori T, Suzuki M, Furuya K, Morita F. A novel 

protein phosphatase-1 inhibitory protein potentiated by protein 

kinase C. Isolation from porcine aorta media and characterization. 

J Biochem 1995; 118: 1104-1107 

111 Hu W, Mahavadi S, Li F, Murthy KS. Upregulation of RGS4 

and downregulation of CPI-17 mediate inhibition of colonic 

muscle contraction by interleukin-1beta. Am J Physiol Cell 

Physiol 2007; 293: C1991-C2000 

112 Hu W, Li F, Mahavadi S, Murthy KS. Upregulation of RGS4 

expression by IL-1beta in colonic smooth muscle is enhanced 

by ERK1/2 and p38 MAPK and inhibited by the PI3K/ 

Akt/GSK3beta pathway. Am J Physiol Cell Physiol 2009; 296: 

C1310-C1320 

S- Editor Wu X L- Editor Hughes D E- Editor Zheng XM 




doi:10.4291/wjgp.v2.i5.82 




Role of connexin-related signalling in hepatic homeostasis 

and its relevance for liver-based in vitro modelling 

Mathieu Vinken 

Mathieu Vinken, Department of Toxicology, Faculty of Medicine 

and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 

B-1090 Brussels, Belgium 

Author contributions: Vinken M solely contributed to this 

manuscript. 

Correspondence to: Mathieu Vinken, �ro�essor, �ro�essor, �h�, �h�, �har� �har� 

m�, ERT, Department of Toxicology, Faculty of Medicine and 

Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 

Brussels, Belgium. mvinken@vub.ac.be 

Telephone: +32-2-4774587 Fax: +32-2-4774582 

Received: January 3, 2011 Revised: September 2, 2011 

Accepted: September 9, 2011 

�ublished online: October 15, 2011 

Abstract 

�irect intercellular communication mediated by gap 

junctions constitutes a major regulatory plat�orm in 

the control o� hepatic homeostasis. Hepatocellular gap 

junctions are composed o� two hemichannels o� ad� 

jacent cells which are built up by connexin proteins, 

in casu Cx32. Mathieu Vinken, �o�essor at the �epart� 

ment o� Toxicology o� the Free University Brussels� 

Belgium, was one of the first investigators to demon� 

strate that hepatic connexin expression is controlled 

by epigenetic mechanisms. In particular, he �ound that 

inhibitors o� histone deacetylase enzymes enhance 

Cx32 production and gap junction activity in cultures 

of primary hepatocytes, a finding that is of importance 

�or liver�based in vitro modelling. �ro�essor �r. Math� 

ieu Vinken’s recent work is �ocussed on the elucidation 

o� the role o� connexin proteins and their channels in 

the hepatocyte life cycle. Specific attention is paid to 

apoptosis in this context, whereby it has been �ound 

that Cx32 hemichannels control the termination o� in� 

duced cell death in cultures o� primary hepatocytes. 

Overall, �ro�essor �r. Mathieu Vinken’s research can be 

considered as an important contribution to the field of 

hepatic connexin physiology. 



AutobiogrAphy of EditoriAl boArd MEMbErs 

Key words: Connexin; Hemichannel; Gap junction; 

�rimary hepatocyte; In vitro modelling; Epigenetics; 

Histone modifications; Cell death; Apoptosis; Hepato� 

toxicity 

Peer reviewer: Julnar Usta, Professor, Department of Biochemistry 

and Molecular Genetics, American University of Beirut, 

DTS bldg, Beirut 11-0236, Lebanon 

Vinken M. Role of connexin-related signalling in hepatic homeostasis 

and its relevance for liver-based in vitro modelling. World 

J Gastrointest Pathophysiol 2011; 2(5): 82-87 Available from: 

URL: http://www.wjgnet.com/2150-5330/full/v2/i5/82.htm DOI: 

http://dx.doi.org/10.4291/wjgp.v2.i5.82 

INTRODUCTION AND EDUCATIONAL 

EXPERIENCE 

Figure 1 Mathieu Vinken, Professor, 

PhD, PharmD, ERT, Department 

of Toxicology, Faculty of Medicine 

and Pharmacy, Vrije Universiteit 

Brussel, Laarbeeklaan 103, B-1090 

Brussels, Belgium. 

Mathieu Vinken (Figure 1) received his master’s degree in 

pharmaceutical sciences at the Free University Brussels- 

Belgium (VUB) in 2001. In the same year, he stepped 

into a doctoral research project at the Department of 

Toxicology of the VUB under supervision of Professor 

Dr. Vera Rogiers and Professor Dr. Tamara Vanhaecke. 


During this research, entitled “effects of hydroxamate 

histone deacetylase (HDAC) inhibitors on the expression 

of connexins in primary cultures of rat hepatocytes”, he 

was a doctoral research fellow of the Fund for Scientific 

Research Flanders-Belgium (FWO). In 2006, he successfully 

completed and publicly defended his doctoral 

research project and received the degree of doctor in 

pharmaceutical sciences. He continued his efforts in 

the field of connexin research in a subsequent FWO 

postdoctoral project called “elucidation of the role of 

connexin proteins in the control of hepatocellular homeostasis: 

development evelopment of a a hepatocyte-based 

hepatocyte-based in vitro model 

for preclinical pharmaco-toxicological research”. In 2011, 

he became a tenure track professor and presently is still 

pursing the connexin research track. Professor Dr. Vinken’s 

work has so far resulted in as many as sixty scientific 

publications in peer-reviewed journals and books. He is 

co-inventor of two patent applications and has been an 

invited speaker at several international and world conferences. 

Professor Dr. Vinken acts as a peer reviewer of 

many scientific journals and as an evaluator of project 

and grant applications for national and international research 

associations and agencies. He is frequently asked 

as a jury member for master and doctoral thesis defences 

and is co-organizer of a number of international scientific 

congresses and courses. Professor Dr. Vinken is a regular 

member of five scientific societies in the area of toxicology 

and is an executive board member of the European 

Society of Toxicology in vitro itro. He is co-founder of the 

FWO group of excellence called “connexin and pannexin 

channels: regulation, function and applications” and has 

received two awards for his work. Professor Dr. Vinken is 

a trained European Chemical Risk Assessor and a European 

Registered Toxicologist. He is actively involved in a 

number of European research projects in the Sixth (FP6) 

and Seventh (FP7) Framework Programme dealing with 

the development of in vitro assays for the toxicity testing 

of chemical compounds. Being an academic and given 

his background in pharmaceutical sciences, Professor 

Dr. Vinken has been an assistant for the practical course 

“pharmaceutical technology: preparations for internal 

use” for a number of years. He was also involved in the 

organization of the “integrated practical course of biopharmacy” 

and “toxicology”, and presently is responsible 

for the practical course “applied toxicology”. Professor 

Dr. Vinken is co-promoter of two doctoral theses in 

pharmaceutical sciences and has supervised several master 

thesis projects. Most of these dissertations serve as contributions 

to the Professor Dr. Vinken’s research on the 

roles of connexins and their channels in hepatic homeostasis 

and its relevance for liver-based in vitro modelling, as 

will be outlined in the following section. 

