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A Darwinian View of the Hygiene or “Old Friends” Hypothesis


Microorganisms and macroorganisms such as helminths from mud, animals, and feces play a critical role in driving immunoregulation. The term "old friends" is broader than "hygiene" to describe this hypothesis, and it implicates exposures to microbes and other organisms during critical phases of human development. Diseases and conditions of the modern era, including multiple sclerosis, type 1 diabetes, and allergies, involve disrupted immunoregulatory circuits, likely reflecting reduced exposures to "old friend" organisms with which humans coevolved. Several clinical trials are testing these concepts, determining whether renewed exposures to "old friend" organisms can help to combat these modern-era diseases.
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A Darwinian View of the Hygiene or
“Old Friends” Hypothesis
When urban living reduced contacts of humans with microbes and
worms, it increased our risk for chronic inflammatory disorders
Graham A. W. Rook
The notion that urban life is associated
with increases in chronic inflamma-
tory disorders traces back to the 19th
century, when physicians in Europe
noticed that allergies were rare
among farmers. In sharp contrast, hay fever was
regarded as the hallmark of prosperous, edu-
cated city sophisticates.
Several rigorous epidemiologic studies of
more recent vintage lend support to the idea that
growing up in a farming environment protects
children against developing hay fever or other
allergies. Further, in 1989 epidemiologist David
Strachan of St. George’s University in London,
United Kingdom, observed allergies as being less
common in children with older siblings, espe-
cially boys, suggesting to him that microbial
encounters might protect against allergic disor-
Strachan’s and other studies led to the view
that microorganisms and macro-organisms
from mud, animals, and feces with which mam-
mals coevolved play a critical role in immuno-
regulation and in inhibiting inappropriate im-
mune responses to self, gut contents, and
allergens. In describing this phenomenon, I pre-
fer the term “old friends” to the more common
“hygiene” hypothesis. The former term is
broader, and implicates the effects of prenatal,
neonatal, and adult exposures to such organ-
isms as well as the crucial effects of microorgan-
isms found in the gut, skin, lung, and the oral
and nasal passages of the host. This area of
clinical research is set to become a major
branch of Darwinian medicine, with the
potential for yielding new strategies for pre-
venting and treating a widening variety of
Several Types of Disease Are
Associated with Urban Living
Increases in inflammatory disorders that ac-
company the modern urban lifestyle are not
confined to allergies. After the 1880s, for
example, inflammatory bowel diseases be-
gan to appear in young adults from prosper-
ous families in London. Later, physicians in
many parts of the world began noticing
lifestyle-related increases in autoimmune
disorders. In 1966, for instance, Israeli in-
vestigators reported that multiple sclerosis
(MS) was more common in families with
advanced hygiene.
Microorganisms and macroorganisms such as
helminths from mud, animals, and feces play a
critical role in driving immunoregulation.
The term “old friends” is broader than “hy-
giene” to describe this hypothesis, and it impli-
cates exposures to microbes and other organ-
isms during critical phases of human
Diseases and conditions of the modern era, in-
cluding multiple sclerosis, type 1 diabetes, and
allergies, involve disrupted immunoregulatory
circuits, likely reflecting reduced exposures to
“old friend” organisms with which humans co-
Several clinical trials are testing these concepts,
determining whether renewed exposures to
“old friend” organisms can help to combat
these modern-era diseases.
Graham A. W. Rook
is Emeritus Profes-
sor of Medical Mi-
crobiology at the
Centre for Clinical
Microbiology, Uni-
versity College Lon-
don, United King-
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Other investigators noted that the incidence
of type 1 diabetes (T1D) varies widely from one
geographic region to another. Some of this vari-
ation is genetic, but much of it occurs within
ethnic groups, and the rises are too recent and
sudden to be explicable by genetics alone. There
must be environmental factors.
For example, ethnic Karelians in Russia have
very low levels of T1D, whereas the disease is six
times more prevalent in Karelians living in nearby
Finland. Thus, although genetically nearly identi-
cal and living at the same latitude, Karelians in
modernized Finland suffer greatly from this dis-
ease, whereas Karelians living in under-
developed settlements just over the bor-
der in Russia do not. One big difference
between these two populations is their
different microbial exposures.
These Diseases also Tie
into the Immune System
These differences in rates of allergy,
IBD, autoimmunity, and type 1 diabetes
are not merely the result of changing
diagnostic criteria, as some investiga-
tors thought at first. Indeed, the con-
tinuing increases in their incidence dur-
ing the last century led to careful studies
that dispelled remaining doubt. Thus,
we now recognize that those increases
are very large, very real, and occur si-
multaneously across those disease
Moreover, although these disease
groups impinge on the immune system,
allergies are mediated by Th2 lympho-
cytes, whereas autoimmunity is medi-
ated by Th1/Th17 lymphocytes. There-
fore, because these two types of disease
are increasing in parallel, the problem is
not likely to stem from an imbalance
between these two effector arms of the
immune system. The epidemiology in-
stead suggests a fundamental defect at
the level of immunoregulation affecting
all arms of the immune response.
