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Gut Microbiota: The conductor in the Orchestra of immune-neuroendocrine
communication
El Aidy, Sahar Farouk Abdelsalam; Dinan, Timothy G; Cryan, John F
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Clinical Therapeutics
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El Aidy, S., Dinan, T. G., & Cryan, J. F. (2015). Gut Microbiota: The conductor in the Orchestra of immuneneuroendocrine communication. Clinical Therapeutics, 37(5), 954-67. DOI: 10.1016/j.clinthera.2015.03.002
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Clinical Therapeutics/Volume 37, Number 5, 2015
Review Article
Gut Microbiota: The Conductor in the Orchestra of
Immune–Neuroendocrine Communication
Sahar El Aidy, PhD1,2; Timothy G. Dinan, PhD1,3; and John F. Cryan, PhD1,4
1
Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork,
Ireland; 2Department of Industrial Biotechnology, Genetic Engineering and Biotechnology Research
Institute, Sadat City University, Sadat City, Egypt; 3Department of Psychiatry, University College Cork,
Cork, Ireland; and 4Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
ABSTRACT
Purpose: It is well established that mammals are socalled super-organisms that coexist with a complex
microbiota. Growing evidence points to the delicacy
of this host–microbe interplay and how disruptive
interventions could have lifelong consequences. The
goal of this article was to provide insights into the
potential role of the gut microbiota in coordinating
the immune–neuroendocrine cross-talk.
Methods: Literature from a range of sources,
including PubMed, Google Scholar, and MEDLINE,
was searched to identify recent reports regarding the
impact of the gut microbiota on the host immune and
neuroendocrine systems in health and disease.
Findings: The immune system and nervous system
are in continuous communication to maintain a state of
homeostasis. Significant gaps in knowledge remain
regarding the effect of the gut microbiota in coordinating the immune–nervous systems dialogue. Recent
evidence from experimental animal models found that
stimulation of subsets of immune cells by the gut
microbiota, and the subsequent cross-talk between the
immune cells and enteric neurons, may have a major
impact on the host in health and disease.
Implications: Data from rodent models, as well as
from a few human studies, suggest that the gut
microbiota may have a major role in coordinating
the communication between the immune and
Accepted for publication March 4, 2015.
http://dx.doi.org/10.1016/j.clinthera.2015.03.002
0149-2918/$ - see front matter
& 2015 Elsevier HS Journals, Inc. All rights reserved.
954
neuroendocrine systems to develop and maintain
homeostasis. However, the underlying mechanisms
remain unclear. The challenge now is to fully decipher
the molecular mechanisms that link the gut microbiota, the immune system, and the neuroendocrine
system in a network of communication to eventually
translate these findings to the human situation, both
in health and disease. (Clin Ther. 2015;37:954–967)
& 2015 Elsevier HS Journals, Inc. All rights reserved.
Key words: brain, enteric nervous system, gut
microbiota, immune system.
INTRODUCTION
Our knowledge of the host–microbe interrelationship
is accelerating because of the availability of rapidly
expanding molecular techniques, especially in combination with the use of reductionist in vivo host
models. A growing body of research continues to
show that the normal mammalian structure and
function are significantly dependent on their constant
engagement in complex interactions with microbes.1
For example, the intestinal microbiota with its
components and metabolites affects the host
physiology in various ways to control energy
homeostasis, gut barrier function, mucosal inflammation, and behavior.2–4 Subsequently, the host
modifies many of the microbial activities, which
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Volume 37 Number 5
S. El Aidy et al.
suggests a feedback mechanism that could influence
the microbiota and drive a further cycle of biological
changes to host physiology.5 This multidirectional
interactive dialogue seems to strongly influence an
expanding repertoire of human disorders, including
obesity, depression, and irritable bowel syndrome; the
goal is to decipher the tête-à-tête between the host and
its commensal organisms.6,7
The present review highlights emerging evidence,
which provides a framework for appreciating the
impact of the host–microbiota interplay on health
that is undoubtedly much broader than previously
thought. This review outlines the impact of the gut
microbiota on the immune system as well as the
neuroendocrine system, both of which point to a
potential role of the microbiota as crucial coordinators in the cross-talk between these systems.
MATERIALS AND METHODS
Literature from a range of sources, including PubMed,
Google Scholar, and MEDLINE, was searched to
identify recent reports on the impact of the gut
microbiota on the host immune and neuroendocrine
systems in health and disease. All data were gathered
for the latest available years.
