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Enteric neuronal density contributes to the severity of intestinal inflammation.

ABSTRACT: Enteric neurons have been reported to be increased in inflamed regions of the bowel in patients with inflammatory bowel disease or intestinal neurogangliomatosis. It is impossible to determine whether this hyperinnervation predates intestinal inflammation, results from it, or contributes to its severity in humans, so we studied this process in mice.To determine whether the density of enteric neurons determines the severity of inflammation, we studied transgenic mice that have greater than normal (NSE-noggin mice, which overexpress noggin under the control of the neuron-specific enolase promoter) or fewer than normal (Hand2(+/-) mice) numbers of neurons in the enteric nervous system. Colitis was induced with trinitrobenzene sulfonic acid or dextran sulfate sodium, and the intensity of the resulting inflammation in Hand2(+/-) and NSE-noggin mice was compared with that of wild-type littermates.Severity of each form of colitis (based on survival, symptom, and histologic scores; intestinal expression of genes that encode proinflammatory molecules; and levels of neutrophil elastase and p50 nuclear factor ?B) were significantly reduced in Hand2(+/-) mice and significantly increased in NSE-noggin animals. Neither mouse differed from wild-type in the severity of delayed-type hypersensitivity (edema, T-cell and neutrophil infiltration, or expression of interleukin-1?, interferon-?, or tumor necrosis factor-?) induced in the ears using 2,4-dinitro-1-fluorobenzene. Transgene effects on inflammation were therefore restricted to the gastrointestinal tract.The severity of intestinal inflammation is associated with the density of the enteric innervation in mice. Abnormalities in development of the enteric nervous system might therefore contribute to the pathogenesis of inflammatory bowel disease.

SUBMITTER: Margolis KG

PROVIDER: S-EPMC4459707 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Enteric neuronal density contributes to the severity of intestinal inflammation.

Margolis Kara Gross KG Stevanovic Korey K Karamooz Nima N Li Zi Shan ZS Ahuja Ankur A D'Autréaux Fabien F Saurman Virginia V Chalazonitis Alcmene A Gershon Michael David MD

Gastroenterology 20110428 2

<h4>Background & aims</h4>Enteric neurons have been reported to be increased in inflamed regions of the bowel in patients with inflammatory bowel disease or intestinal neurogangliomatosis. It is impossible to determine whether this hyperinnervation predates intestinal inflammation, results from it, or contributes to its severity in humans, so we studied this process in mice.<h4>Methods</h4>To determine whether the density of enteric neurons determines the severity of inflammation, we studied tra ...[more]

PMID: 21635893

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Project description:The enteric nervous system (ENS) regulates the motor, secretory and defensive functions of the gastrointestinal tract. Enteric neurons integrate mechanical and chemical inputs from the gut lumen to generate complex motor outputs. How intact enteric neural circuits respond to changes in the gut lumen is not well understood. We recorded intracellular calcium in live-cell confocal recordings in neurons from intact segments of mouse intestine in order to investigate neuronal response to luminal mechanical and chemical stimuli. Wnt1-, ChAT- and Calb1-GCaMP6 mice were used to record neurons from the jejunum and colon. We measured neuronal calcium response to KCl (75 mM), veratridine (10 μM), 1,1-dimethyl-4-phenylpiperazinium (DMPP; 100 μM) or luminal nutrients (Ensure®), in the presence or absence of intraluminal distension. In the jejunum and colon, distension generated by the presence of luminal content (chyme and faecal pellets, respectively) renders the underlying enteric circuit unresponsive to depolarizing stimuli. In the distal colon, high levels of distension inhibit neuronal response to KCl, while intermediate levels of distension reorganize Ca2+ response in circumferentially propagating slow waves. Mechanosensitive channel inhibition suppresses distension-induced Ca2+ elevations, and calcium-activated potassium channel inhibition restores neuronal response to KCl, but not DMPP in the distended colon. In the jejunum, distension prevents a previously unknown tetrodotoxin-resistant neuronal response to luminal nutrient stimulation. Our results demonstrate that intestinal distension regulates the excitability of ENS circuits via mechanosensitive channels. Physiological levels of distension locally silence or synchronize neurons, dynamically regulating the excitability of enteric neural circuits based on the content of the intestinal lumen. KEY POINTS: How the enteric nervous system of the gastrointestinal tract responds to luminal distension remains to be fully elucidated. Here it is shown that intestinal distension modifies intracellular calcium levels in the underlying enteric neuronal network, locally and reversibly silencing neurons in the distended regions. In the distal colon, luminal distension is integrated by specific mechanosensitive channels and coordinates the dynamics of neuronal activation within the enteric network. In the jejunum, distension suppresses the neuronal calcium responses induced by luminal nutrients. Physiological levels of distension dynamically regulate the excitability of enteric neuronal circuits.

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Enteric neuronal density contributes to the severity of intestinal inflammation.

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Enteric neuronal density contributes to the severity of intestinal inflammation.

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