A broad defect in immunoregulation
can lead to all these types of pathology
because genetic defects in the transcrip-
tion factor Foxp3, which controls the
maturation and function of many regu-
latory cells, lead to a syndrome that
includes features of allergy, autoimmunity, and
enteropathy. We also now know that all these
disease groups are accompanied by striking de-
fects in immunoregulatory circuits, so an immu-
noregulatory hypothesis is probable. What links
defective immunoregulation with urbanization
and hygiene?
How Microbes in the Environment
Can Affect Immunoregulation
Epidemiologists continue to search for and iden-
tify organisms that our urban lifestyle depletes
Major changes in microbial exposures that are implicated in the contemporary changes
in immunoregulation. Organisms that throughout evolution associated with humans and
other animals via mud and feces were not depleted until the early 19
century. Their
depletion correlates with the rise in chronic inflammatory disorders. Those organisms
exert potent immunoregulatory effects on mammals, which developed various means
for tolerating them.
174 YMicrobe / Volume 7, Number 4, 2012
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Rook: From a Narrow Focus to a Broad Scientific View,
and a Delight in Restoring Ruins
Early in his career, Graham Ar-
thur William Rook overheard
someone describing him as know-
ing “more and more about less
and less.” It led him to worry that
he was “drifting too far from any
possibility of understanding any-
thing in a physiological context,”
he recalls. Thus, to his interests in
tuberculosis and leprosy, Rook
added interests in autoimmune
diseases, endocrinology, glycosyl-
ation, and allergic disorders. That
breadth “was crazy by modern
standards,” he says. “This is not a
good plan for a young scientist.
But I could not work like that.”
Rook, Emeritus Professor of
medical microbiology at Univer-
sity College London, still believes
that too few scientists take the
broad view. “I regard myself as
‘an integrative physiologist,’ try-
ing to take a holistic and evolu-
tionary view of biological sci-
ence,” he says. “Curiously, the
public is often ahead of the scien-
tists in this respect. But it is easy to
see why scientists tend to be so
narrow. You have to be to do a
Ph.D., or to write grant applica-
It takes enormous energy to
stay on top of neuroscience, endo-
crinology, microbiology, immu-
nology, psychiatry, and oncology
“to write the kinds of paper that I
produce now,” Rook says. “And
it goes without saying that it is not
possible to do this without coau-
thors who are card-carrying spe-
cialists in the fields that are out-
side my own domain of infectious
disease immunology. Now that,
in theory, I am retired, I have the
opportunity to do more of this
very time-consuming interdisci-
plinary thinking.”
Recently, he became interested
in evolutionary psychology and
sociobiology. “It is great fun try-
ing to apply ideas from these dis-
ciplines to the development of hu-
man thought and culture,” he
says. “As always I am arguing
against the narrow view. So I have
strayed a long way from my orig-
inal territory. I hope to stray even
Rook, 66, spent his research
and teaching career at Middlesex
Hospital Medical School in Lon-
don, which transferred staff and
services to University College
Hospitals after closing in 2005.
“After doing a basic science de-
gree at the University of Cam-
bridge, I studied clinical medicine
despite the fact that I always in-
tended to do research because I
wanted to be sure that my work
was relevant to real human prob-
lems,” he says. “That also ex-
plains why, after becoming a fully
registered physician, I immedi-
ately abandoned clinical medi-
Rook was born in London, the
middle of three sons, and moved
as an infant to Cardiff, Wales,
where his father worked as a
dermatologist and wrote Rook’s
Textbook on Dermatology,
once the definitive textbook on
that subject. The family moved
to Cambridge when Rook was
seven. “My bedroom was more
laboratory than bedroom,’’ he
recalls. “I used to use an electric
heater as a resistance, and I ac-
quired two amazing old rectifi-
ers, huge primitive things, [and]
ran electrophoresis as a child
with this kit . . . and experienced
huge numbers of electric shocks,
which really didn’t bother me. I
also used this system for cooking
sausages, by passing the current
through them. It worked best
with frankfurters. Too much fat
in U.K. sausages led to more
smoke and sparks than cook-
Rook studied basic natural sci-
ences at the University of Cam-
bridge, then clinical medicine at
the University of London, and
holds a series of degrees. He is
married to Anne Demarquay
(Anne Rook), a French artist.
They have two sons, a physician
and an artist, and four grandchil-
For more than three decades, he
and his wife have been restoring a
set of medieval ruins in south-
western France, where they live
for part of the year. Initially, the
place was a mess, with “trees
growing inside the house, no roof,
no drains, one cold water tap, one
light bulb, one species of snake,
rodents of three species, bats of
three species, spiders, and insects
of innumerable species,” Rook
says. He did much of the restor-
ative work, including wiring and
plumbing. “It is all so much easier
than science,” he says. “I spend a
lot of time with a glass of red wine
in my hand, staring at my handi-
work and congratulating myself. I
hope it will never be finished.
What would I do then?”
Marlene Cimons
Marlene Cimons lives and writes in
Bethesda, Md.
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and whose loss correlates with increases in
chronic inflammatory disorders. They report
two crucial findings.