RESULTS
The Host–Microbiota Dialogue
Over the past decade, remarkable advances toward
a better understanding of how the host–microbe
interactome is linked with most pathways that affect
health, disease, and aging were made possible with
novel technologies; these include high-throughput
DNA sequencing, bioinformatics, and gnotobiotic
animal models.1 The intimate interactions between
the host and its microbes that outnumber the host’s
cells by 10 to 1 are required to stimulate the complete
maturation of an efficient intestinal barrier that can
promote niche colonization by commensals and
opposes colonization by pathogens.4,8 Only microbial
populations that are capable of establishing a mutualistic relation with the host can be maintained in the
gut ecosystem,3 creating a habitat that exerts
restrictive selection on its microbial inhabitants. This
restrictive selection of specific microbial groups is
illustrated by the relatively low phylum-level diversity
observed in the microbiota of the gastrointestinal (GI)
tract of many mammalian organisms, including mice
and humans; this is dominated by the phyla of the
May 2015
Bacteroidetes and the Firmicutes, with Proteobacteria,
Actinobacteria, Fusobacteria, and Verrucomicrobia
phyla present in relatively low abundance.9 In
contrast, the diversity at the genus and species levels
is enormous. Advances in metagenomic approaches
helped to illustrate that despite the variation in species
composition, the microbial communities encompass a
relatively similar set of metabolic functions in healthy
individuals, which are referred to as the “core
microbiome.”10 Furthermore, diet and its nutritional
value are partly shaped by (and they in turn can
shape) the gut microbial community, supporting the
notion that “we are what we eat,” a process that starts
early in life.11,12 Indeed, this scenario is now being
exploited for medical innovations along the diet–host
interface in line with Hippocrates’ dictum that “Let
food be thy medicine and medicine be thy food.”
The primary individual microbiota colonize at
birth. However, there is growing evidence that the in
utero environment may not be sterile, as originally
thought: bacteria such as Enterococcus faecalis,
Staphylococcus epidermidis, and Escherichia coli have
been isolated from the meconium of healthy neonates.13 The infant gut microbiota is more variable in
its composition and less stable over time. In the first
year of life, the infant intestinal tract progresses from
sterility to extremely dense colonization, ending with a
mixture of microbes that is relatively stable and largely
similar to that found in the adult intestine.14,15 The
composition of the gut microbiota is shaped by a
variety of factors, including prenatal and postnatal
variables as well as birth factors.16 Altering the
intestinal microbiota, particularly during early life,
has been shown to have lasting consequences on the
host.17 For example, the variation in early-life environmental exposure that includes the method and place of
delivery and a nourishing neonate regimen influences
the microbiota of infants.18,19 The microbiota of
infants delivered vaginally is dominated by microbial
groups that colonize the vagina, whereas infants born
by cesarean delivery have microbiota that more closely
resembles those of the maternal skin community.16,20
However, the duration of the influence of these factors
on the host remains obscure, with contradicting findings available to date. As a final age-related microbial
shift, the elderly have a core microbiome different from
that of younger adults, and the composition is directly
correlated with health outcomes and the decline in the
immune system.21
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The gut is home to a diverse array of trillions of
microbes that influence almost all aspects of human
biology through their interactions with their host.1
Although the host provides the microbiota with the
ecological niche and nutrients required of its survival,
the indigenous microbiota, in turn, provides the host
with full maturation of the innate and adaptive arms
of the immune system, modulation of the nervous
system function, nutrient absorption and fat
distribution, contribution to digestion (eg, the ability
of microbes to break down host nondigestible
polysaccharides), the generation of short-chain fatty
acids (SCFAs), metabolism of xenobiotics (which aids
in protection from environmental toxins), and regulation of the gut motility.2,22–25 Colonization resistance is another protective function that the microbes
provide to their host. This protective function results
from a combination of various functions of commensals, which include their metabolic competition with
the pathogen for the available nutrient resources. The
microbiota provides colonization resistance; in addition, several of the host’s anatomical and physiological factors, including protective mucosal barrier,
secretion of secretory immunoglobulin A (sIgA) and
normal gastric motility, are also involved.26 This
procedure promotes the establishment of an
intestinal environment that prevents colonization
with disease-inducing bacteria, which are abundant
in unhealthy subjects.27
The Gut Microbiota Is Engaged in a Dynamic
Interaction with the Host Immune System
Initially, all microorganisms were considered as
pathogens that are harmful and cause infectious
diseases, and the host immune system should recognize and eliminate these invaders (non-self) while
tolerating self-molecules to maintain homeostasis.