ACADEMIC AC�IE�EMENT� 

AC�IE�EMENT� 

General research context 

Cultures of primary hepatocytes are generally considered 

as the golden standard in the field of liver-based in vitro 


Vinken M. Hepatic connexin and liver�based in vitro modelling 

modelling since they provide a good reflection of the 

hepatic in vivo situation. In fact, these in vitro systems 

are abundantly used in several research fields, including 

pharmaco-toxicology and liver (patho)physiology. A 

major shortcoming of cultures of primary hepatocytes, 

however, is that they can only be used for short-term applications 

due to the occurrence of dedifferentiation, i.e., 

the progressive loss of the differentiated phenotype at 

the morphological level and at the functional level. Over 

the years, a number of strategies have been developed to 

counteract this dedifferentiation process. Such protocols 

are mainly based on mimicking the natural hepatocyte 

micro-environment in vitro, for instance by re-establishing 

cell-cell and cell-extracellular matrix contacts, but have 

only been of rather limited success [1-3] . In the last decade, 

the Department of Toxicology-VUB has explored a 

novel anti-dedifferentiation strategy for cultured hepatocytes 

based on chromatin remodelling. In this approach, 

HDAC inhibitors are used as culture medium additives 

for primary hepatocytes. These epigenetic modifiers 

interfere with the chromatin structure and thereby alter 

transcriptional activity [2-6] . Research from the Department 

of Toxicology-VUB collectively showed that HDAC 

inhibitors suppress spontaneous cell death [7] , induce cell 

cycle arrests [8,9] and concomitantly promote the (functional) 

differentiated phenotype in cultures of primary 

rat hepatocytes [10,11] . This is also associated with enhanced 

gap junctional communication between the hepatocytes. 

Gap junctional intercellular communication (GJIC) 

denotes the passive flux of small and hydrophilic homeostasis 

regulators between cells. Gap junctions consist 

of two hemichannels of neighbouring cells, which 

in turn are built up by six connexin proteins (Figure 2). 

Connexin proteins are expressed in a cell-specific manner 

and are named after their molecular weight [3,12-16] . In 

the liver, hepatocytes produce Cx32 (32 kDa), next to 

small amounts of Cx26 (26 kDa). By contrast, non-parenchymal 

liver cells, including Kupffer cells and stellate 

cells, mainly express Cx43 (43 kDa) [3,14] . As such, GJIC is 

considered as a key mechanism in the control of tissue 

homeostasis. It has indeed been shown that GJIC plays a 

crucial role in the performance of liver-specific functionality, 

particularly in xenobiotic biotransformation capacity 

and albumin secretory activity, as well as in hepatocyte 

proliferation [3,14,15] . The involvement of GJIC in (hepatocyte) 

apoptosis is less clear. In fact, the latter constitutes a 

relatively new research field, which has been complicated 

by the finding that structural precursors of gap junctions 

can affect tissue homeostasis by performing actions 

not related to GJIC. Thus, connexin hemichannels also 

foresee a pathway for communication, albeit between 

the intracellular compartment and the extracellular environment, 

while connexin proteins as such can directly 

or indirectly influence the production of homeostasis 

regulators independently of their channel activities. Furthermore, 

a novel set of connexin-like proteins, the socalled 

pannexins, have lately joined in as regulators of 

the homeostatic balance (Figure 3) [12,16,17] . Such atypical 



Gap junction 

functions of connexins and their channels, specifically 

in the context of hepatocyte apoptosis, define Professor 

Dr. Vinken’s second area of interest, as will be clarified 

further in this paper. 

Study of epigenetic regulation of hepatocellular connexin 

expression 

Given its importance in the maintenance of tissue homeo- 


�laque 

NT 

EL 

CL 

TM 

CT 

Hemichannel 

Connexin 

Figure 2�� Molecular Molecular architecture architecture of of gap gap junctions. junctions. Gap junctions are grouped in plaques at the cell plasma membrane surface and are composed of twelve connexin 

proteins, organized as two hexameric hemichannels of two apposed cells. The connexin protein as such is organized as four membrane-spanning domains 

(TM1-4), two extracellular loops (EL1-2), one c�toplasmic c�toplasmic �toplasmic loop (�L), (�L), (�L), one c�toplasmic c�toplasmic c�toplasmic c�toplasmic �toplasmic amino amino tail tail (�T) (�T) (�T) (�T) (�T) and and one one c�toplasmic c�toplasmic c�toplasmic c�toplasmic c�toplasmic c�toplasmic �toplasmic carbox� carbox� carbox� carbox� carbox� carbox� carbox� tail tail tail (�T). (�T). (�T). (�T). (�T). (�T). (�T). 

Alendronate 

Src 

4 

ERK 

AT� 

Glutathione 

Na + , Ca 2+ , ROS 

Glucose 

pBad 

p90 RSK 

pC/EB�b 

5 

2 

Mitochondrium 

Adenosine, glutamate, prostaglandin E2 

AT� 

Glucose, ascorbic acid, 

AT�, reduced glutathione 

1 

Ca 2+ , I�3, AT�, cAM�, cGM� 

GCV, viral proteins 

Factors promoting cell death 

Factors promoting cell survival 

Factors promoting cell death and cell survival 

3 

Nucleus 

Bax, Bak 

Bcl�xL, ASK1 

�ro�apoptotic genes 

Anti�apopototic genes 

Figure 3 �onnexin-related �onnexin-related �onnexin-related signaling in cell death. �onnexins can affect the cell death process through a number of mechanisms, involving GJI� (1), hemichannels 

(2-5) and connexins proteins as such (6, �). �). �). Gap junctions can accommodate direct exchange exchange of of cell cell death death and and cell cell survival survival signals signals between between cells cells (1). (1). �emichan- 

�emichan�emichannels 

ma� contribute to cell death b� four different mechanisms, namel� b� the entr� of cell death or the loss of cell survival signals (2), through paracrine signaling of 

death or survival messengers (3), b� hemichannel-mediated transmembrane signal transduction (4), or b� affecting mitochondrial functioning (5). �onnexin proteins 

as such can associate with cell death regulators (6) or influence the expression of these molecules (7). Hemichannels composed of pannexins may act as a permeabilization 

pore b� itself or as a part of the P2X�R death complex (8), allowing adenosine denosine triphosphate (�TP) (�TP) (�TP) to leave the cell or bacterial molecules to ma�e ma�e ma�e their 

way into the cell. Although solid scientific data are currently not available, both processes might contribute to cell death. It should be noted that many of the first and 

second messengers depicted are not cell death or survival messengers per se, but rather substances that may lead to cell death or survival under specific conditions 

that are discussed in the text. �SK1�� poptosis �poptosis �poptosis �poptosis poptosis signal-regulating signal-regulating �inase �inase �inase �inase �inase 1�� 1�� 1�� 1�� 1�� c�MP�� c�MP�� c�MP�� c�MP�� c�MP�� clic ��clic ��clic ��clic ��clic ��clic ��clic ��clic �clic adenosine adenosine adenosine monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� cGMP�� cGMP�� cGMP�� cGMP�� cGMP�� cGMP�� cGMP�� cGMP�� cGMP�� clic ��clic ��clic ��clic ��clic ��clic ��clic ��clic ��clic ��clic ��clic ��clic �clic guanosine guanosine guanosine guanosine guanosine monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� monophosphate�� ERK�� ERK�� ERK�� ERK�� ERK�� ERK�� ERK�� ERK�� ERK�� ERK�� ERK�� ERK�� ERK�� 

Extracellular xtracellular signal-regulated �inase�� inase�� G�� G�� Ganciclovir�� Ganciclovir�� Ganciclovir�� Ganciclovir�� Ganciclovir�� anciclovir�� IP 

IP3�� IP 

Inositol nositol trisphosphate�� trisphosphate�� trisphosphate�� trisphosphate�� p�ad�� p�ad�� p�ad�� p�ad�� Phosphor�lated Phosphor�lated Phosphor�lated Phosphor�lated Phosphor�lated hosphor�lated �ad�� ad�� ad�� ad�� ad�� ad�� p��E�P�� p��E�P�� p��E�P�� p��E�P�� p��E�P�� p��E�P�� Phosphor�lated Phosphor�lated Phosphor�lated Phosphor�lated Phosphor�lated Phosphor�lated Phosphor�lated Phosphor�lated Phosphor�lated hosphor�lated ��T�enhancer-binding 

��T�enhancer-binding 









protein�� ROS�� Reactive eactive ox�gen ox�gen ox�gen ox�gen ox�gen species. 

species. 

stasis, a well-orchestrated control of GJIC is critical. At 

the transcriptional level, the classical cis/trans machinery is 

known to act as a major gatekeeper of connexin expression 

[13] . In the last decades, it has become clear that epigenetic 

determinants also drive gene transcription. Professor 

Dr. Vinken was among the first to demonstrate that epigenetic 

mechanisms, particularly reversible histone acetylation, 

are essentially involved in the control of connexin 

84 October 15, 2011|Volume 2|Issue 5| 

6 

7

production. In a pilot study, cultures of primary rat hepatocytes 

were exposed to the prototypical HDAC inhibitor 

Trichostatin A (TSA) and it was found that TSA increases 

Cx32 protein levels but negatively affects the Cx26 protein 

amounts. The latter was preferentially located in the 

cytoplasm of the cultured cells. TSA also promoted the 

appearance of Cx43 in the nuclear compartment of primary 

cultured hepatocytes. This connexin species is not 

expressed by hepatocytes in vivo but becomes increasingly 

detectable upon cultivation of freshly isolated primary rat 

hepatocytes. Overall, the TSA-induced connexin modifications 

resulted in enhanced GJIC activity [18] . 

