1. YEAR IN REVIEW
of the CCL5 chemokine, which recruits
neutrophils and manifests as IBD.7
The identity of the activating trigger for
the NLRP6 inflammasome in epithelial cells
is unknown. The trigger might be a damageinduced molecular pattern, which is one
mechanism by which the host could distinguish harmless commensals from pathogens,
both of which express similar molecular patterns as ligands for TLRs. However, in some
instances, the pathogen and commensal
dichotomy might simply relate to the context
of their encounter with the immune system.
Thus, a commensal in the wrong place will
be treated as a pathogen; likewise, the handling of commensals in certain genetically
susceptible individuals might be similar
to that of pathogens. Another explanation
for immunologic discrimination between
pathogens and commensals could involve
recognition of symbiotic bacterial molecules in a process that favors colonization
with commensals.8 An immunomodulatory
polysaccharide produced by the prominent
gut commensal, Bacteroides fragilis, has
been reported to suppress T H17 effector
cells by signaling through TLR2 on regulatory T cells, thereby enabling the commensal
to avoid an adverse immune response and
successfully colonize the host. The response
to polysaccharide is distinct from that seen
with other TLR2 ligands that promote clearance of pathogens. The immunomodulatory
properties of polysaccharide also have efficacy in an animal model of IBD, confirming
the potential for mining the microbiota for
drug discovery (Figure 1).
Other examples of bacterial-derived
metabolites with therapeutic potential
include the production of a soluble protein
ligand for the epidermal growth factor
receptor by Lactobacillus rhamnosus GG
(which attenuates intestinal inflammation
by inhibiting cytokine-induced apoptosis in
intestinal epithelial cells), and the discovery of an antimicrobial agent with narrow-­
spectrum activity against Clostridium
difficile.9,10 The latter was uncovered by an
extensive screen of fecal colonies for antimicrobial producers and resulted in the
identification of a strain of B. thuringiensis
that produces a heterodimeric bacteriocin, thuricin CD, which has potent activity against C. difficile. Using a distal colon
model, thuricin CD was shown to be as
effective as vancomycin and metronid­azole
but exhibited a narrower spectrum of activity without causing ‘collateral damage’ to the
dominant phyla within the surrounding
commensal microbiota.
74 | FEBRUARY 2012 | VOLUME 9
What can we expect from this field in the
immediate future? Microbial enterotypes
are likely to be refined and correlated with
human genotypes with respect to disease
risk, and longitudinal studies will shed light
on the impact of lifestyle variables over time.
However, as molecular profiling continues
apace, studies of the microbiota should be
complemented with a return to culturebased in vitro studies to fulfil the promise
of mining the microbiota and to understand the molecular basis of host–microbe
interactions in health and disease.
Department of Medicine, Clinical Sciences
Building, Cork University Hospital, Wilton, Cork,
Ireland.
f.shanahan@ucc.ie
Acknowledgments
F. Shanahan is supported, in part, by Science
Foundation Ireland.
Competing interests
The author declares associations with the following
companies: Alimentary Health Ltd, GlaxoSmithKline,
Procter Gamble. See the article online for full
details of the relationships.
1.
Arumugam, M. et al. Enterotypes of the human
gut microbiome. Nature 473, 174–180 (2011).
2.
Wu, G. U. et al. Linking long-term dietary
patterns with gut microbial enterotypes.
Science 334, 105–108 (2011).
3. Shanahan, F. Murphy, E. The hybrid science
of diet, microbes, and metabolic health. Am.
J. Clin. Nutr. 94, 1–2 (2011).
4. Wang, Z. et al. Gut flora metabolism of
phosphatidylcholine promotes cardiovascular
disease. Nature 472, 57–63 (2011).
5. Vijay-Kumar, M. et al. Metabolic syndrome
and altered gut microbiota in mice lacking
Toll-like receptor 5. Science 328, 228–231
(2010).
6. Bloom, S. M. et al. Commensal Bacteroides
species induce colitis in
host‑genotype‑specific fashion in a mouse
model of inflammatory bowel disease. Cell
Host Microbe 9, 390–403 (2011).