However, the persistent association of host species
with commensal organisms illustrates the major contribution of the gut microbiota in the education and
regulation of the immune system.28 It is now well
established that the immune system depends on
colonization with a microbiota for its maturation.29
The initial microbial colonization is associated with
prominent changes in mucosal and systemic immunity. For example, the physiologic phenomenon of
maturation of the immune system, initiated within the
fetal period, is dynamic in its character and expands in
time through the first months (and even years) of a
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child’s life; within the neonatal period, infancy, and
early childhood, dysfunction of numerous components of the immune system is observed.30 Neonates
have a decreased expression of costimulatory
molecules, diminished dendritic cell (DC) differentiation, and impaired phagocytosis as well as a
defective interaction between DCs, T lymphocytes,
and regulatory T cells, impaired cytotoxic activity of
T cells.31,32 Moreover, the suppressive activity of the
transplacentally transmitted maternal IgG antibodies
contributes to the deficiency of specific humoral response, including the low production of IgA in human
neonates.33 Immune immaturities have also been
reported in animal studies, in which germ-free (GF)
mice and those in the first days of colonization share
many traits, characterized by smaller Peyer’s patches
and reduced cellularity of the lamina propria with
lower Cd4þ and Cd8þ T cells.34,35 Plasma cells and
intraepithelial lymphocytes are rare in the small intestinal mucosa, and sIgA levels are significantly lower
with reduced expression of genes and activation
markers of intestinal macrophages.35,36 sIgA, for instance, represents an intriguing example of how the
microbiota mediates the host physiology through immune modulation. sIgA binds to luminal bacteria to
prevent microbial translocation across the epithelial
barrier,37 but it also influences the balance of immune
and metabolic pathways in intestinal epithelial cells
through a microbiota-dependent mechanism.38 In the
absence of IgA, there is a shift toward the expression of
genes involved in host defense, excessive production of
antimicrobial proteins, and inflammatory-like responses to compensate for the deficiency in microbial
compartmentalization via the sIgA. Instead, in the
presence of IgA, the intestinal microbiota alters the
expression of genes involved in lipid metabolism and
storage, thereby shifting toward a homeostatic microbiota–immune–metabolic response.38,39
The initial engagement of the microbiota in the
education of the host immune system appears to
involve specific strains of the microbial community
(pathobionts) of potential inflammatory allies, which
survive and flourish in an environment enriched by the
inflammatory process.25,40 To date, the few reports
available suggest that these specific bacteria presumably activate mucosal immune priming for the bacterial sampling process to minimize their exposure to
the systemic immune system by transient breaching of
the epithelial barrier; they also stimulate the
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S. El Aidy et al.
production of antimicrobial proteins and a variety of
immune pro-inflammatory and regulatory immune
components.40–42 Elimination of the penetrant bacteria would thus lead to the induction of antigen
presentation and processing molecules, innate and
adaptive constituents that reside in the lamina propria.
Hence, this initial close but regulated contact could
benefit the host by strengthening its gut barrier, and it
confers protection against true invading pathogens.
Segmented filamentous bacteria represent an interesting example of such microbial–host initial immune
engagement. In mice, these bacteria adhere transiently
to the surface epithelium of the ileum and Peyer’s
patches shortly after weaning43 to induce Th17 in the
intestinal lamina propria via a mechanism that
involves host production of serum amyloid A.44
These segmented filamentous bacteria induce Th17
locally in the GI tract; this effect was also shown to
expand to the central nervous system (CNS),45
indicating that improving our understanding of the
intestinal microbiota has therapeutic implications, not
only for intestinal immunopathologies but also for
systemic immune diseases. Combined transcriptional
and immunohistochemical analyses of GF mice and
ex-GF mice helped in detailing how the microbiota
results in reprogramming of the intestinal mucosal
immune responses, with the goal of initiating and
maintaining a balanced immune response that leads to
major molecular immune responses starting only few
days after colonization.35,46
Cumulatively, the early life stage marks the most
extensive changes in the host biology in response to
the colonization of the microbial entities. At that
point, the host encounters challenges, which, at the
molecular level, elicit responses that involve genes
associated with several illnesses (inflammatorylike response, metabolic disorder, and behavioral
changes). Thus, abrupt shifts during the infant’s
unique developmental path through this early unstable
phase may have longer term health implications.47
Indeed, emerging evidence supports the concept of a
critical window of development during early life that
allows for the full-scale establishment of an adequate
host–microbial homeostasis.19
After stabilization of the gut microbiota community, the immune system is continuously stimulated by
several structural components of the microbial cells
and responds by producing a wide range of lymphocytes and cytokines. In a state of homeostasis, the gut
May 2015
microbiota stimulates a chronic state of low-level
activation of the (innate) immune system in the host,
in which bacterial particles stimulate intestinal macrophages and T cells to produce pro-inflammatory
cytokines (eg, interleukin [IL]-1β, tumor necrosis
factor-α, IL-18).48,49 The produced cytokines create
a basal state of immune activation that starts at the
intestinal mucosal surface and eventually affects the
entire body. The adult human gut is believed to
contain up to 1 g of lipopolysaccharides (LPS), and
the low level exposure of immune cells to these
bacterial cell wall components is essential in the
establishment and maintenance of mucosal homeostasis.50 The specific mechanisms underlying host
immune–microbe cross-talk remains unclear; nonetheless, a number of reports have been fundamental in
revealing the mechanistic interaction that orchestrates
this interaction between the host immune system and
its microbiota. The regulation of the chemokine
CXCL16, which is important for the invariant natural
killer T-cell migration and homeostasis by the gut
microbiota, represents an elegant example of this
tightly regulated host–microbe dialogue. This chemokine regulation occurs via epigenetic changes (in
particular, the reduction of methylation status of the
CXCl16 gene), thereby reducing the number of invariant natural killer T cells in the lung and colonic
lamina propria.51
Bacteroides fragilis is another well-studied example
found to be critical for the normal function of the
mammalian immune system via the production of a
glycosphingolipid that inhibits natural killer T-cell
proliferation in the colonic lamina propria.52
B fragilis polysaccharide A, conversely, interacts
with the Toll-like receptor (TLR)-2 on DCs to induce
colonic regulatory T cells (Tregs).53 Colonic Tregs
have been demonstrated to also be induced by a group
of Clostridium species, presumably via bacterial
production of SCFAs.54 Strikingly, the difference
between Treg stimulation with B fragilis and
Clostridium species is that the latter can induce
Tregs in both healthy and inflamed tissues; however,
B fragilis induces Tregs only in inflamed tissues.28
These results indicate that commensals, once they
escape their normal habitats and interact with the
host in a different context, become pathogenic.