In a subsequent study, a similar experimental set-up 

was used, whereby the metabolically more stable TSA 

structural analogue 5-(4-dimethylaminobenzoyl)-aminovaleric 

acid hydroxamide (4-Me2N-BAVAH) was added 

to the cell culture medium of the primary rat hepatocytes. 

With the exception of Cx43 protein levels, which 

were negatively affected by 4-Me2N-BAVAH, the findings 

were identical to those obtained with TSA. In the same 

study, the biological impact of 4-Me2N-BAVAH on adherens 

junctions was investigated, being a group of cell 

contacts composed of cadherin-catenin complexes that 

mediate intercellular adhesion. Neither the expressions 

nor the cellular localizations of E-cadherin, b-catenin and 

γ-catenin were altered by 4-Me2N-BAVAH [19] . 

In summary, Professor Dr. Vinken’s studies show that 

HDAC inhibitors positively affect GJIC in cultures of 

primary rat hepatocytes. This finding further underscores 

the potential of the epigenetics-based strategy to counteract 

hepatocellular dedifferentiation in vitro, which is 

thoroughly explored by the Department of Toxicology- 

VUB. In addition, the differential effects of the HDAC 

inhibitors on connexin proteins in cultures of primary rat 

hepatocytes suggest distinct roles of the different connexin 

species in the control of hepatic homeostasis. 

Establishment and application of an in vitro model of 

liver cell death 

The Department of Toxicology-VUB has a long-standing 

expertise in the development and optimization of liverbased 

in vitro systems. Particular attention has been paid 

to the establishment of in vitro models of hepatocyte proliferation 

[20] and (functional) differentiation [10] . Professor 

Dr. Vinken has been in charge of a project that was 

targeted towards the introduction of an in vitro system 

that enabled the study of the third cornerstone of hepatic 

homeostasis, namely cell death. In this research, 

emphasis was on Fas-mediated cell death, which is a cell 

death mode that is of major physiological and pathological 

relevance, in casu in liver disease and hepatotoxicity. 

The developed in vitro model consists of freshly isolated 

rat hepatocytes, cultured in a monolayer configuration, 

that are exposed to a combination of Fas ligand and cycloheximide. 

This in vitro setting has been biochemically 

characterized by addressing a set of well-acknowledged 

cell death markers. In essence, the developed and fully 

characterized in vitro system allowed the entire course of 



Fas-mediated hepatocellular apoptotic cell death to be 

monitored, going from early apoptosis towards the transition 

to a (secondary) necrotic phenotype [21] . 

The produced in vitro model of liver cell death was 

subsequently applied in a number of studies. In a first 

study, the effects of cell death on the expression of 

DNA methyltransferase (DNMT) isoenzymes were 

investigated. DNMT isoenzymes mediate DNA methylation, 

an epigenetic mechanism that acts in concert 

with histone (de)acetylation in gene transcriptional control. 

Similarly to the hepatic in vivo situation, DNMT1, 

DNMT2 and DNMT3b could not be detected in cultures 

of primary rat hepatocytes, whereas relatively high levels 

of DNMT3a protein were observed. Upon induction of 

Fas-mediated cell death, a progressive decrease in DN- 

MT3a protein amount was noticed which was preceded 

by parallel changes in DNMT3a mRNA production. This 

finding suggests the existence of an epigenetic signature 

of hepatocyte apoptosis [22] . 

In a second study, the outcome of Fas-mediated cell 

death on adherens junctions was investigated. Basically, it 

was found that E-cadherin expression gradually declined 

during the cell death process, whereas both b-catenin and 

γ-catenin were progressively degraded, yielding a number 

of proteolytic fragments. These results support the notion 

that dismantling of adherens junctions during hepatocyte 

apoptosis depends on proteolytic processing of its 

components [23] . 

Elucidation of the role of connexins and their channels 

in cell death 

In the light of Professor Dr. Vinken’s interest in gap 

junction biology and physiology, most efforts were put in 

to the application of the developed cell death model for 

investigating the fate of Cx32 and its channels in hepatocellular 

apoptosis. This research revealed that GJIC rapidly 

declines upon progression of cell death in cultures 

of primary rat hepatocytes, which is associated with a decay 

of the gap junctional Cx32 protein pool. Simultaneously, 

levels of newly synthesized Cx32 protein increase 

and gather in a hemichannel configuration. This becomes 

particularly evident towards the end stages of the cell 

death process and is not reflected at the transcriptional 

level. The silencing of Cx32 expression and the inhibition 

of Cx32 hemichannel activity prior to cell death induction 

both result in a delayed termination of the cell death 

response. Based on these findings, it was concluded that 

Cx32 hemichannels facilitate the apoptotic-to-necrotic 

transition during Fas-mediated cell death [24] . 

Professor Dr. Vinken was also actively involved in a 

study whereby apoptosis was induced in rat glioma cells, 

stably transfected with Cx43, by in situ electroporation 

with cytochrome C. Work with various cell death markers, 

wild-type and Cx43-expressing cells, GJIC inhibitors and 

hemichannel inhibitors, and Cx43 gene silencing showed 

that gap junctions contribute to the spread of apoptosis 

in a zone next to where apoptosis was triggered, whereas 

hemichannels also promoted cell death beyond this area. 



It was concluded that Cx43 hemichannels, in conjunction 

with their gap junction counterparts, play a role in communicating 

cytochrome C-induced apoptotic cell death 

messages [25] . 

In an ongoing study conducted by Professor Dr. Vinken, 

the relevance of induced Cx43 expression in cultures 

of primary rat hepatocytes is investigated. It is anticipated 

that Cx43 plays a role in spontaneous cell death in this 

in vitro setting, which is an inevitable consequence of the 

dedifferentiation process. To investigate the relevance of 

this hypothesis, a number of Cx43 inhibitor strategies has 

been developed and applied, and their outcome on cell 

death parameters is tested. The preliminary results support 

the assumption that Cx43 mediates the spontaneous cell 

death phenomenon in cultures of primary rat hepatocytes. 

Current experiments are focussed on the involvement of 

the different Cx43 channel types in this process as well as 

on the large-scale outcome of the Cx43 inhibitor strategies 

on the hepatocellular phenotype by applying omicsbased 

technologies. 

CONCLU�ION 

Professor Dr. Vinken’s studies show that GJIC can be 

upregulated in cultures of primary rat hepatocytes by 

inhibition of HDAC enzymes, which not only fundamentally 

shows that gap junctions are subjective to epigenetic 

regulation but which is also of utmost importance for the 

development of liver-based in vitro models that can be used 

for long-term research and screening purposes. Experiments 

are planned to investigate whether other determinants 

of the epigenome, including DNA methylation and 

microRNA-related mechanisms, are equally involved in 

GJIC control. Professor Dr. Vinken’s work also shows that 

connexin proteins and their channels fulfil critical functions 

in spontaneous and induced hepatocyte apoptosis, which 

as such contributes to the overall study of the relevance of 

connexin-related signalling in liver homeostasis. Future research 

will be focussed on the role of pannexin-based communication 

in several aspects of the hepatocyte life cycle. 