7. Elinav, E. et al. NLRP6 inflammasome
regulates colonic microbial ecology and risk
for colitis. Cell 145, 745–757 (2011).
8. Round, J. L. et al. The Toll-like receptor 2
pathway establishes colonization by a
commensal of the human microbiota. Science
332, 974–977 (2011).
9. Yan, F. et al. Colon-specific delivery of a
probiotic-derived soluble protein ameliorates
intestinal inflammation in mice through an
EGFR-dependent mechanism. J. Clin. Invest.
121, 2242–2253 (2011).
10. Rea, M. C. et al. Effect of broad- and narrowspectrum antimicrobials on Clostridium
difficile and microbial diversity in a model of
the distal colon. Proc. Natl Acad. Sci. USA 108
(Suppl. 1), 4639–4644 (2011).
NEUROGASTROENTEROLOGY IN 2011
Emerging concepts in
neurogastroenterology and motility
Keith A. Sharkey and Gary M. Mawe
Neurogastroenterology encompasses intrinsic and extrinsic neural
processes that regulate gut functions, sensation and related behaviors
such as ingestion. In 2011, key advances were made in understanding
gut–brain interactions, visceral sensation, serotonin signaling,
neurogenesis and neuromuscular transmission.
Sharkey, K. A. Mawe, G. M. Nat. Rev. Gastroenterol. Hepatol. 9, 74–76 (2012);
published online 13 December 2011; doi:10.1038/nrgastro.2011.247
Neural control of the gastrointestinal tract
in both health and disease is a rapidly
evolving and intriguing subject area. Key
advances have been made on several fronts
in neurogastroenterology in 2011. Here, we
highlight a breadth of studies that represent
major milestones in our understanding of
the effect of nutrients and gut microbiota on
emotion and food intake; the role of stress
in visceral hypersensitivity; the concept
that enteric glia can serve as neuronal pre­
cursors; and the roles of serotonin signaling in the gut. In addition, we discuss the
identifica­ ion of a novel class of cells that
t
could mediate inhibitory neuromuscular
signaling in the gastrointestinal tract.
It is becoming increasingly clear that
signals arising in the lumen of the gastro­
intestinal tract can lead to changes in emotional state and behaviors such as food
intake. The notion that foods with a high fat
content are ‘comfort foods’ was substantiated this year by MRI studies demon­strating
that intragastric infusion of fatty acid positively enhanced emotional states, decreased
hunger scores and increased neural activity in the regions of the brain that process
emotions. 1 These findings indicate that
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© 2012 Macmillan Publishers Limited. All rights reserved

2. YEAR IN REVIEW
luminal nutrients can have acute effects on
mood as well as satiety. Evidence indicates
that endocannabinoid signaling in the gut
regulates fat consumption. Thus, the capacity to regulate fat intake exists within the
gut, and this process could, in turn, have
an effect on emotional state and long-term
energy balance.
In addition to nutrients, gut–brain
communication can also be influenced
by enteric microflora, including resident
microbes and ingested probiotics. A recent
study has shown that probiotic bacteria
influence emotional behavior by modulating the subunits of receptors of the neuro­
transmitter γ-aminobutyric acid, and
attenuate anxiety via activation of vagal
pathways.2 Probiotic treatment strategies
might, therefore, prove to be beneficial in
stress-related disorders (such as anxiety and
depression), which are common comorbidi­
ties of functional and inflammator y
bowel disorders.
Although stress is known to potentiate visceral pain and discomfort, a lack of
adequate animal models has meant that
the mechanisms that underlie this form
of visceral hypersensitivity have not been
resolved. Advances in the past year have
provided insights into peripheral and central
mechanisms and have helped to explain how
stress exacerbates visceral pain. Following
the resolution of infectious colitis in mice,
induction of stress resulted in exaggerated
peripheral nociceptive signaling—which is
analogous to post­infectious IBS.3 The hyperexcitabity of primary afferent neurons in this
model is associated with enhanced expression of β-adrenergic and gluco­ orticoid
c
receptors in these cells. Interestingly, the
effects of stress are mimicked by agonists
of these receptors, thus providing potential new therapeutic targets. In addition to
changes in primary afferent neurons, stressinduced activation of astroglial cells in the
spinal cord also seems to contribute to visceral hypersensitivity through the modulation of glutaminergic signaling.4 These novel
observations highlight the importance of
spinal glia and glutamate metabolism in the
sensation of pain.