Collectively, reports to date confirm the hygiene
hypothesis, which has recently been reformulated as
the “Old Friends” hypothesis; it postulates that
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Clinical Therapeutics
colonization with a “healthy” microbiota during the
vulnerable developmental period exerts effects that
may decrease susceptibility to diseases, whereas its
absence or dysbiosis, as in antibiotic treatment in
childhood, may have reverse effects.55 This concept is
highlighted in the expanding repertoire of human
diseases that are associated with changes in the
intestinal microbiota, such as inflammatory bowel
disease, allergic disorders, autoimmunity, and major
depression.56
Gut Microbiota Talk to the Brain: Language Is an
Enigma
For 4150 years, it has been clear that there is a
bidirectional gut–brain interaction, which regulates
homeostasis. However, the concept of a microbiome–
gut–brain axis is a recent phenomenon, and the
mechanisms that underlie this axis are only slowly
being resolved. Communication between the gut microbiota and the gut–brain axis can occur via multiple
conduits that include gut-secreted neuropeptides, vagal
nerve, sensory nerves, and immune mediators.57 The
brain can influence the commensals directly via the
receptor-mediated signaling and signaling molecules
released in the gut lumen from immune cells or
epithelial cells (in particular, enteroendocrine cells) or
indirectly via changes in the intestinal motility and
secretion.58 Similarly, the enteric bacteria have been
shown to profoundly affect brain function and
behavior.59 On the molecular level, GF mice exhibit
an altered expression of genes involved in neuropeptide production,39 which are involved in brain
development and behavior.60,61 On the behavioral
level, GF mice exhibit increased spontaneous motor
activity compared with that of conventional mice60 and
become more exploratory (more like their donors) after
fecal transfer from mice with anxiety-like behavior.62
Lactobacillus rhamnosus (JB-1), when fed to mice,
reduces stress-induced corticosterone hormone levels.
Moreover, the same strain makes the mice less anxious,
an effect which seems to be dependent on the vagus
nerve.63
Emerging data point to the involvement of bacterial
components and by-products in the dialogue with the
gut–brain axis. The mammalian behavior and neuroendocrine responses are dramatically affected by the
metabolites circulating in the blood, many of which are
dependent on the microbiota for their synthesis.64 Even
cerebral metabolites are influenced by the commensals
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through the microbiota–gut–brain axis, demonstrating
how closely connected the gut microbiota is with brain
health and disease, development, attenuation, learning,
memory, and behavior.65
The gut microbiota is capable of altering the levels
of metabolites that serve as precursors for the synthesis
of the signaling molecules; for example, neuropeptides
such as glutamine and tyrosine, as revealed from
experiments performed in gnotobiotic animals.40,66,67
Although these metabolites can communicate the message around the entire body, our knowledge of which
bacterial species produce which metabolites or display
which components (and which of these synthesized
products can bring about the host–microbial equilibrium) is limited (apart from the capsular polysaccharide A and glycophospholipid in B fragilis that exert
potent immunoregulatory and neurologic effects42,68).
For instance, we do not know which bacteria are
involved in the synthesis of the bacterial metabolite
hippurate, which is known to be modulated by diet,
stress, and disease and is widely detected in several
mammalian species.69 Bacterial LPS and peptidoglycan
components are possible candidates in communicating
the host–microbe interplay. For example, LPS can be
carried directly to the brain via the blood circulation to
act on the TLRs in the brain to give rise to
neuroinflammatory processes, thereby modify the
brain function.70 These outcomes show that the
physiologic effect of the commensals is not limited to
the GI tract but extends to the systemic immune system
and the brain.57 SCFAs such as acetate, propionate,
and n-butyrate, produced during fermentation of
nondigestible polysaccharides, also represent probable
candidates to be involved in setting up the balance.71
N-butyrate especially has been the focus of many
studies aiming to unravel its overall impact on the
human physiology. It has been shown, in in vitro
experiments and in mice, to regulate energy homeostasis, stimulate leptin production in adipocytes, and
induce the secretion of several neuropeptides, such as
glucagon-like peptide-1. This action is proposed to
modulate insulin secretion, lipid and glucose metabolism, and food intake, and it also exhibits antiinflammatory effects.72,73 On the level of the CNS,
n-butyrate reportedly has profound effects on mood
and behavior.74 Through their effect on gastric motility
and intestinal transit stimulation, SCFAs result in an
elevation in serotonin release, as reported in an in vitro
colonic mucosal system.75 Therefore, SCFAs provide a
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S. El Aidy et al.