First, the common viral diseases of childhood
do not protect against such disorders. Indeed, in
some cases they help to induce chronic inflam-
matory disorders. This role as co-inducers is not
so surprising because so many of these viral
diseases were relatively recently ac-
quired from other animal host species
during the Neolithic period (Fig. 1).
Those diseases did not circulate widely
among humans until towns with large
populations developed, and European
explorers and empire-builders intro-
duced them into the American and Aus-
tralian continents. Because these dis-
eases came to humans so recently, the
immune system did not reach a state of
evolved dependence on those viruses.
Second, the organisms that appeared
relevant to the hygiene hypothesis are
those that coevolved with humans and
other mammals. Prominent among
these organisms are the helminths,
which induce carrier states following
fecal-oral transmission during the neo-
natal period, various microbiotas asso-
ciated with the host gut, skin, and air-
ways, and various environmental
saprophytes encountered when hosts
come into contact with mud and un-
treated water.
The host immune system tolerates all
these organisms either because attempts
to eliminate them lead to immunopa-
thology, as is the case with helminths,
or because the agents are so widely distributed,
making contact with them nearly inevitable, as
is the case with the hepatitis A virus and perhaps
salmonella bacteria; because they are common
and nonpathogenic contaminants of food and
untreated water, as is the case with saprophytes;
or because they are essential components of
human physiology, as is the case with micro-
biota. Thus, it is easy to see how such organ-
isms could have co-evolved with their mam-
malian hosts, taking on roles as inducers of
immunoregulatory circuits (Fig. 2).
This example typifies what happens be-
tween separate species that develop evolved
dependence on one another. To put it an-
other way, instead of being encoded in the
human genome, some of the genes for setting
up immunoregulatory circuits are found
within the genomes of organisms with which
we coevolved. They include microorganisms
and other multicellular organisms that live in
places such as mud and feces. Such environ-
ments are depleted in towns that are covered
with concrete or other solid materials. This
Table 1. Helminths used for treatment in animal models or clinical
Helminths used for treatment Disorder treated
Animal models of disorder
Heligmosomoides polygyrus Allergy, T1D, colitis
Schistosoma mansoni Allergy, T1D, EAE, colitis, arthritis
Strongyloides stercoralis Allergy
Fasciola hepatica EAE
Trichinella spiralis T1D, EAE
Hymenolepsis diminuta Colitis, arthritis
Clinical trials (completed or in progress)
Trichuris suis Multiple sclerosis
Trichuris suis Inflammatory bowel disease
Necator americanus Asthma
Two overlapping pathways of microbial immunoregulation. Although intestinal microbiota
play a major role in driving Immunoregulation, non-commensal organisms also play a role,
driving T-reg proliferation and changing the immune system by modulating host-
microbiota relationships.
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“entrusting” of genes to other species for spe-
cialized activities is not unusual. For instance,
humans depend on fruits and vegetables to ob-
tain vitamin C, which other mammals make for
Helminths Can Develop an
Immunoregulatory Hold over Hosts
Experiments with various mammalian species
support this concept—namely, that microorgan-
isms or multicellular organisms such as hel-
minths can trigger the immunoregulatory poten-
tial of their hosts. For example, several helminth
species, when tested in animals such as rodents,
induce immunoregulatory circuits and thus can
protect those host animals from developing a
variety of conditions and diseases, including al-
lergies, T1D, autoimmune encephalomyelitis (a
model for MS), colitis, and arthritis (Table 1).
Clinical trials testing this concept in patients
with some of these same conditions are either
completed, in progress, or being planned (Table
1). Trials in MS have been encouraged by the
clinical observation that among a group of MS
patients, those who spontaneously developed
chronic helminth infections experienced fewer
exacerbations, or flare-ups, according to Jorge
Correale of Rau´ l Carrea Institute for Neurolog-
ical Research in Buenos Aires, Argentina, and
his collaborators. Those patients also developed
circulating myelin-recognizing regulatory T cells
(T-reg) that secreted anti-inflammatory cyto-
kines. In contrast, the disease progressed inexo-
rably in those patients with MS who did not
develop helminth infections.
The helminths apparently are acting as T-reg
adjuvants (Fig. 2). Thus, they are driving not
just the T cells that suppress responses to hel-
minths, but also those that suppress an autoim-
mune response to human myelin, according to
That and other studies inspired a recent clin-
ical trial in which patients with MS were delib-
erately infected with the helminth Trichuris suis
rather than waiting for some of them to become
infected by natural means. Although a Phase 1
safety study, and thus not intended to assess
efficacy, the results were compatible with the
view that such infections protect some MS pa-
tients against flare-ups. Further clinical trials are
under way to evaluate whether infections with
helminths can protect individuals against this
and other chronic inflammatory disorders.
Microbiota also Exert Partial
Immunoregulatory Control over Hosts
Similarly, the microbiota of the gastrointestinal
(GI) tract exerts partial immunoregulatory
control over their mammalian hosts. Indeed,
germ-free animals have poorly developed im-
mune systems, and particularly poorly devel-
oped immunoregulatory circuits.
For example, unlike animals with a fully
formed GI microbiota, germ-free animals do not
develop tolerance to allergens when exposed to
them orally. However, colonizing such germ-
free mice with a defined intestinal flora, either a
mixture of 46 Clostridium species or a single
strain of Bacteroides fragilis, leads the T-reg cell
population to expand, and consequently the an-
imals develop increased resistance to several
chronic inflammatory diseases.