Glia in the brain and gut serve a wide
array of functions beyond their original
definition as the ‘glue’ that holds neurons
together. In the gut, these functions are
known to include metabolic regulation,
neurotransmission and support of barrier
integrity. Two independent studies published during the past year provide compelling evidence that enteric glia have the
Key advances
■■ Nutrients and bacteria in the lumen of
the gut can affect mood and ingestive
behavior through vagal pathways1,2
■■ Peripheral and central mechanisms
contribute to stress-induced visceral
hypersensitivity3,4
■■ Enteric glia can give rise to new enteric
neurons5,6
■■ Neuronal serotonin protects the integrity
of the enteric nervous system and
regulates gastrointestinal motility and
inflammation7–9
■■ Fibroblast-like cells mediate inhibitory
purinergic neuromuscular transmission10
potential to give rise to neurons in adult
gut or in culture under certain restricted
conditions. Laranjeira and colleagues5 used
genetic lineage tracing to confirm previous results showing that neurogenesis does
not seem to occur in the enteric nervous
system under steady state conditions. This
observa­ ion was corroborated by Joseph
t
and colleagues6 who used incorporation
of a thymidine analogue to investigate
cell division. Remarkably, after injury to
the myenteric plexus, glia were shown to
generate new neurons in vivo.5 However,
the conditions under which neurons can
be replaced seem to be limited to injury to
the plexus. Gliogenesis was observed both
in steady-state conditions and in response
to injury, but the function of new glial cells
remains to be determined. In culture conditions, enteric glia could readily form new
neurons, which indicates that endogenous
pre­ ursors exist within a patient’s own
c
bowel and could be used for transplantation to replace neurons lost or damaged as
a result of idiopathic or acquired enteric
neuropathies.
Serotonin (5-hydroxytryptamine; 5-HT)
in the gastrointestinal tract can trigger
motor, secretory and vasodilator reflexes
under physiological conditions, and acts
as a proinflammatory mediator and stimulator of emesis, pain and discomfort in
pathophysiological conditions. Changes
in serotonin signaling have been reported
in patients with functional gastrointestinal
disorders; however, the causative role of
serotonin in the symptoms of these conditions is not yet fully established. A report
suggests that mucosal serotonin could contribute to visceral pain in these individuals.7
In patients with IBS, spontaneous serotonin
release from the mucosa is increased, which
correlates with the severity of abdominal pain. Moreover, biopsy supernatants
NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY
© 2012 Macmillan Publishers Limited. All rights reserved
from these individuals activate discharge
of extrinsic afferent fibers in an ex vivo rat
preparation, and this response is inhibited by granisetron—an antagonist of the
5-HT3 receptor.
The majority of serotonin is synthesized,
stored and released by entero­ hromaffin
c
cells in the gastrointestinal mucosa; serotonin also serves as an enteric neuro­
transmitter, but the physiological role of
enterochromaffin cell and neuronal serotonin signaling has not been fully determined. Li and colleagues8 addressed this
issue using mice that lack the genes for
tryptophan hydroxylase 1 or 2 (enzymes
required for serotonin biosynthesis in
enterochromaffin cells and neurons, respectively). Although mice lacking mucosal
serotonin did not exhibit a clear phenotype
with regard to gut function, mice deficient
in neuronal serotonin exhibited lower neuronal density, slower intestinal transit and
accelerated gastric emptying when compared with healthy mice. These findings
indicate that neuronal serotonin protects
the integrity of the enteric nervous system
and contributes to normal gastrointestinal
motility. Mucosal serotonin can act as a
proinflammatory mediator, but Tsuchida
et al.9 demonstrated that activation of 5-HT4
receptors on enteric nerve terminals triggers an anti-inflammatory effect. 5-HT4
agonists facilitate acetylcholine release,
which, in turn, can dampen proinflammatory cytokine induction via α7 nicotinic
receptors on macrophages. This finding
suggests that 5-HT4 agonists might, by
inhibiting the inflammatory response and
promoting propulsive motility, have a bene­
ficial effect in certain conditions, such as
postoperative ileus.