perfect example to illustrate the connectivity between
the microbiota and the gut–brain axis.76–78 For example, Wang et al79 highlighted changes in the fecal
concentrations of the SCFAs in children with autism
spectrum disorders, suggesting that altered production
of these microbial metabolites, which were shown to
exhibit neuroactivity, may be a mechanism by which
bacteria can alter brain function. Together, these
findings suggest that the modification of the amount
of dietary fiber across the microbe–host food network
would influence the composition of the microbiota,
which in turn modulates the luminal concentrations of
intestinal SCFAs, a potential target for restoring the
host overall physiology. In fact, an unbalanced diet that
is poor in dietary fiber content (and thus does not
require complex metabolic interactions between the
microbial members) would result in lower microbial
diversity and in the imbalanced host–microbial
relationship that is observed in the emerging Western
lifestyle–associated human diseases.80 In a recent
attempt to unravel which bacterial metabolites can
bring about the host–microbial balance, Williams
et al81 used a combination of genetics and biochemistry to identify a key microbial enzyme that
converts dietary tryptophan to the neuropeptide
tryptamine (ie, tryptophan decarboxylase enzyme,
which was found to be present in several bacteria
that colonize 10% of the human population). This
finding suggests that the gut microbiota can sequester
tryptophan from the diet and alter its metabolites in the
host, eventually resulting in altered brain levels of the
neuropeptide serotonin, which ultimately affects brain
function.82 Similarly, although the gut microbiota can
alter the metabolism of several other neuropeptides, the
limited knowledge available regarding the microbial
mechanisms hinders efforts to close this gap in
research. The assumption by Williams et al is
supported by the elevated levels of tryptophan in GF
animals compared with their conventional and
conventionalized counterparts.66,67 Serotonin release
from enterochromaffin epithelial cells is stimulated by
tryptamine83 and is a key regulator of the gut motility
and secretion.84 Recently, it has been shown that gut
microbiota, acting through SCFAs, is an important
determinant of enteric serotonin production and
homeostasis. The gut microbiota from ex-GF mice
colonized with human gut microbiota and conventionally raised mice the colonic rate limiting for mucosal
serotonin synthesis; tryptophan hydroxylase 1 mRNAs
May 2015
as well as the neuroendocrine secretion gene; chromogranin A with no effect on the serotonin transporter or
serotonin catabolic gene; monoamine oxidase A.85
Interestingly, the reported effects did not result from
an increase in the number of the cells producing
serotonin but rather through the action of SCFAs.
Changes in the levels of serotonin were also linked to
the pathology of GI disorders, in which modulation of
serotonin secretion is proposed as a treatment given its
significant role in the enteric nervous system (ENS) and
gut motility.86
Bacterial by-products that come in contact with the
gut epithelium stimulate enteroendocrine cells (EECs)
to produce several neuropeptides such as peptide YY,
neuropeptide Y, cholecystokinin, glucagon-like peptide-1
and -2, and substance P.87 As an example, the gut senses
the bacterial by-product SCFAs through G protein–
coupled receptors 41 and 43 expressed on EECs.88
Upon their secretion by EECs, the neuropeptides
presumably diffuse throughout the lamina propria,
which is occupied with a variety of immune cells, until
they reach the bloodstream or act on the vagal nerve or
intrinsic sensory neurons.89,90 However, the exact mechanisms and whether the neuropeptides have a direct
contribution in the bidirectional communication between the microbiota and CNS are still unknown.
Recently, Bohorquez et al91 demonstrated a direct
communication between EECs and neurons innervating
the small intestine and colon that the paracrine
transmission. The authors discovered a neuroepithelial
circuit that can act as both sensory channels for food
and as gut microbiota to communicate the message from
the lumen to the ENS and CNS and vice versa. This
physical innervation of sensory EECs suggests an
accurate temporal transfer of the sensory signals
originating in the gut lumen with a real-time modulatory
feedback onto the EECs. Nonetheless, neuropeptides
remain an intriguing way by which the gut microbiota
initiates an effective dialogue with the host.