The modern lifestyle alters the gut microbiota
of humans. A recent study compared the bacte-
rial microbiota of children in urban Europe to
those from children living in a rural village in
Burkina Faso in west Africa. The bacteria within
these sets of microbiota were substantially dif-
ferent. Although there is no formal proof that
the European microbiota is less immunoregula-
tory than the African microbiota, this difference
appears likely.
Encounters with other “old friends,” such as
helminths and bacterial pathogens, and differ-
ences in diet also can change the composition of
the GI microbiota. Further, manipulating the
immune system may change the gut microbiota.
For example, a specific strain of pathogen-free,
nonobese diabetic (NOD) mice, which sponta-
neously develop T1D, are protected from the
autoimmune disease following knockout of a
gene involved in innate immune responses, ac-
cording to Li Wen at Yale University, Jeffrey
Gordon at Washington University, and their
collaborators at several institutions. However,
this gene was not directly involved in the auto-
immune response. Rather, that knockout led to
changes in interactions between the immune
system and the microbiota, and to subsequent
changes in composition of that microbiota. This
modified microbiota, rather than the gene
knockout itself, was responsible for blocking
development of T1D. Thus, it is important to
Volume 7, Number 4, 2012 / Microbe Y177
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note that helminth infections can modulate the
microbiota, apparently with beneficial effects on
More broadly, any modulation of the immune
system, whether through infections by “old
friends” such as helminths or from scientists
knocking out genes that modulate the same mi-
crobiota, may lead to long-term health conse-
quences that are mediated through changes in
microbiota (Fig. 2). Similarly, some of the long-
term immunological effects from dietary
changes likely operate through changes within
the microbiota.
Reconciling Competing Theories
The hygiene hypothesis and the emerging micro-
biota story fall along a continuum. Each de-
pends on the other, and the term “old friends
hypothesis” can be used to describe them both.
This approach to linking these two lines of
thought leads to the issue of competing hypoth-
eses. The view that setting up appropriate im-
munoregulatory mechanisms requires interac-
tion between the immune system and organisms
with which the mammalian immune system has
coevolved is well accepted. However, it is in
danger of fragmenting, which is regrettable be-
cause the underlying principles are shared
among supposedly competing hypotheses.
Although the hygiene hypothesis and more
recent microbiota-based research fall along a
continuum encapsulated within the old friends
hypothesis, the hygiene hypothesis tends to split
in other ways. For example, evidence that expo-
sure to the microbiologically rich farming envi-
ronment is most effective during the first few
Genetics and the old friends. Heavy loads of immunoregulatory organisms such as helminths led to accumulation of single nucleotide
polymorphisms (SNP) that increase the potential for inflammatory responses. This evolutionary balance is upset when the old friends are
depleted by the modern lifestyle, making these SNPs risk factors for chronic inflammatory disorders. These effects are exacerbated by other
environmental changes such as vitamin D deficiency and obesity.
178 YMicrobe / Volume 7, Number 4, 2012
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years of life gave rise to the neonatal priming
hypothesis. Further, because exposing pregnant
women to this same environment apparently
protects their children against subsequent aller-
gic disorders, some investigators speak of the
prenatal priming hypothesis.
Meanwhile, studies such as that of Correale
or the effects on allergic manifestations of long-
term elimination of helminths indicate that
adults are also susceptible to immunomodula-
tion by the “old friends,” and indeed the current
spate of clinical trials is based on the view that
this immunomodulation is clinically applicable.
Instead of fragmenting these results into differ-
ent hypotheses, it makes more sense to include
them as examples of a more comprehensively
framed old friends hypothesis that begins oper-
ating before birth and continues into adulthood.
Other Factors, Interaction with Genes
Although diet accounts for some differences in
microbiota from children in Europe and
Burkina Faso, it cannot explain the effects of the
farming environment or the effects of helminths
on MS patients in Argentina. Diet mainly
changes the immunoregulatory microbiota.
Other factors that exacerbate the effects from
loss of helminths or other old friends include
delayed exposure to viruses that trigger autoim-
munity when they are encountered later than the
neonatal period, deficiencies in vitamin D
which plays a crucial role in immunoregulation,
and exposure to pollutants such as diesel partic-
ulates and dioxins, which drive differentiation
of Th17 cells (Fig. 3).
Humans living in regions with heavy loads of
old friend organisms such as helminths tend to
have higher levels of single-nucleotide polymor-
phisms (SNP) or other gene variants that partly
compensate for this form of immunoregulation.
Examples include genes encoding IgE, pro-in-
flammatory cytokines, STAT6 (a transcription
factor involved in Th2 responses), and a trun-
cated form of the serotonin transporter that has
a marked pro-inflammatory effect. When old
friend organisms are withdrawn, these pro-in-
flammatory genetic variants become risk factors
for chronic inflammatory disorders.
Broader Implications
We need to ask whether the same thinking is
relevant to other inflammation-associated disor-
ders that are increasing in the modern urban
environment. Chronic inflammation can trigger
cancer and also provide growth and angiogenic
factors that enhance its growth and spread.
