Enteric Neuronal Density Contributes to the Severity of Intestinal Inflammation

Abstract

Background & Aims Enteric neurons have been reported to be increased in inflamed regions of the bowel in patients with inflammatory bowel disease (IBD) 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. Methods To determine whether the density of enteric neurons determines the severity of inflammation, we studied transgenic mice that have greater-than-normal (Hand2+/− mice) or fewer-than-normal (NSE-noggin mice, which overexpress noggin under the control of the neuron-specific enolase promoter) numbers of neurons in the enteric nervous system (ENS). 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. Results 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 NF- 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- - - -dinitro-1-fluorobenzene. Transgene effects on inflammation were therefore restricted to the gastrointestinal tract. Conclusion The severity of intestinal inflammation is associated with the density of the enteric innervation in mice. Abnormalities in ENS development might therefore contribute to the pathogenesis of IBD.

Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

“…Children exposed to SSRIs or tricyclic antidepressants in utero were found to be 10-fold more likely to require laxatives for constipation, which is consistent with the idea that antenatal SERT inhibition disturbs ENS development and leads to persistent defects in GI motility (54). The ENS contributes to many GI disorders in adults, including irritable bowel syndrome (55) and inflammatory bowel disease (23,56). Given the importance of 5-HT signaling to ENS development and the long-lasting effects of fluoxetine treatment on sympathetic output, further investigation is probably warranted of the administration to pregnant or lactating women of antidepressants that affect SERT or 5-HT function.…”

Long-lived intestinal tuft cells serve as colon cancer–initiating cells

“…The interaction between epithelial cells and neurons may not be unique to DCLK1 + tuft cells and has, in fact, been suggested in other secretory and enteroendocrine cell types (53). However, a potential nerve/tuft cell axis also appears to be important in intestinal homeostasis, as intestinal proliferation, and thus the state of intestinal progenitors, was found to be highly dependent on neural innervation (52,54). Our data indicate that the neural signal is at least partly mediated through DCLK1 + tuft cells, since genetic ablation of DCLK1 + cells markedly reduced epithelial proliferation.…”

Building a second brain in the bowel

“…Hand2 mutations reduce NCAM1, among many other defects. For example, HAND2 is needed for terminal differentiation of enteric neurons (12,87,88) and this more global effect on neurogenesis may underlie the effect of Hand2 mutations on ganglion formation and bowel motility. Additional work is needed to identify HAND2 targets and to define mechanisms controlling enteric ganglia formation.…”

“…In IBS, altered bowel motility and sensory responses cause pain accompanied by diarrhea or constipation, but health is not otherwise affected. ENS defects also occur in Parkinson's disease (8), diabetes (9), and inflammatory bowel disease (IBD) (10), and recent data suggest that ENS damage might play an early etiologic role in IBD (11,12) and Parkinson's disease (13)(14)(15). Here, we focus on cellular and molecular mechanisms controlling ENS development, highlighting areas that require further investigation and potential clinical implications of new discoveries.…”