ACKNOWLEDGMENT� 

The several studies presented in this paper were financially 

supported by grants of the FWO, the research council 

of the VUB and the European Union. Professor Dr. 

Vinken is grateful to the past and present members of 

the Department of Toxicology-VUB for their contributions 

to his work. Professor Dr. Vinken also wishes to express 

his gratitude to Professor Dr. Paolo Meda (University 

of Geneva-Switzerland), Professor Dr. James Kevin 

Chipman (University of Birmingham-United Kingdom), 

Professor Dr. Geert Bultynck (University of Leuven- 

Belgium) and Professor Dr. Luc Leybaert (University of 

Ghent-Belgium) for the fruitful collaboration. 

REFERENCE� 

1 Elaut G, Henkens T, Papeleu P, Snykers S, Vinken M, Van- 


haecke T, Rogiers V. Molecular mechanisms underlying the 

dedifferentiation process of isolated hepatocytes and their 

cultures. Curr Drug Metab 2006; 7: 629-660 

2 Papeleu P, Vanhaecke T, Rogiers V. Histone deacetylase 

eacetylase 

inhibition: nhibition: a differentiation differentiation ifferentiation therapy therapy herapy for for cultured cultured ultured primary 

primary 

primary rimary 

hepatocytes�� 

epatocytes�� Curr Enzym Inhib 2006; 2: 91-104 

3 Vinken M, Papeleu P, Snykers S, De Rop E, Henkens T, 

Chipman JK, Rogiers V, Vanhaecke T. Involvement of cell 

junctions in hepatocyte culture functionality. Crit Rev Toxicol 

2006; 36: 299-318 

4 Papeleu P, Vanhaecke T, Elaut G, Vinken M, Henkens T, 

Snykers S, Rogiers V. Differential effects of histone deacetylase 

inhibitors in tumor and normal cells-what is the toxicological 

relevance�� Crit Rev Toxicol 2005; 35: 363-378 

5 Vanhaecke T, Papeleu P, Elaut G, Rogiers V. Trichostatin 

A-like hydroxamate histone deacetylase inhibitors as therapeutic 

agents: toxicological point of view. Curr Med Chem 

2004; 11: 1629-1643 

6 Vinken M, Peggy P, Vera R, Tamara V. Histone deacetylase 

inhibitors as potent modulators of cellular contacts. Curr 

Drug Targets 2006; 7: 773-787 

7 Vanhaecke T, Henkens T, Kass GE, Rogiers V. Effect of the 

histone deacetylase inhibitor trichostatin A on spontaneous 

apoptosis in various types of adult rat hepatocyte cultures. 

Biochem Pharmacol 2004; 68: 753-760 

8 Papeleu P, Loyer P, Vanhaecke T, Elaut G, Geerts A, Guguen- 

Guillouzo C, Rogiers V. Trichostatin A induces differential 

cell cycle arrests but does not induce apoptosis in primary 

cultures of mitogen-stimulated rat hepatocytes. J Hepatol 

2003; 39: 374-382 

9 Papeleu P, Wullaert A, Elaut G, Henkens T, Vinken M, Laus 

G, Tourwé D, Beyaert R, Rogiers V, Vanhaecke T. Inhibition 

of NF-kappaB activation by the histone deacetylase inhibitor 

4-Me2N-BAVAH induces an early G1 cell cycle arrest in primary 

hepatocytes. Cell Prolif 2007; 40: 640-655 

10 Henkens T, Papeleu P, Elaut G, Vinken M, Rogiers V, Vanhaecke 

T. Trichostatin A, a critical factor in maintaining the 

functional differentiation of primary cultured rat hepatocytes. 

Toxicol Appl Pharmacol 2007; 218: 64-71 

11 Henkens T, Snykers S, Vinken M, Fraczek J, Lukaszuk A, 

Tourwé D, Verheyen G, Van Gompel J, Vanparys P, Rogiers 

V, Vanhaecke T. Preservation of hepatocellular functionality 

in cultures of primary rat hepatocytes upon exposure to 

4-Me2N-BAVAH, a hydroxamate-based HDAC-inhibitor. 

Toxicol In Vitro 2011; 25: 100-109 

12 Vinken M, Vanhaecke T, Papeleu P, Snykers S, Henkens T, 

Rogiers V. Connexins and their channels in cell growth and 

cell death. Cell Signal 2006; 18: 592-600 

13 Vinken M, De Rop E, Decrock E, De Vuyst E, Leybaert L, 

Vanhaecke T, Rogiers V. Epigenetic regulation of gap junctional 

intercellular communication: more than a way to keep 

cells quiet�� Biochim Biophys Acta 2009; 1795: 53-61 

14 Vinken M, Henkens T, De Rop E, Fraczek J, Vanhaecke T, 

Rogiers V. Biology and pathobiology of gap junctional channels 

in hepatocytes. Hepatology 2008; 47: 1077-1088 

15 Vinken M, Doktorova T, Decrock E, Leybaert L, Vanhaecke 

T, Rogiers V. Gap junctional intercellular communication as 

a target for liver toxicity and carcinogenicity. Crit Rev Biochem 

Mol Biol 2009; 44: 201-222 

16 Vinken M, Decrock E, De Vuyst E, Ponsaerts R, D’hondt C, 

Bultynck G, Ceelen L, Vanhaecke T, Leybaert L, Rogiers V. 

Connexins: sensors and regulators of cell cycling. Biochim 

Biophys Acta 2011; 1815: 13-25 

17 Decrock E, Vinken M, De Vuyst E, Krysko DV, D’Herde K, 

Vanhaecke T, Vandenabeele P, Rogiers V, Leybaert L. Connexin-related 

signaling in cell death: to live or let die�� Cell 

Death Differ 2009; 16: 524-536 

18 Vinken M, Henkens T, Vanhaecke T, Papeleu P, Geerts A, 

Van Rossen E, Chipman JK, Meda P, Rogiers V. Trichostatin 

a enhances gap junctional intercellular communication in 

primary cultures of adult rat hepatocytes. Toxicol Sci 2006; 


91: 484-492 

19 Vinken M, Henkens T, Snykers S, Lukaszuk A, Tourwé D, 

Rogiers V, Vanhaecke T. The novel histone deacetylase inhibitor 

4-Me2N-BAVAH differentially affects cell junctions 

between primary hepatocytes. Toxicology 2007; 236: 92-102 

20 Henkens T, Vinken M, Lukaszuk A, Tourwé D, Vanhaecke 

T, Rogiers V. Differential effects of hydroxamate histone 

deacetylase inhibitors on cellular functionality and gap junctions 

in primary cultures of mitogen-stimulated hepatocytes. 

Toxicol Lett 2008; 178: 37-43 

21 Vinken M, Decrock E, De Vuyst E, Leybaert L, Vanhaecke T, 

Rogiers V. Biochemical characterisation of an in vitro model 

of hepatocellular apoptotic cell death. Altern Lab Anim 2009; 

37: 209-218 

22 Vinken M, Snykers S, Fraczek J, Decrock E, Leybaert L, Rogiers 

V, Vanhaecke T. DNA methyltransferase 3a expression 

decreases during apoptosis in primary cultures of hepato- 



cytes. Toxicol In Vitro 2010; 24: 445-451 

23 Vinken M, Decrock E, Leybaert L, Vanhaecke T, Rogiers V. 

Proteolytic cleavage of adherens junction components during 

Fas-dependent cell death in primary cultures of rat hepatocytes. 