Some types of cancer (for example, acute lym-
phatic leukemia of childhood, Hodgkin’s lym-
phoma, and colorectal and prostate cancer)
show urbanization-related increases that are
similar to those of the chronic inflammatory
disorders discussed above.
Another important issue is major depressive
disorder. In a large subset of patients this disor-
der is accompanied by raised levels of circulating
pro-inflammatory cytokines even in the absence
of any clinically apparent inflammatory disease,
and we know that cytokines, when used clini-
cally as therapeutic agents, can trigger depres-
sion. This increasingly important problem is
more common in urban environments, and re-
cent functional MRI studies have shown that a
rural upbringing causes long-term changes to
CNS function. There is accumulating evidence
that anti-inflammatory strategies might be ther-
Research to identify causes for diseases that
were rare before the modern era might be ren-
dered irrelevant if the old friends were still pres-
ent. For example, the claim that Crohn’s disease
is due to a genetic defect in the homing of
neutrophils is difficult to reconcile with the fact
that 100 years ago the disease barely existed.
Perhaps recent environmental changes led that
genotype to become a risk factor (Fig. 3). Simi-
larly, other hypotheses attributing autoimmune
diseases to molecular mimicry or viral infections
might be secondary to underlying defects in
Correale, J., and M. Farez. 2007. Association between parasite infection and immune responses in multiple sclerosis. Ann.
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Matricardi, P. M., F. Rosmini, S. Riondino, et al. 2000. Exposure to foodborne and orofecal microbes versus airborne viruses
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Raison, C. L., C. A. Lowry, and G. A. W. Rook. 2010. Inflammation, sanitation and consternation: loss of contact with
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Riedler, J., C. Braun-Fahrlander, W. Eder, et al. 2001. Exposure to farming in early life and development of asthma and
allergy: a cross-sectional survey. Lancet 358:1129–1133.
Rook, G. A. W. 2010. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: darwinian
medicine and the ‘hygiene’ or ‘old friends’ hypothesis. Clin. Exp. Immunol. 160:70–79.
Rook, G. A. W., and A. Dalgleish. 2011. Infection, immunoregulation and cancer. Immunol. Rev. 240:141–159.
Round, J. L., and S. K. Mazmanian. 2009. The gut microbiota shapes intestinal immune responses during health and disease.
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180 YMicrobe / Volume 7, Number 4, 2012
... Indeed, our current and highly hygienic way of life-thanks to which we avoid the spread and the development of the infective diseases that caused numerous deaths in the past-caused a mismatch between these environmental conditions and the past high pathogens exposure under which the immune system evolved. The so-called Hygiene Hypothesis seems to have found an explanation for the considerable spread of asthma, eczema, rhinitis, food allergies, but also for type 1 diabetes, and inflammatory bowel diseases [52]. It is worth noting that the study of Von Hertzen and colleagues [53] correlated microbial-rich drinking water with reduced risk for atopy. ...
... It is worth noting that the study of Von Hertzen and colleagues [53] correlated microbial-rich drinking water with reduced risk for atopy. The Hygiene Hypothesis principle, together with the recent increasing interest in the study of microbiota, lead to the development of the Old Friends Hypothesis [52]. This describes how some mechanisms of immunomodulation are encoded in the genes of organisms that coevolved with humans; thus, the interaction of the immune system with these organisms is essential for an appropriate immune response. ...
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Microbial communities interact with us and affect our health in ways that are only beginning to be understood. Microorganisms have been detected in every ecosystem on Earth, as well as in any built environment that has been investigated. Drinking water sources, drinking water treatment plants and distribution systems provide peculiar microbial ecological niches, dismantling the belief of the “biological simplicity” of drinking water. Nevertheless, drinking water microbiomes are understudied compared to other microbiomes. Recent DNA sequencing and meta-omics advancements allow a deeper understanding of drinking water microbiota. Thus, moving beyond the limits of day-to-day testing for specific pathogenic microbes, new approaches aim at predicting microbiome changes driven by disturbances at the macro-scale and overtime. This will foster an effective and proactive management of water sources, improving the drinking water supply system and the monitoring activities to lower public health risk. Here, we want to give a new angle on drinking water microbiome research. Starting from a selection of 231 scientific publications on this topic, we emphasize the value of biodiversity in drinking water ecosystems and how it can be related with industrialization. We then discuss how microbiome research can support sustainable drinking water management, encouraging collaborations across sectors and involving the society through responsible research and innovation.
... Coevolution of microbes, macrobiotic organisms and their animal hosts over the past 500 million years has resulted in the development of some symbiotic relationships that enable animals to adapt to the ambient environment and protect themselves against pathogens (Strachan, 1989;Chakrabarty, 2003;Tlaskalova-Hogenova et al., 2011;Rook, 2012). Such relationships involve bidirectional signaling between the gastrointestinal tract and the brain via neural, hormonal and immune interactions (Grenham et al., 2011). ...