One of the ongoing controversies in
neuro­gastroenterology over the past decade
has been the mechanism by which smooth
muscle cells receive inhibitory purinergic
signals from enteric motor neurons. These
signals do not seem to be mediated either
directly by smooth muscle or indirectly
by interstitial cells of Cajal because mice
lacking interstitial cells of Cajal still exhibit
purinergic inhibitory junction potentials,
and isolated smooth muscle cells exhibit
mixed excitatory and inhibitory responses
to ATP. Kurahashi and colleagues 10 shed
light on this dilemma in a report demonstrating that a novel class of excitable cells
(referred to as ‘fibroblast-like cells’), which
express platelet-derived growth factor
receptor α, exhibit all of the properties necessary to detect and transmit puri­ ergic
n
VOLUME 9 | FEBRUARY 2012 | 75

3. YEAR IN REVIEW
signals from nerve terminals to smooth
muscle. These interstitial cells should be
investigated for potential contributions to
gastrointestinal motor disorders.
The gastrointestinal dysfunctions that
fit under the umbrella of neurogastro­
enterology represent a considerable burden
to society with limited treatment options.
Continued efforts, such as those highlighted
here, will provide a better understanding of
these enigmatic disorders and open new
avenues for therapies of the future.
Hotchkiss Brain Institute Snyder Institute of
Infection, Immunity and Inflammation,
Department of Physiology Pharmacology,
University of Calgary, AB T2N 4N1, Canada
(K. A. Sharkey). Department of Anatomy
Neurobiology, University of Vermont, Burlington,
VT 05405, USA (G. M. Mawe).
76 | FEBRUARY 2012 | VOLUME 9
Correspondence to: K. A. Sharkey
ksharkey@ucalgary.ca
Competing interests
The authors declare no competing interests.
1.
2.
3.
4.
Van Oudenhove, L. et al. Fatty acid-induced gutbrain signaling attenuates neural and behavioral
effects of sad emotion in humans. J. Clin. Invest.
121, 3094–3099 (2011).
Bravo, J. A. et al. Ingestion of Lactobacillus strain
regulates emotional behavior and central GABA
receptor expression in a mouse via the vagus
nerve. Proc. Natl Acad. Sci. USA 108,
16050–16055 (2011).
Ibeakanma, C. et al. Brain-gut interactions
increase peripheral nociceptive signaling in mice
with postinfectious irritable bowel syndrome.
Gastroenterology 141, 2098–2108 (2011).
Bradesi, S. et al. Role of astrocytes and altered
regulation of spinal glutamatergic
neurotransmission in stress-induced visceral
hyperalgesia in rats. Am. J. Physiol. Gastrointest.
Liver Physiol. 301, G580–G589 (2011).
5.
Laranjeira, C. et al. Glial cells in the mouse
enteric nervous system can undergo
neurogenesis in response to injury. J. Clin.
Invest. 121, 3412–3424 (2011).
6. Joseph, N. M. et al. Enteric glia are multipotent
in culture but primarily form glia in the adult
rodent gut. J. Clin. Invest. 121, 3398–3411
(2011).
7. Cremon, C. et al. Intestinal serotonin release,
sensory neuron activation, and abdominal pain
in irritable bowel syndrome. Am. J.
Gastroenterol. 106, 1290–1298 (2011).
8. Li, Z. et al. Essential roles of enteric neuronal
serotonin in gastrointestinal motility and the
development/survival of enteric dopaminergic
neurons. J. Neurosci. 31, 8998–9009 (2011).
9. Tsuchida, Y. et al. Neuronal stimulation with
5hydroxytryptamine 4 receptor induces antiinflammatory actions via α7nACh receptors on
muscularis macrophages associated with
postoperative ileus. Gut 60, 638–647 (2011).
10. Kurahashi, M. et al. A functional role for the
‘fibroblast-like cells’ in gastrointestinal smooth
muscles. J. Physiol. 589, 697–710 (2011).
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© 2012 Macmillan Publishers Limited. All rights reserved