ALTEX 2010; 27: 151-157 -157 157 

24 Vinken M, Decrock E, De Vuyst E, De Bock M, Vandenbroucke 

RE, De Geest BG, Demeester J, Sanders NN, Vanhaecke 

T, Leybaert L, Rogiers V. Connexin32 hemichannels 

contribute to the apoptotic-to-necrotic transition during Fasmediated 

hepatocyte cell death. Cell Mol Life Sci 2010; 67: 

907-918 

25 Decrock E, De Vuyst E, Vinken M, Van Moorhem M, 

Vranckx K, Wang N, Van Laeken L, De Bock M, D’Herde K, 

Lai CP, Rogiers V, Evans WH, Naus CC, Leybaert L. Connexin 

43 hemichannels contribute to the propagation of apoptotic 

cell death in a rat C6 glioma cell model. Cell Death Differ 2009; 

16: 151-163 

S- Editor Wu X L- Editor Roemmele A E- Editor Zheng XM 





ACKNOWLEDGMENTS 

Acknowledgments to reviewers of World Journal of 

Gastrointestinal Pathophysiology 

Many reviewers have contributed their expertise and 

time to the peer review, a critical process to ensure the 

quality of World Journal of Gastrointestinal Pathophysiology. 

The editors and authors of the articles submitted to 

the journal are grateful to the following reviewers for 

evaluating the articles (including those published in this 

issue and those rejected for this issue) during the last 

editing time period. 

Zhao-Xiang Bian, Professor, School of Chinese Medicine, 

Hong Kong Baptist University, Hong Kong, China 

Shi Liu, Professor, Union Hospital of Tongji Medical College, 

Department of Gastroenterology, Huazhong University of Science 

and Technology, 1277 Jie Fang Road, Wuhan 430022, Hubei 

Province, China 

Daniel Keszthelyi, Dr., Institute of Maastricht, PO Box 5800, 

Maastricht 6202 AZ, The Netherlands 

Stelios F Assimakopoulos, Dr., Department of Internal Medicine, 

University Hospital of Patras, Patras 26504, Greece 

Angelo Izzo, Professor, Department of Experimental Pharmacology, 

University of Naples Federico II, via D Montesano 49, 

80131 Naples, Italy 

Julnar Usta, Professor, Department of Biochemistry and Molecular 

Genetics, American University of Beirut, DTS bldg, Beirut 

11-0236, Lebanon 


World J Gastrointest Pathophysiol 2011 October 15; 2(5): I 







Meetings 

Events Calendar 2011 

January 14-15, 2011 

AGA Clinical Congress of 

Gastroenterology and Hepatology: 

Best Practices in 2011 Miami, FL 

33101, United States 

January 20-22, 2011 

Gastrointestinal Cancers Symposium 

2011, San Francisco, CA 94143, 

United States 

January 27-28, 2011 

Falk Workshop, Liver and 

Immunology, Medical University, 

Franz-Josef-Strauss-Allee 11, 93053 

Regensburg, Germany 

January 28-29, 2011 

9. Gastro Forum München, Munich, 

Germany 

February 13-27, 2011 

Gastroenterology: New Zealand 

CME Cruise Conference, Sydney, 

NSW, Australia 

February 17-20, 2011 

APASL 2011-The 21st Conference of 

the Asian Pacific Association for the 

Study of the Liver 

Bangkok, Thailand 

February 24-26, 2011 

Inflammatory Bowel Diseases 

2011-6th Congress of the European 

Crohn's and Colitis Organisation, 

Dublin, Ireland 

February 24-26, 2011 

International Colorectal Disease 

Symposium 2011, Hong Kong, China 

February 26-March 1, 2011 

Canadian Digestive Diseases Week, 

Westin Bayshore, Vancouver, British 

Columbia, Canada 

March 03-05, 2011 

42nd Annual Topics in Internal 

Medicine, Gainesville, FL 32614, 

United States 

March 07-11, 2011 

Infectious Diseases: Adult Issues 

in the Outpatient and Inpatient 

Settings, Sarasota, FL 34234, 

United States 

March 14-17, 2011 

British Society of Gastroenterology 

Annual Meeting 2011, Birmingham, 

England, United Kingdom 

March 17-20, 2011 

Mayo Clinic Gastroenterology & 

Hepatology 2011, Jacksonville, FL 


March 25-27, 2011 

MedicReS IC 2011 Good Medical 

Research, Istanbul, Turkey 

March 26-27, 2011 

26th Annual New Treatments in 

Chronic Liver Disease, San Diego, 

CA 94143, United States 

April 06-07, 2011 

IBS-A Global Perspective, Pfister 

Hotel, 424 East Wisconsin Avenue, 

Milwaukee, WI 53202, United States 

April 07-09, 2011 

International and Interdisciplinary 

Conference Excellence in Female 

Surgery, Florence, Italy 

April 20-23, 2011 

9th International Gastric Cancer 

Congress, COEX, World Trade 

Center, Samseong-dong, Gangnamgu, 

Seoul 135-731, South Korea 


World J Gastrointest Pathophysiol 2011 October 15; 2(5): I 



April 25-27, 2011 

The Second International Conference 

of the Saudi Society of Pediatric 

Gastroenterology, Hepatology & 

Nutrition, Riyadh, Saudi Arabia 

April 25-29, 2011 

Neurology Updates for Primary 

Care, Sarasota, FL 34230-6947, 

United States 

April 28-30, 2011 

4th Central European Congress of 

Surgery, Budapest, Hungary 

May 07-10, 2011 

Digestive Disease Week, Chicago, IL 


May 12-13, 2011 

2nd National Conference Clinical 

Advances in Cystic Fibrosis, London, 

England, United Kingdom 

May 19-22, 2011 

1st World Congress on Controversies 

in the Management of Viral Hepatitis 

(C-Hep), Palau de Congressos de 

Catalunya, Av. Diagonal, 661-671 

Barcelona 08028, Spain 

May 25-28, 2011 

4th Congress of the Gastroenterology 

Association of Bosnia and 

Herzegovina with international 

participation, Hotel Holiday Inn, 

Sarajevo, Bosnia and Herzegovina 

June 11-12, 2011 

The International Digestive Disease 

Forum 2011, Hong Kong, China 

June 13-16, 2011 

Surgery and Disillusion XXIV 

SPIGC, II ESYS, Napoli, Italy 

MEETING 

June 22-25, 2011 

ESMO Conference: 13th World 

Congress on Gastrointestinal Cancer, 

Barcelona, Spain 

September 2-3, 2011 Falk Symposium 

178, Diverticular Disease, A Fresh 

Approach to a Neglected Disease, 

Gürzenich Cologne, Martinstr. 29-37, 

50667 Cologne, Germany 

September 10-11, 2011 

New Advances in Inflammatory 

Bowel Disease, La Jolla, CA 92093, 

United States 

September 30-October 1, 2011 

Falk Symposium 179, Revisiting 

IBD Management: Dogmas to be 

Challenged, Sheraton Brussels 

Hotel, Place Rogier 3, 1210 Brussels, 

Belgium 

October 19-29, 2011 

Cardiology & Gastroenterology 

Tahiti 10 night CME Cruise, Papeete, 

French Polynesia 

October 22-26, 2011 

19th United European 

Gastroenterology Week, Stockholm, 

Sweden 

November 11-12, 2011 

Falk Symposium 180, IBD 2011: 

Progress and Future for Lifelong 

Management, ANA Interconti Hotel, 

1-12-33 Akasaka, Minato-ku, Tokyo 

107-0052, Japan 

December 01-04, 2011 

2011 Advances in Inflammatory 

Bowel Diseases/Crohn's & Colitis 

Foundation's Clinical & Research 

Conference, Hollywood, FL 34234, 

United States 





GENERAL INFORMATION 

World Journal of Gastrointestinal Pathophysiology (World J Gastrointest 

Pathophysiol, WJGP, online ISSN 2150-5330, DOI: 10.4291), is a 

bimonthly, open-access (OA), peer-reviewed journal supported 

by an editorial board of 296 experts in gastrointestinal pathophysiology 

from 39 countries. 

The biggest advantage of the OA model is that it provides 

free, full-text articles in PDF and other formats for experts and 

the public without registration, which eliminates the obstacle 

that traditional journals possess and usually delays the speed 

of the propagation and communication of scientific research 

results. 