... Since allergies are mediated by T helper (T H 2) lymphocytes, and autoimmunity is mediated by T helper (T H 1/T H 17) lymphocytes, the immune dysregulation caused by lack of exposure to "old friends" likely involves disruptions not only in innate immunity but to the adaptive immune system as well. Such dysregulation of immunoregulatory circuits of the immune system may also potentially affect mood, cognitive function and behavior (Rook et al., 2003Raison et al., 2010;Rook, 2012). These same homeostatic processes are likely important to the behavioral ecology of all mammals. ...
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Coevolution of microbes and their hosts has resulted in the formation of symbiotic relationships that enable animals to adapt to their environments and protect themselves against pathogens. Recent studies show that contact with tolerogenic microbes is important for the proper functioning of immunoregulatory circuits affecting behavior, emotionality and health. Few studies have examined the potential influence of ambient bacteria, such as Mycobacterium vaccae on the gut-brain-microbiota axis. In this preliminary research, we show that mice fed live M. vaccae prior to and during a maze learning task demonstrated a reduction in anxiety-related behaviors and maze completion time, when tested at three maze difficulty levels over 12 trials for four weeks. Treated mice given M. vaccae in their reward completed the maze twice as fast as controls, and with reduced anxiety-related behaviors. In a consecutive set of 12 maze trials without M. vaccae exposure, treated mice continued to run the maze faster for the first three trials, and with fewer errors overall, suggesting a treatment persistence of about one week. Following a three-week hiatus, a final maze run revealed no differences between the experimentals and controls. Additionally, M. vaccae-treated mice showed more exploratory head-dip behavior in a zero maze, and M. vaccae treatment did not appear to affect overall activity levels as measured by activity wheel usage. Collectively, our results suggest a beneficial effect of naturally delivered, live M. vaccae on anxiety-related behaviors and maze performance, supporting a positive role for ambient microbes in the immunomodulation of animal behavior.
... We expect changes in microbial exposure from human-animal interfaces arising from direct animal contact or via a shared environment to shape the microbiome and, in turn, to contribute to differential human health across populations. This thought echoes, but broadens, the hygiene hypothesis, which posits that since microbial exposure early in life drives immune development and training (72) and promotes relationships with coevolved commensals that aid in human immunomodulatory functions (73), reduced microbial exposure due to heightened hygiene would have a negative impact on health, a pattern particularly noticeable in high rates of allergic and autoimmune disease. We argue the effects of microbial exposure are broader than just immune system training. ...
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The human gut microbiome varies between populations, largely reflecting ecological differences. One ecological variable that is rarely considered but may contribute substantially to microbiome variation is the multifaceted nature of human-animal interfaces. We present the hypothesis that different interactions with animals contribute to shaping the human microbiome globally. We utilize a One Health framework to explore how changes in microbial exposure from human-animal interfaces shape the microbiome and, in turn, contribute to differential human health across populations, focusing on commensal and pathogen exposure, changes in colonization resistance and immune system training, and the potential for other functional shifts. Although human-animal interfaces are known to underlie human health and particularly infectious disease disparities, since their impact on the human microbiome remains woefully understudied, we propose foci for future research. We believe it will be crucial to understand this critical aspect of biology and its impacts on human health around the globe.
... As mentioned above, helminth infection is thought to be an important part of the old friends hypothesis (102,103,105,107,(435)(436)(437). There is evidence that over the thousands of years of coevolution with their human hosts, many helminths have adapted to modulate the immune system, thereby allowing them to persist in chronic infections. ...
The importance of the microbiome to human health is increasingly recognized and has become a major focus of recent research. However, much of the work has focused on a few aspects, particularly the bacterial component of the microbiome, most frequently in the gastrointestinal tract. Yet humans and other animals can be colonized by a wide array of organisms spanning all domains of life, including bacteria and archaea, unicellular eukaryotes such as fungi, multicellular eukaryotes such as helminths, and viruses. As they share the same host niches, they can compete with, synergize with, and antagonize each other, with potential impacts on their host. Here, we discuss these major groups making up the human microbiome, with a focus on how they interact with each other and their multicellular host.
... Feed and its method of acquisition as well as the environment are critical determinants governing evolution of many animal species (Ley et al., 2008) and their microbiota (Rook, 2012). Selection pressure on the host (e.g. ...
Domestication of chickens from the wild red jungle fowl and modernisation of the poultry industry has changed both poultry and their intestinal microbiome, specifically the eimerian-microbiome-host relationship. Eimeria spp. represent an enteric parasite that has a long co-evolutionary history with their hosts. These parasites have adapted to suit an environment in which chickens thrive and the chickens’ intestinal environment, including the changing host microbiome. This review will delve into the changes in eimerian-host interactions with wild red jungle fowl versus domesticated chickens. The changing nature and composition of the intestinal microbiota as it followed the red jungle fowl into domestication and the relationship of this evolving microbiota with coccidia will be explored. Better comprehension of the web of interactions among the evolving eimerian-microbiome-host relationship will allow for the responsible exploitation of these relationships to maximise poultry health and productivity.