Several reports have shown the changes in neuropeptides and neurotransmitters in response to changes
in the gut microbiota composition. For example,
Lactobacillus acidophilus stimulates the expression
of cannabinoid and opioid receptors in rodents and
in in vitro human epithelial cell cultures, thereby
reducing experimentally evoked visceral pain.92
Antibiotic-induced microbial dysbiosis is associated
with elevated levels of substance P in the colon.93 Not
only does the host respond to the gut microbes by
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Clinical Therapeutics
producing neuropeptides, a variety of different components of intestinal microbiota can also produce a
plethora of neurochemicals, which act to reduce
inflammation, dampen the stress response, and potentially improve mood.94,95 For example, the metabolism of commensals has been shown to produce
histamines and catecholamines, both of which can stimulate the ENS and the CNS via the primary afferent
fibers of the vagal nerve.77,96 Dopamine is also
produced in large quantities by a variety of bacteria
including E coli, Bacillus cereus, Bacillus subtilis,
and Staphylococcus aureus.97 However, the host
produces enzymes that degrade these bacterial
neurochemicals. For example, dopamine is silenced
by the host-produced enzyme monoamine oxidase.57
It is tempting to speculate that the microbiota has
evolved gene analogues to the host signaling molecules
such as neuropeptides to manipulate its host to create
a mutualistic relationship; for the host to prevent that
manipulation in which it conflicts with the host’s
fitness interests, however, corresponding host genes
have evolved to eradicate the microbial attempts to
invade. In fact, the same strategy is emphasized in the
detoxification of enzymes evolved by mammals to
eliminate gut-derived toxins and xenobiotics by rendering them more polar, enabling them to be easily
secreted in the urine and thereby modifying both
gut microbial products and drugs.23 For example,
the compound 4-cresyl, which is formed from the
purification of tyrosine (the precursor of the neuropeptide dopamine) by colonic microbiota, is converted
into a more polar form (4-cresyl sulfate, an abundant
urinary microbial metabolite) by host sulfotransferases.98 This microbial influence on the process of
drug detoxification may also explain individual
variations in certain drug responses, owing to the
enormous interpersonal variations in the gut
microbiota species.6,99 In fact, when rats were administered the antipsychotic olanzapine in the presence of
a cocktail of broad-spectrum antibiotics, the Firmicutes phylum was suppressed and the relative abundance of Bacteroidetes was increased while at the
same time ameliorating the olanzapine-induced weight
gain, uterine fat deposition, plasma free fatty acid levels,
and macrophage infiltration of adipose tissue.100 These
findings of a microbiota-dependent, olanzapine-induced
weight gain have recently been confirmed in GF mice,
and in in vitro studies point to a direct interaction
between olanzapine and microbes.101
960
Gut Microbiota Coordinates the Immune–
Neuroendocrine Cross-Talk
It has been an evolving subject since the beginning
of modern medicine that the immune system and the
brain, the 2 major adaptive systems of the body, talk
to each other through a network of direct- and
indirect-signaling pathways that involve the hypothalamic–pituitary–adrenal axis and the sympathetic
nervous system. It is crucial for the nervous system to
communicate with the immune system to maintain the
host homeostasis because any challenge to the immune system would affect body temperature, visceral
pain, and reflex withdrawal, all of which lead to pain
sensation and behavioral changes but also negatively
impact the immune system.102 However, assessing the
host responses toward its commensal inhabitants,
which are reflected in the complex interrelationships
between nutrient metabolism, the immune system, and
the neuro-endocrine system that occur at many levels
(ranging from endocrine signaling to direct sensing
of bacteria and their products), strongly suggests that
the microbiota is an instrumental component of
the psychoneuroimmunology network (Figure).103
Neuropeptides may be 1 of the signals by which the
microbiota coordinates this communication network
because neurons, epithelial cells, microbial cells, and
immune cells can all produce and respond to them by
expressing the appropriate receptors. For example, at
the start of a local immune response (eg, during the
initial microbial colonization), migration of immature
DCs to lymph nodes was found to be mediated via
α1-adrenergic receptors, emphasizing the early effects
of the sympathetic nervous system.104 Moreover,
various immune cells travel through the blood, and
when they come within sensing distance of a given
neuropeptide, they begin to chemotactically orient
toward it; they then communicate with other
immune cells in the adaptive arm (eg, B and T
lymphocytes) to ensure a well-coordinated immune
response.
Neuropeptides are produced by the host second
brain: the ENS (as well as the CNS), which functions
to regulate blood flow and GI motility, partly through
its interaction with the immune system and gut microbiota.105 Any changes in the luminal chemistry are
sensed by the ENS, which transfers this information to
the intrinsic neurons to cause the release of excitatory
or inhibitory neuropeptides from a subset of cells
named the intestinal cells of Cajal in the myenteric
Volume 37 Number 5
S. El Aidy et al.
Microbiota
Microbiota
signaling
GCPRs
Neuropeptides
Microbial signaling
Enteroendocrine
signaling
Dendritic cell
Epithelium
ChA
T
ChAT
T cell
Immune regulation
Mood and behaviour
Intestinal motility and secretion
Barrier function
Neuropeptide release
Microbiota
signaling;
Excitatory/
inhibitory
signals
-microbial products,
-microbial compounds,
-neuropeptide analogues
Mucosal immune signaling,
Endocrine signaling
Vagal nerve activation
B cell
Mucosa
Submucosa
Enteric neurons
Smooth muscle
Ma
Immune–neuroendocrine
signaling
cro
ph
age
Excitatory/
inhibitory
signals
Gut motility
Muscularis
Figure. The multidirectional dialogue between the gut microbiota, the (mucosal) immune system, and the
neuroendocrine system. Within the gastrointestinal tract, the intestinal microbiota (via microbial
signals) stimulates the immune system and the enteric nervous system, which in turn modulate the
functionality of the central nervous system by various means of communication, including vagus nerve
activation and cytokine release. In response, the brain modulates these multiple signaling pathways
via the hypothalamic–pituitary–adrenal axis and sympathetic and vagal efferents. GCPRs ¼ G proteincoupled receptors.
plexus.106 A recent study showed that in a state of
homeostasis, the GI motility is regulated via the
interactions between the ENS, microbiota, and a
class of macrophages that reside in close proximity
to the myenteric plexus and intestinal cells of Cajal,
named muscularis macrophages (MMs). Muller
et al107 unraveled the mechanisms regulating the
cross-talk between the gut microbiota, the MM
May 2015
immune cells, and eventually the ENS, in which the
gut microbiota (particularly its component LPS) stimulates the production of the cytokine colonystimulating factor 1 in MMs, followed by the
production of bone morphogenetic protein (BMP) 2;
this in turn stimulates the ENS via activation of the
receptors of BMP2 and downstream signaling molecules, resulting in modulation of the gut motility.