Maximization of personal benefits 

The role of academic journals is to exhibit the scientific levels 

of a country, a university, a center, a department, and even a 

scientist, and build an important bridge for communication 

between scientists and the public. As we all know, the significance 

of the publication of scientific articles lies not only in 

disseminating and communicating innovative scientific achievements 

and academic views, as well as promoting the application 

of scientific achievements, but also in formally recognizing 

the “priority” and “copyright” of innovative achievements 

published, as well as evaluating research performance and aca- 

demic levels. So, to realize these desired attributes of WJGP 

and create a wellrecognized journal, the following four types 

of personal benefits should be maximized. The maximization 

of personal benefits refers to the pursuit of the maximum 

personal benefits in a wellconsidered optimal manner without 

violation of the laws, ethical rules and the benefits of others. 

(1) Maximization of the benefits of editorial board members: 

The primary task of editorial board members is to give a peer 

review of an unpublished scientific article via online office 

system to evaluate its innovativeness, scientific and practical 

values and determine whether it should be published or not. 

During peer review, editorial board members can also obtain 

cuttingedge information in that field at first hand. As leaders 

in their field, they have priority to be invited to write articles 

and publish commentary articles. We will put peer reviewers’ 

names and affiliations along with the article they reviewed in the 

journal to acknowledge their contribution; (2) Maximization of 

the benefits of authors: Since WJGP is an open-access journal, 

readers around the world can immediately download and read, 

free of charge, high-quality, peer-reviewed articles from WJGP 

official website, thereby realizing the goals and significance 

of the communication between authors and peers as well as 

public reading; (3) Maximization of the benefits of readers: 

Readers can read or use, free of charge, high-quality peerreviewed 

articles without any limits, and cite the arguments, 

viewpoints, concepts, theories, methods, results, conclusion or 

facts and data of pertinent literature so as to validate the innovativeness, 

scientific and practical values of their own research 

achievements, thus ensuring that their articles have novel arguments 

or viewpoints, solid evidence and correct conclusion; 

and (4) Maximization of the benefits of employees: It is an 

iron law that a firstclass journal is unable to exist without firstclass 

editors, and only firstclass editors can create a firstclass 

academic journal. We insist on strengthening our team culti- 


I 

World J Gastrointest Pathophysiol 2011 October 15; 2(5): I-V 



vation and construction so that every employee, in an open, fair 

and transparent environment, could contribute their wisdom 

to edit and publish highquality articles, thereby realizing the 

maximization of the personal benefits of editorial board members, 

authors and readers, and yielding the greatest social and 

economic benefits. 

Aims and scope 

The major task of WJGP is to report rapidly the most recent 

results in basic and clinical research on gastrointestinal pathophysiology, 

including all aspects of normal or abnormal function 

of the gastrointestinal tract, hepatobiliary system, and pancreas. 

WJGP specifically covers growth and development, digestion, 

secretion, absorption, metabolism and motility relative to the 

gastrointestinal organs, as well as immune and inflammatory 

processes, and neural, endocrine and circulatory control mechanisms 

that affect these organs. This journal will also report new 

methods and techniques in gastrointestinal pathophysiological 

research. 

Columns 

The columns in the issues of WJGP will include: (1) Editorial: 

To introduce and comment on major advances and developments 

in the field; (2) Frontier: To review representative achievements, 

comment on the state of current research, and propose 

directions for future research; (3) Topic Highlight: This column 

consists of three formats, including (A) 10 invited review articles 

on a hot topic, (B) a commentary on common issues of 

this hot topic, and (C) a commentary on the 10 individual articles; 

(4) Observation: To update the development of old and 

new questions, highlight unsolved problems, and provide strategies 

on how to solve the questions; (5) Guidelines for Basic 

Research: To provide guidelines for basic research; (6) Guidelines 

for Clinical Practice: To provide guidelines for clinical 

diagnosis and treatment; (7) Review: To review systemically 

progress and unresolved problems in the field, comment on the 

state of current research, and make suggestions for future work; 

(8) Original Articles: To report innovative and original findings 

in gastrointestinal pathophysiology; (9) Brief Articles: To briefly 

report the novel and innovative findings in gastrointestinal 

pathophysiology; (10) Case Report: To report a rare or typical 

case; (11) Letters to the Editor: To discuss and make reply to 

the contributions published in WJGP, or to introduce and comment 

on a controversial issue of general interest; (12) Book 

Reviews: To introduce and comment on quality monographs 

of gastrointestinal pathophysiology; and (13) Guidelines: To 

introduce consensuses and guidelines reached by international 

and national academic authorities worldwide on basic research 

and clinical practice in gastrointestinal pathophysiology. 

Name of journal 


ISSN 


INSTRUCTIONS TO AUTHORS 

Indexing/abstracting 

PubMed Central, PubMed, Digital Object Identifer, and Directory 


Instructions to authors 

of Open Access Journals. 

Published by 

Baishideng Publishing Group Co., Limited 

SPECIAL STATEMENT 

All articles published in this journal represent the viewpoints of 

the authors except where indicated otherwise. 

Biostatistical editing 

Statisital review is performed after peer review. We invite an 

expert in Biomedical Statistics from to evaluate the statistical 

method used in the paper, including t-test (group or paired 

comparisons), chi-squared test, Ridit, probit, logit, regression 

(linear, curvilinear, or stepwise), correlation, analysis of variance, 

analysis of covariance, etc. The reviewing points include: (1) 

Statistical methods should be described when they are used to 

verify the results; (2) Whether the statistical techniques are suitable 

or correct; (3) Only homogeneous data can be averaged. 

Standard deviations are preferred to standard errors. Give the 

number of observations and subjects (n). Losses in observations, 

such as drop-outs from the study should be reported; (4) Values 

such as ED50, LD50, IC50 should have their 95% confidence 

limits calculated and compared by weighted probit analysis 

(Bliss and Finney); and (5) The word ‘significantly’ should be 

replaced by its synonyms (if it indicates extent) or the P value (if 

it indicates statistical significance). 

Conflict-of-interest statement 

In the interests of transparency and to help reviewers assess any 

potential bias, WJGP requires authors of all papers to declare 

any competing commercial, personal, political, intellectual, or 

religious interests in relation to the submitted work. Referees 

are also asked to indicate any potential conflict they might have 

reviewing a particular paper. Before submitting, authors are 

suggested to read “Uniform Requirements for Manuscripts 

Submitted to Biomedical Journals: Ethical Considerations in the 

Conduct and Reporting of Research: Conflicts of Interest” from 

International Committee of Medical Journal Editors (ICMJE), 

which is available at: http://www.icmje.org/ethical_4conflicts. 

html. 

Sample wording: [Name of individual] has received fees for 

serving as a speaker, a consultant and an advisory board member 

for [names of organizations], and has received research funding 

from [names of organization]. [Name of individual] is an 

employee of [name of organization]. [Name of individual] owns 

stocks and shares in [name of organization]. [Name of individual] 

owns patent [patent identification and brief description]. 

Statement of informed consent 

Manuscripts should contain a statement to the effect that all 

human studies have been reviewed by the appropriate ethics 

committee or it should be stated clearly in the text that all persons 

gave their informed consent prior to their inclusion in the 

study. Details that might disclose the identity of the subjects 

under study should be omitted. Authors should also draw attention 

to the Code of Ethics of the World Medical Association 

(Declaration of Helsinki, 1964, as revised in 2004). 

Statement of human and animal rights 

When reporting the results from experiments, authors should 

follow the highest standards and the trial should comform to 

Good Clinical Practice (for example, US Food and Drug Administration 

Good Clinical Practice in FDA-Regulated Clinical 

Trials; UK Medicines Research Council Guidelines for Good 

Clinical Practice in Clinical Trials) and/or the World Medical 

Association Declaration of Helsinki. Generally, we suggest 

authors follow the lead investigator’s national standard. If doubt 

exists whether the research was conducted in accordance with 

the above standards, the authors must explain the rationale for 

their approach and demonstrate that the institutional review 

WJGP|www.wjgnet.com II 

body explicitly approved the doubtful aspects of the study. 

