Connecting Global Priorities Biodiversity and Human Health

and is in any case not associated with changes
in immunoregulatory circuits. Indeed, these
infections often act as triggers of allergy or
autoimmunity (Yoo et al. 2007). The original
formulation of the hygiene hypothesis focused
attention on the crowd infections, but this was
an error, and the protection against allergic
disorders attributed to the presence of older
siblings (Strachan 1989), and assumed by many at
that time to be a protective effect of the childhood
virus infections, is now attributed to enhanced
transmission of microbiota (Penders et al. 2013).
2.2 Lifestyle factors that reduce
exposure to microbial biodiversity
While modern medicine tends to eliminate the
Old infections, lifestyle factors in high-income
urban settings reduce exposure both to maternal
microbiota and to organisms from the natural
environment (categories 2 and 3 above). Delivery
by caesarean section, lack of breast feeding and
excessive use of antibiotics in early childhood all
delay, reduce or modify accumulation of essential
microbiota (reviewed referenced in Rook et al.
2014a). The protective effect of cleaning a child’s
dummy/pacifier by sucking it, and immediately
replacing it in the baby’s mouth is an elegant
illustration of the need for trans-generational
transmission of microbiota (Hesselmar et
al. 2013).
2.3 Links to socioeconomic status (SES)
The factors mentioned in the previous paragraph
might be exacerbated in families of low SES, who
tend to eat unvaried fast-food diets and more
highly processed foods that lack any trace of soil
and its microbes, whose homes are less likely to
include gardens, and who lack access to travel,
overseas holidays and rural second homes (Rook
et al. 2013).
2.4 Immunoregulatory pathways driven
by organisms of categories 1, 2 and 3
The immune system is potentially dangerous if
it attacks inappropriate targets such as harmless
allergens in air or food, the host’s own tissues, or
essential gut microbiota. When these three types of
inappropriate immune response occur they result
in allergy, autoimmune disease or inflammatory
bowel disease respectively. The immune system
has a number of complex mechanisms, known
collectively as immunoregulation, to suppress
unwanted responses. While a full exploration of
this topic falls outside the scope of this chapter, it
is important to note that the immunoregulatory
effects of categories 1, 2 and 3 are well documented.
Old infections (such as helminths) have been
shown to drive immunoregulation in humans
(Babu et al. 2006; Correale and Farez 2013), and
to block or treat animal models of numerous
chronic inflammatory conditions (reviewed
in Osada and Kanazawa 2010). Molecular
structures responsible for immunoregulation are
being identified (Grainger et al. 2010; Harnett
et al. 2010; Kron et al. 2012). Regulatory T cells
(Treg), provide one important immunoregulatory
mechanism. When Argentinian multiple sclerosis
(MS) patients become infected with helminths,
the disease stops progressing and circulating
myelin-recognising regulatory T cells (Treg)
appear in the peripheral blood (Correale and Farez
2007), indicating that the helminths act as Treg
adjuvants. Thus some helminths can be shown to
specifically expand Treg populations (Grainger et
al. 2010), or to cause dendritic cells (DC) to switch
to regulatory phenotypes that preferentially drive
immunoregulation (Hang et al. 2010; Smits et
al. 2005).
Gut bacteria are also able to do this. A
polysaccharide from Bacteroides fragilis, commonly
present in the human gut, can expand Treg
populations (Round and Mazmanian 2010), as
can some members of clusters IV and XIVa of the
genus Clostridium (Atarashi et al. 2011), some
lactobacilli (Poutahidis et al. 2013), and very
probably unidentified organisms from the natural
environment, discussed later (Lewis et al. 2012).
Some of these effects are mediated via short chain
fatty acids (SCFA) that act on G-protein-coupled
receptors (GPCR) (Thorburn et al. 2014). SCFA are
generated by microbiota that ferment dietary fibre.
It seems unlikely that we will want to bring
back all the Old infections, unless we create a
‘domesticated’, perhaps genetically modified
152 Connecting Global Priorities: Biodiversity and Human Health