961
Clinical Therapeutics
Subsequent to illustrating that MMs are sensitive to
changes in the luminal environment after antibiotic
treatment, the question remains whether the underlying mechanisms use a combination of downstream
immune and neuronal signaling in the mucosa, including signals provided by EECs.
Another plausible mechanism by which the gut
microbiota with its components and accumulating
metabolites can play a critical role in shuttling
information with the host nervous and immune
systems is through signaling pathways. These pathways include warning signals similar to those produced during injury or inflammation. In this case, the
brain may receive the sentinel signals from the
peripheral afferent nerves and elicit neural reflexes,
which in turn regulate the immune responses to avoid
any unwarranted inflammatory response. This scenario resembles what happens in endotoxemia, in
which the signaling is conducted to the brain by the
vagus nerve, and it responds by activating the efferent
cholinergic signaling, which prevents the immune cells
from producing inflammatory cytokines via the stimulation of their cholinergic receptors.108 Immune cells
such as macrophages, neutrophils, DCs, and B and T
lymphocytes not only produce neuropeptides but also
express receptors to the neuropeptides. For example,
acetylcholine, the principle vagal neuropeptide that
attenuates the release of pro-inflammatory cytokines
tumor necrosis factor-α, IL-1β, IL-6, and IL-18 (but not
IL-10), is released from a subset of CD4þ T cells that
transfer the signal to other immune cells through the
activation of α7-nicotinic acetylcholine receptors on
macrophages.109 Acetylcholine is also produced by a
specific type of T cells known as ChATþ T cells, whose
activation by norepinephrine, via β2-adrenergic receptors, results in the production of proinflammatory and
anti-inflammatory cytokines.110 The location of
ChATþ T cells is interesting: they are present in a
low percentage in the spleen but are much more
abundant in the Peyer’s patches,111 which are
surrounded by enteric ganglia and are directly
innervated by enteric and parasympathetic neurons
whose fibers transverse in close proximity to immune
cells. The high abundance of ChATþ T cells in Peyer’s
patches suggests that their stimulation by microbial
components exhibits both defensive and regulatory
roles at the gut mucosal surface, in which trillions of
microbiota reside. Acetylcholine receptor is also
expressed on B cells (named ChATþB cells); similar
962
to ChATþT cells (but only in mucosal-associated
lymphoid tissues and not in other peripheral lymphoid
organs), they release acetylcholine when stimulated
by another neuropeptide (ie, cholecystokinin).112
Intriguingly, it has been shown that the expression of
ChATþB cells begins after birth, following the
microbial colonization via MyD88-dependent TLR
pathways in a transit manner. The assumption was
evident by the reduction in Ach receptor expression
after antibiotic treatment. The specific function of the
ChATþB cells to control local recruitment of neutrophils during endotoxemia as shown in this study seems
crucial to prevent severe tissue damage that is associated with the neutrophil recruitment or dysregulation
of their proteolytic enzymes, as observed in cases of GI
inflammation.113 Together, these evolving data support
the key role of the gut microbes in orchestrating the
existing immune–neuroendocrine dialogue.
When Intimate Friends Turn into Foes
The gut microbiota is normally thought of as
including the “friendly” bacteria that perform many
beneficial functions, until dysbiosis occurs. In this
situation, the imbalanced gut microbiota represents
an environmental alteration and may become harmful
to the host. Microbial dysbiosis is characterized by
reduced diversity and the outgrowth of pathobionts,
which can lead to inadequate immune functioning and
inflammatory responses by an imbalance between
regulatory and pro-inflammatory lymphocytes, GI
motility and permeability, and subsequent changes in
metabolism and extra-intestinal milieus, including the
behavior and CNS functions. Therefore, the host may
encounter major challenges, which are linked at the
molecular level to diverse, complex diseases (eg,
inflammatory bowel disease and metabolic, neurologic, and cardiovascular disorders).114
Altered exposure to the microbiota and its components
has been associated with separately modified immune,
endocrine, and CNS functions, and it may therefore
disrupt the normal immune–neuroendocrine network.