Before submitting, authors should make their study approved 

by the relevant research ethics committee or institutional review 

board. If human participants were involved, manuscripts must 

be accompanied by a statement that the experiments were undertaken 

with the understanding and appropriate informed 

consent of each. Any personal item or information will not be 

published without explicit consents from the involved patients. 

If experimental animals were used, the materials and methods 

(experimental procedures) section must clearly indicate that 

appropriate measures were taken to minimize pain or discomfort, 

and details of animal care should be provided. 

SUBMISSION OF MANUSCRIPTS 

Manuscripts should be typed in 1.5 line spacing and 12 pt. Book 

Antiqua with ample margins. Number all pages consecutively, 

and start each of the following sections on a new page: Title 

Page, Abstract, Introduction, Materials and Methods, Results, 

Discussion, Acknowledgements, References, Tables, Figures, 

and Figure Legends. Neither the editors nor the publisher 

are responsible for the opinions expressed by contributors. 

Manuscripts formally accepted for publication become the permanent 

property of Baishideng Publishing Group Co., Limited, 

and may not be reproduced by any means, in whole or in 

part, without the written permission of both the authors and 

the publisher. We reserve the right to copy-edit and put onto 

our website accepted manuscripts. Authors should follow the 

relevant guidelines for the care and use of laboratory animals of 

their institution or national animal welfare committee. For the 

sake of transparency in regard to the performance and reporting 

of clinical trials, we endorse the policy of the International 

Committee of Medical Journal Editors to refuse to publish 

papers on clinical trial results if the trial was not recorded in a 

publicly-accessible registry at its outset. The only register now 

available, to our knowledge, is http://www. clinicaltrials.gov 

sponsored by the United States National Library of Medicine 

and we encourage all potential contributors to register with it. 

However, in the case that other registers become available you 

will be duly notified. A letter of recommendation from each 

author’s organization should be provided with the contributed 

article to ensure the privacy and secrecy of research is protected. 

Authors should retain one copy of the text, tables, photographs 

and illustrations because rejected manuscripts will not be 

returned to the author(s) and the editors will not be responsible 

for loss or damage to photographs and illustrations sustained 

during mailing. 

Online submissions 

Manuscripts should be submitted through the Online Submission 

System at: http://www.wjgnet.com/2150-5330office/. 

Authors are highly recommended to consult the ONLINE 

INSTRUCTIONS TO AUTHORS (http://www.wjgnet. 

com/2150-5330/g_info_20100316080008.htm) before attempting 

to submit online. For assistance, authors encountering 

problems with the Online Submission System may send an email 

describing the problem to wjgp@wjgnet.com, or by telephone: 

+86-10-59080038. If you submit your manuscript online, do not 

make a postal contribution. Repeated online submission for the 

same manuscript is strictly prohibited. 

MANUSCRIPT PREPARATION 

All contributions should be written in English. All articles must 

be submitted using word-processing software. All submissions 

must be typed in 1.5 line spacing and 12 pt. Book Antiqua with 

ample margins. Style should conform to our house format. 

Required information for each of the manuscript sections is as 

follows: 

Title page 

Title: Title should be less than 12 words. 


Running title: A short running title of less than 6 words should 

be provided. 

Authorship: Authorship credit should be in accordance with 

the standard proposed by International Committee of Medical 

Journal Editors, based on (1) substantial contributions to conception 

and design, acquisition of data, or analysis and interpretation 

of data; (2) drafting the article or revising it critically 

for important intellectual content; and (3) final approval of the 

version to be published. Authors should meet conditions 1, 2, 

and 3. 

Institution: Author names should be given first, then the complete 

name of institution, city, province and postcode. For example, 

Xu-Chen Zhang, Li-Xin Mei, Department of Pathology, 

Chengde Medical College, Chengde 067000, Hebei Province, 

China. One author may be represented from two institutions, for 

example, George Sgourakis, Department of General, Visceral, 

and Transplantation Surgery, Essen 45122, Germany; George 

Sgourakis, 2nd Surgical Department, Korgialenio-Benakio Red 

Cross Hospital, Athens 15451, Greece. 

Author contributions: The format of this section should be: 

Author contributions: Wang CL and Liang L contributed equally 

to this work; Wang CL, Liang L, Fu JF, Zou CC, Hong F and 

Wu XM designed the research; Wang CL, Zou CC, Hong F and 

Wu XM performed the research; Xue JZ and Lu JR contributed 

new reagents/analytic tools; Wang CL, Liang L and Fu JF 

analyzed the data; and Wang CL, Liang L and Fu JF wrote the 

paper. 

Supportive foundations: The complete name and number of 

supportive foundations should be provided, e.g., Supported by 

National Natural Science Foundation of China, No. 30224801. 

Correspondence to: Only one corresponding address should 

be provided. Author names should be given first, then author 

title, affiliation, the complete name of institution, city, postcode, 

province, country, and email. All the letters in the email should 

be in lower case. A space interval should be inserted between 

country name and email address. For example, Montgomery 

Bissell, MD, Professor of Medicine, Chief, Liver Center, Gastroenterology 

Division, University of California, Box 0538, San 

Francisco, CA 94143, United States. montgomery.bissell@ucsf. 

edu 

Telephone and fax: Telephone and fax should consist of +, 

country number, district number and telephone or fax number, 

e.g., Telephone: +86-10-59080039 Fax: +86-10-85381893 

Peer reviewers: All articles received are subject to peer review. 

Normally, three experts are invited for each article. Decision for 

acceptance is made only when at least two experts recommend 

an article for publication. Reviewers for accepted manuscripts 

are acknowledged in each manuscript, and reviewers of articles 

which were not accepted will be acknowledged at the end of 

each issue. To ensure the quality of the articles published in 

WJGP, reviewers of accepted manuscripts will be announced 

by publishing the name, title/position and institution of the reviewer 

in the footnote accompanying the printed article. For example, 

reviewers: Professor Jing-Yuan Fang, Shanghai Institute 

of Digestive Disease, Shanghai, Affiliated Renji Hospital, 

Medical Faculty, Shanghai Jiaotong University, Shanghai, China; 

Professor Xin-Wei Han, Department of Radiology, The First 

Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 

Province, China; and Professor Anren Kuang, Department of 

Nuclear Medicine, Huaxi Hospital, Sichuan University, Chengdu, 

Sichuan Province, China. 

Abstract 

There are unstructured abstracts (no more than 256 words) and 

structured abstracts (no more than 480). The specific requirements 

for structured abstracts are as follows: 

WJGP|www.wjgnet.com III 


An informative, structured abstracts of no more than 480 

words should accompany each manuscript. Abstracts for original 

contributions should be structured into the following sections. 

AIM (no more than 20 words): Only the purpose should be 

included. Please write the aim as the form of “To investigate/ 

study/…; MATERIALS AND METHODS (no more than 

140 words); RESULTS (no more than 294 words): You should 

present P values where appropriate and must provide relevant 

data to illustrate how they were obtained, e.g. 6.92 ± 3.86 vs 3.61 

± 1.67, P < 0.001; CONCLUSION (no more than 26 words). 

Key words 

Please list 5-10 key words, selected mainly from Index Medicus, 

which reflect the content of the study. 

Text 

For articles of these sections, original articles, rapid communication 

and case reports, the main text should be structured 

into the following sections: INTRODUCTION, MATERIALS 

AND METHODS, RESULTS and DISCUSSION, and should 

include appropriate Figures and Tables. Data should be presented 

in the main text or in Figures and Tables, but not in both. 

The main text format of these sections, editorial, topic highlight, 

case report, letters to the editors, can be found at: http://www. 

wjgnet.com/2150-5330/g_info_20100316080000.htm. 

Illustrations 

Figures should be numbered as 1, 2, 3, etc., and mentioned clearly 

in the main text. Provide a brief title for each figure on a separate 

page. Detailed legends should not be provided under the figures. 