... Furthermore, diversity of life in natural environments may enhance experiences that promote stress reduction, support the development of cognitive resources, stimulate social contacts, attract people for physical activity, and support personal development throughout an individual's lifespan (Kaplan and Kaplan 1989, Kellert 2008, Skevington 2009, Hartig et al 2011). Moreover, recent studies show that declining (contact with) some forms of life may contribute to the rapidly increasing prevalence of allergies and other chronic inflammatory diseases among urban populations worldwide (Rook 2010, von Hertzen et al 2011, Hanski et al 2012). Biodiversity thus can have an important contribution to both public health related ecosystem services and in reduction of health risks. ...
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Internationally, the importance of a coordinated effort to protect both biodiversity and public health is more and more recognized. These issues are often concentrated or particularly challenging in urban areas, and therefore on-going urbanization worldwide raises particular issues both for the conservation of living natural resources and for population health strategies. These challenges include significant difficulties associated with sustainable management of urban ecosystems, urban development planning, social cohesion and public health. An important element of the challenge is the need to interface between different forms of knowledge and different actors from science and policy. We illustrate this with examples from Belgium, showcasing concrete cases of human–nature interaction. To better tackle these challenges, since 2011, actors in science, policy and the broader Belgian society have launched a number of initiatives to deal in a more integrated manner with combined biodiversity and public health challenges in the face of ongoing urbanization. This emerging community of practice in Belgium exemplifies the importance of interfacing at different levels. (1) Bridges must be built between science and the complex biodiversity/ecosystem–human/public health–urbanization phenomena. (2) Bridges between different professional communities and disciplines are urgently needed. (3) Closer collaboration between science and policy, and between science and societal practice is needed. Moreover, within each of these communities closer collaboration between specialized sections is needed.
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Atopic eczema (AE) is an inflammatory skin disease with involvement of genetic, immunological, and environmental factors. One hallmark of AE is a skin barrier disruption on multiple, highly interconnected levels: filaggrin mutations, increased skin pH, and a microbiome dysbiosis towards Staphylococcus aureus overgrowth are observed in addition to an abnormal type 2 immune response. Extrinsic factors seem to play a major role in the development of AE. As AE is a first step in the atopic march, its prevention and appropriate treatment is essential. Although standard therapy remains topical treatment, powerful systemic treatment options emerged in the last years. However, thorough endotyping of the individual patients is still required for ideal precision medicine approaches in the future. Therefore, novel microbial and immunological biomarkers were described recently for the prediction of disease development and treatment response. This review summarizes the current state of the art in AE research.
La maladie de Crohn (MC) appartient au groupe des maladies inflammatoires chroniques del’intestin (MICI). Elle est caractérisée par une réponse inflammatoire excessive, évoluant parpoussées, et se manifestent cliniquement par des diarrhées chroniques, des douleursabdominales récurrentes, une importante perte de poids et des signes systémiques comme desmalaises ou de la fièvre.L’incidence et la prévalence de la MC sont en constante augmentation dans le monde. Sonétiologie reste inconnue, bien que des facteurs génétiques et environnementaux jouent un rôleimportant dans sa survenue et son évolution.L’objectif de ce travail est de faire le point sur la physiopathologie de la MC, en insistant surle rôle de la flore endogène bactérienne (microbiote) dans sa survenue.
Evolution is commonly measured using comparative phylogenetic analysis. Comparisons of orthologous characters and sequences from different species are used to infer organismal evolution. Analyses of duplicated genes can be used to root phylogenetic trees and infer ancestral groups. The expansion of gene families through gene and genome duplications allowed more complex regulatory and developmental pathways to evolve in multicellular eukaryotes. In prokaryotes and single-celled eukaryotes, the acquisition of foreign genes by horizontal gene transfer is the main mechanism for gene family expansion; it allows genomes to evolve new traits quickly and facilitates the assembly of new metabolic pathways. Additionally, prokaryotic organisms with short generation times will accumulate genetic adaptations at a much faster rate than organisms with longer generation times (e.g. humans). In multicellular animals where somatic cells and gametes are separate, acquisition of foreign genes is rare, leading to high levels of similarity in gene content. However, multicellular eukaryotes have evolved in close association with prokaryotic symbionts that impact development, physiology and ecology of the association. To understand the evolution of the complex human systems, we must consider the genomes of the associated microbiota, known as the microbiome. We must therefore consider the human as a holobiont, a complex ecosystem, whose evolutionary fitness is determined by the host, the symbionts and their interactions.
We hypothesize that variations in the frequency of genetic polymorphisms, reflecting ancestral differences in living conditions and exposure to microorganisms, increase susceptibility to adverse pregnancy outcome among present day Black North American women. Striking differences were observed in the frequency of genetic variants between Black and White or Hispanic women in 5 genes (IL1RN, MBL2, PPARA, ATG16L1, CIAS1) associated with inflammation and anti-microbial immunity. The CIAS1 and IL1RN polymorphisms were associated with altered interleukin-1β serum levels; the MBL2 polymorphism resulted in a decreased serum mannose-binding lectin concentration. Gene polymorphisms associated with an alteration in innate immunity were most frequent in Black women. This may reflect an evolutionary selection in response to an ancient environment containing a high multitude of microorganisms, and may increase susceptibility of Black women to infection-associated preterm birth in the current North American environment.