For example, elevated levels of inflammatory response
during microbial dysbiosis appear to have direct effects
on the tryptophan metabolic pathway. Dysregulation of
the kynurenine arm in the tryptophan metabolic
pathway, which is observed in many disorders of
the brain and the GI tract,66 involves the catalytic
enzyme indoleamine-2,3-dioxygenase,40 the activity of
which is induced by inflammatory mediators and by
Volume 37 Number 5
S. El Aidy et al.
corticosteroids.115 These findings suggest that alterations
in the production of neuropeptides by dysbiosis would in
turn alter the neuroendocrine–immune signaling or act
directly on the CNS. The gut microbiota also impacts
brain health in several ways.116 Exposure of GF adult
mice to the gut microbiota decreased permeability of the
blood–brain barrier.117 Bacteria and their components
such as LPS cause leakage of the gut barrier and the
subsequent stimulation of the innate immune response
and inflammation. Excessive production of cytokines is
associated with systemic inflammation and high plasma
levels of proinflammatory and anti-inflammatory cytokines, along with salivary and plasma cortisol and
norepinephrine levels. Elevated levels of cytokines and
neuropeptides were shown to be associated with disrupted sleep, depressed mood, increased anxiety levels,
impaired long-term memory for emotional stimuli, and
elevated visceral pain sensitivity.116,118 Particularly in
elderly patients, elevated levels of the gut microbiota–
delivered LPS, and the resulting endotoxemia, are
more frequent as a result of small intestinal bacterial
overgrowth that is caused by disturbed gut motility
and increased intestinal permeability.119 Indeed, gut
microbiota alterations have been described in several
diseases with altered GI motility, raising the urgency
that increased attention be given to the role of the gut
microbiome in modulating GI function. Patients with
schizophrenia are also known to have high gut bacterial
translocation, and the presence of CD14 as a translocator
marker (which was found to be associated with the
bacterial component C-reactive protein) tripled the risk of
schizophrenia.120
The host responds to specific microbes with antibodies or antigen-specific cellular immune responses.
Thereby, when microbial dysbiosis occurs, CNS dysfunction could result from the autoimmune reaction
caused by molecular mimicry between bacteria and hostself proteins, as in case of multiple sclerosis.121 Multiple
sclerosis, a devastating autoimmune disease that leads to
progressive deterioration of neurologic function, has
been shown to be profoundly influenced by the gut
microbiota via its ability to stimulate proinflammatory
T-cell responses during experimental-associated encephalomyelitis.45 Moreover, the commensal microbes
were shown to be essential in triggering immune
processes that led to a relapsing-remitting autoimmune
disease driven by myelin-specific CD4þT cells.122 The
same study demonstrated that the recruitment and
activation of autoantibody-producing B cells from the
May 2015
endogenous immune repertoire depend on the availability of the target auto-antigen, myelin oligodendrocyte
glycoprotein, and commensal microbiota. This finding
again highlights the crucial role of the gut microbiota in
coordinating the neuro–endocrine–immune cross-talk.
CONCLUSIONS
Over the past decade, preclinical trials, as well as a
few clinical studies, have highlighted the crucial role of
the gut microbiota in maintaining host homeostasis.
Analogously, microbiota dysbiosis has been associated
with a wide range of host disorders, including inflammatory bowel disorders, neuroendocrine disorders,
and behavioral disorders. This growing body of
research illustrates the significant direct effect that
microbes have on the host immune and neuroendocrine systems. Nonetheless, the underlying molecular
mechanisms that orchestrate this dialogue are far less
certain than what is required to open new avenues of
therapeutic intervention. A better understanding of the
causative mechanisms that govern the microbiota–
host interactions is urgently needed to provide novel
avenues to rationally intervene in disease situations,
using either microbial or dietary interventions, with
the goal of correcting situations of microbial dysbiosis
and thereby restoring homeostasis.
Despite the availability of an enormous array of
data from preclinical studies, limited information is
available on how these findings may translate to the
human situation in health and disease. The huge
interindividual variation among human subjects, not
only in terms of microbiota composition and its
genome but also diet, sex-related differences, genetics,
and environmental factors, adds to the complexity of
deciphering the host–microbe interplay in clinical
studies. Another major challenge in clinical studies is
that the food industry does not have as strong of a
clinical trials culture as there has been traditionally in
the pharma sector, and the cost of large-scale trials is
often prohibitive.
ACKNOWLEDGMENTS
Drs. Dinan and Cryan are supported by Science
Foundation Ireland (grant no. 07/CE/B1368 and 12/
RC/2273) and by the Irish Health Research Board,
Health Research Awards (HRA_POR/2011/23)
and (HRA_POR/2012/32). Sahar El Aidy contribution: literature search, figure creation, writing.
Timothy G. Dinan and John Cryan: critical reviewing.
963
Clinical Therapeutics
CONFLICTS OF INTEREST
The authors’ research at the Alimentary Pharmabiotic
Centre is funded by Science Foundation Ireland,
through the Irish Government’s National Development
Plan in collaboration with a variety of pharmaceutical
and food industries. The authors have indicated that
they have no other conflicts of interest regarding the
content of this article.
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Address correspondence to: John F. Cryan, PhD, Department of Anatomy
and Neuroscience, University College Cork, Cork, Ireland. E-mail: j.cryan@
ucc.ie
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