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Brief acknowledgments of persons who have made genuine 

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REFERENCES 

Coding system 

The author should number the references in Arabic numerals according 

to the citation order in the text. Put reference numbers 

in square brackets in superscript at the end of citation content 

or after the cited author’s name. For citation content which is 

part of the narration, the coding number and square brackets 

should be typeset normally. For example, “Crohn’s disease 

(CD) is associated with increased intestinal permeability [1,2] ”. If 

references are cited directly in the text, they should be put together 

within the text, for example, “From references [19,22-24] , we 

know that...” 

When the authors write the references, please ensure that 

the order in text is the same as in the references section, and 

also ensure the spelling accuracy of the first author’s name. Do 

not list the same citation twice. 

PMID and DOI 

Pleased provide PubMed citation numbers to the reference list, 

e.g. PMID and DOI, which can be found at http://www.ncbi. 

nlm.nih.gov/sites/entrez?db=pubmed and http://www.crossref.org/SimpleTextQuery/, 

respectively. The numbers will be 

used in E-version of this journal. 

Style for journal references 

Authors: the name of the first author should be typed in boldfaced 

letters. The family name of all authors should be typed 

with the initial letter capitalized, followed by their abbreviated 

first and middle initials. (For example, LianSheng Ma is abbreviated 

as Ma LS, Bo-Rong Pan as Pan BR). The title of the 

cited article and italicized journal title (journal title should be in 

its abbreviated form as shown in PubMed), publication date, 

volume number (in black), start page, and end page [PMID: 

11819634 DOI: 10.3748/wjg.13.5396]. 

Style for book references 

Authors: the name of the first author should be typed in boldfaced 

letters. The surname of all authors should be typed with 

the initial letter capitalized, followed by their abbreviated middle 

and first initials. (For example, LianSheng Ma is abbreviated as 

Ma LS, Bo-Rong Pan as Pan BR) Book title. Publication number. 

Publication place: Publication press, Year: start page and end 

page. 

Format 

Journals 

English journal article (list all authors and include the PMID where 

applicable) 

1 Jung EM, Clevert DA, Schreyer AG, Schmitt S, Rennert J, 

Kubale R, Feuerbach S, Jung F. Evaluation of quantitative 

contrast harmonic imaging to assess malignancy of liver 

tumors: A prospective controlled two-center study. World J 

Gastroenterol 2007; 13: 6356-6364 [PMID: 18081224 DOI: 

10.3748/wjg.13.6356] 

Chinese journal article (list all authors and include the PMID where 

applicable) 

2 Lin GZ, Wang XZ, Wang P, Lin J, Yang FD. Immunologic 

effect of Jianpi Yishen decoction in treatment of Pixu-diarrhoea. 

Shijie Huaren Xiaohua Zazhi 1999; 7: 285-287 

In press 

3 Tian D, Araki H, Stahl E, Bergelson J, Kreitman M. Signature 

of balancing selection in Arabidopsis. Proc Natl Acad 

Sci USA 2006; In press 

Organization as author 

4 Diabetes Prevention Program Research Group. Hyper 

tension, insulin, and proinsulin in participants with impaired 

glucose tolerance. Hypertension 2002; 40: 679-686 

[PMID: 12411462 PMCID:2516377 DOI:10.1161/01. 

HYP.0000035706.28494.09] 

WJGP|www.wjgnet.com IV 

Both personal authors and an organization as author 

5 Vallancien G, Emberton M, Harving N, van Moorselaar 

RJ; Alf-One Study Group. Sexual dysfunction in 1, 274 

European men suffering from lower urinary tract symptoms. 

J Urol 2003; 169: 2257-2261 [PMID: 12771764 

DOI:10.1097/01.ju.0000067940.76090.73] 

No author given 

6 21st century heart solution may have a sting in the tail. 

BMJ 2002; 325: 184 [PMID: 12142303 DOI:10.1136/ 

bmj.325.7357.184] 

Volume with supplement 

7 Geraud G, Spierings EL, Keywood C. Tolerability and 

safety of frovatriptan with short- and long-term use for 

treatment of migraine and in comparison with sumatriptan. 

Headache 2002; 42 Suppl 2: S93-99 [PMID: 12028325 

DOI:10.1046/j.1526-4610.42.s2.7.x] 

Issue with no volume 

8 Banit DM, Kaufer H, Hartford JM. Intraoperative frozen 

section analysis in revision total joint arthroplasty. Clin 

Orthop Relat Res 2002; (401): 230-238 [PMID: 12151900 

DOI:10.1097/00003086-200208000-00026] 

No volume or issue 

9 Outreach: Bringing HIV-positive individuals into care. 

HRSA Careaction 2002; 1-6 [PMID: 12154804] 

Books 

Personal author(s) 

10 Sherlock S, Dooley J. Diseases of the liver and billiary system. 

9th ed. Oxford: Blackwell Sci Pub, 1993: 258-296 

Chapter in a book (list all authors) 

11 Lam SK. Academic investigator’s perspectives of medical 

treatment for peptic ulcer. In: Swabb EA, Azabo S. Ulcer 

disease: investigation and basis for therapy. New York: 

Marcel Dekker, 1991: 431-450 

Author(s) and editor(s) 

12 Breedlove GK, Schorfheide AM. Adolescent pregnancy. 

2nd ed. Wieczorek RR, editor. White Plains (NY): March 

of Dimes Education Services, 2001: 20-34 

Conference proceedings 

13 Harnden P, Joffe JK, Jones WG, editors. Germ cell tumours 

V. Proceedings of the 5th Germ cell tumours Conference; 

2001 Sep 13-15; Leeds, UK. New York: Springer, 

2002: 30-56 

Conference paper 

14 Christensen S, Oppacher F. An analysis of Koza's computational 

effort statistic for genetic programming. In: Foster 

JA, Lutton E, Miller J, Ryan C, Tettamanzi AG, editors. 

Genetic programming. EuroGP 2002: Proceedings of the 

5th European Conference on Genetic Programming; 2002 

Apr 3-5; Kinsdale, Ireland. Berlin: Springer, 2002: 182-191 

Electronic journal (list all authors) 

15 Morse SS. Factors in the emergence of infectious diseases. 

Emerg Infect Dis serial online, 1995-01-03, cited 

1996-06-05; 1(1): 24 screens. Available from: URL: http:// 

www.cdc.gov/ncidod/eid/index.htm 

Patent (list all authors) 

16 Pagedas AC, inventor; Ancel Surgical R&D Inc., assignee. 

Flexible endoscopic grasping and cutting device 

and positioning tool assembly. United States patent US 

20020103498. 2002 Aug 1 

Statistical data 

Write as mean ± SD or mean ± SE. 

Statistical expression 

Express t test as t (in italics), F test as F (in italics), chi square 

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= 96 h, blood glucose concentration, c (glucose) 6.4 ± 2.1 

mmol/L; blood CEA mass concentration, p (CEA) = 8.6 24.5 

mg/L; CO 2 volume fraction, 50 mL/L CO 2, not 5% CO 2; 

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The format for how to accurately write common units and 

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Units, Symbols and Abbreviations: A Guide for Biological and 

Medical Editors and Authors (Ed. Baron DN, 1988) published 

by The Royal Society of Medicine, London. Certain commonly 

used abbreviations, such as DNA, RNA, HIV, LD50, PCR, 

HBV, ECG, WBC, RBC, CT, ESR, CSF, IgG, ELISA, PBS, ATP, 

EDTA, mAb, can be used directly without further explanation. 

Italics 

Quantities: t time or temperature, c concentration, A area, l 

length, m mass, V volume. 

Genotypes: gyrA, arg 1, c myc, c fos, etc. 

Restriction enzymes: EcoRI, HindI, BamHI, Kbo I, Kpn I, etc. 

Biology: H. pylori, E coli, etc. 

Examples for paper writing 

Editorial: http://www.wjgnet.com/2150-5330/g_info_2010 

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