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Inflammation is increasingly recognized as contributing to the pathogenesis of major depressive disorder (MDD), even in individuals who are otherwise medically healthy. Most studies in search of sources for this increased inflammation have focused on factors such as psychosocial stress and obesity that are known to activate inflammatory processes and increase the risk for depression. However, MDD may be so prevalent in the modern world not just because proinflammatory factors are widespread, but also because we have lost contact with previously available sources of anti-inflammatory, immunoregulatory signaling. To examine evidence that disruptions in coevolved relationships with a variety of tolerogenic microorganisms that were previously ubiquitous in soil, food, and the gut, but that are largely missing from industrialized societies, may contribute to increasing rates of MDD in the modern world. Relevant studies were identified using PubMed and Ovid MEDLINE. Included were laboratory animal and human studies relevant to immune functioning, the hygiene hypothesis, and major depressive disorder identified via PubMed and Ovid MEDLINE searches. Studies were reviewed by all authors, and data considered to be potentially relevant to the contribution of hygiene-related immune variables to major depressive disorder were extracted. Significant data suggest that a variety of microorganisms (frequently referred to as the "old friends") were tasked by coevolutionary processes with training the human immune system to tolerate a wide array of non-threatening but potentially proinflammatory stimuli. Lacking such immune training, vulnerable individuals in the modern world are at significantly increased risk of mounting inappropriate inflammatory attacks on harmless environmental antigens (leading to asthma), benign food contents and commensals in the gut (leading to inflammatory bowel disease), or self-antigens (leading to any of a host of autoimmune diseases). Loss of exposure to the old friends may promote MDD by increasing background levels of depressogenic cytokines and may predispose vulnerable individuals in industrialized societies to mount inappropriately aggressive inflammatory responses to psychosocial stressors, again leading to increased rates of depression. Measured exposure to the old friends or their antigens may offer promise for the prevention and treatment of MDD in modern industrialized societies.
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The prevalence of allergic and autoimmune diseases is increasing in developed countries, possibly due to reduced exposure to microorganisms in childhood (hygiene hypothesis). Epidemiological and experimental evidence in support of this hypothesis is accumulating. In this context, parasitic helminths are now important candidates for antiallergic/anti-inflammatory agents. Here we summarize antiallergic/anti-inflammatory effects of helminths together along with our own study of the effects of Schistosoma mansoni on Th17-dependent experimental arthritis. We also discuss possible mechanisms of helminth-induced suppression according to the recent advances of immunology.
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Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host-symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.
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Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated destruction of insulin-producing beta-cells. Its incidence has increased during the past several decades in developed countries, suggesting that changes in the environment (including the human microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal housing facility or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products. Here we show that specific pathogen-free NOD mice lacking MyD88 protein (an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop T1D. The effect is dependent on commensal microbes because germ-free MyD88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free MyD88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates T1D. We also find that MyD88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free MyD88-negative NOD donors attenuates T1D in germ-free NOD recipients. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition.
As man has moved rapidly from the hunter-gatherer environment to the living conditions of the industrialized countries, the incidences of some cancers have increased alarmingly. Recent increases are usually attributed to dietary changes or to altered exposures to putative carcinogens associated with the modern lifestyle. However, the changes in cancer incidence parallel similar increases in non-neoplastic chronic inflammatory disorders (inflammatory bowel disease, allergies, and autoimmunity), and the epidemiology is often strikingly similar. This parallel is worth exploring, because the increases in chronic inflammatory disorders are at least partly explained by immunoregulatory defects resulting from diminished exposure to microorganisms that co-evolved with mammals and developed a role in driving immunoregulatory circuits (the hygiene hypothesis). Dysregulated chronic inflammation can drive oncogenesis and also provides growth and angiogenic factors that enhance the subsequent proliferation and spread of tumor cells. Thus, a modern failure to downregulate inappropriate inflammation could underlie increases in some cancers in parallel with the increases in chronic inflammatory disorders. This possibility is supported by recent work showing that in some circumstances regulatory T cells protect against cancer, rather than aggravating it, as previously assumed. A greater understanding of these interactions might pave the way to improved microbe-based immunotherapies.
The current synthesis of the 'hygiene hypothesis' suggests that the recent increase in chronic inflammatory disorders is at least partly attributable to immunodysregulation resulting from lack of exposure to microorganisms that have evolved an essential role in the establishment of the immune system. This document provides a background for discussion of the following propositions. 1. The essential role of these organisms is an example of 'evolved dependence'. 2. The most relevant organisms are those that co-evolved with mammals, and already accompanied early hominids in the Paleolithic. 3. More recently evolved 'childhood infections' are not likely to have evolved this role, and recent epidemiology supports this contention. 4. This mechanism is interacting with other modern environmental changes that also lead to enhanced inflammatory responses [inappropriate diet, obesity, psychological stress, vitamin D deficiency, pollution (dioxins), etc.]. 5. The range of chronic inflammatory disorders that is affected is potentially larger than usually assumed [allergies, autoimmunity, inflammatory bowel disease, but also vascular disease, some cancers, depression/anxiety (when accompanied by raised inflammatory cytokines), and perhaps neurodegenerative disorders and type 2 diabetes].