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Background: Enterochromaffin (EC) cells are dispersed throughout the gastrointestinal (GI) mucosa and are the main source of 5-hydroxytryptamine (5-HT) in the gut. 5-HT has been implicated in the pathophysiology of several GI disorders, but the mechanisms regulating 5-HT production in the gut are unknown. Aim: To investigate the role of CD4 + T cells in the production of 5-HT using a model of enteric parasitic infection. Methods and results: Severe combined immunodeficient (SCID) mice and their wild-type controls were infected with the nematode Trichuris muris and killed on various days after infection to study colonic EC cells and 5-HT production. The number of EC cells and the amount of 5-HT produced were significantly higher in infected wild-type mice than in non-infected mice. The number of EC cells and the amount of 5-HT after infection were significantly lower in SCID mice after infection than in wild-type mice. The number of EC cells and the amount of 5-HT was significantly increased after reconstitution of SCID mice with CD4 + T cells from infected mice and this was accompanied by an upregulation of colonic CD3 T cells and T helper 2 (Th2) cytokines. Laser capture microdissection-based molecular and immunofluorescence techniques revealed the presence of interleukin 13 receptor a1-chain on EC cells. Conclusion: These results show an important immunoendocrine axis in the gut, where secretory products from CD4 + T cells interact with EC cells to enhance the production of 5-HT in the gut via Th2-based mechanisms. These results show new insights into the mechanisms of gut function, which may ultimately lead to improved therapeutic strategies in functional and inflammatory disorders of the GI tract.

Mucosal changes in inflammatory bowel disease (IBD) are characterized by ulcerative lesions accompanied by a prominent infiltrate of inflammatory cells including lymphocytes, macrophages, and neutrophils and alterations in 5-hydroxytryptamine (5-HT)-producing enterochromaffin (EC) cells. Mechanisms involved in recruiting and activating these cells are thought to involve a complex interplay of inflammatory mediators. Studies in clinical and experimental IBD have shown the upregulation of various chemokines including monocyte chemoattractant protein (MCP)-1 in mucosal tissues. However, precise information on the roles of this chemokine or the mechanisms by which it takes part in the pathogenesis of IBD are not clear. In this study, we investigated the role of MCP-1 in the development of hapten-induced experimental colitis in mice deficient in MCP-1. Our results showed a significant reduction in the severity of colitis both macroscopically and histologically along with a decrease in mortality in MCP-1-deficient mice compared with wild-type control mice. This was correlated with a downregulation of myeloperoxidase activity, IL-1beta, IL-12p40, and IFN-gamma production, and infiltration of CD3+ T cells and macrophages in the colonic mucosa. In addition, we observed significantly lower numbers of 5-HT-expressing EC cells in the colon of MCP-1-deficient mice compared with those in wild-type mice after dinitrobenzenesulfonic acid. These results provide evidence for a critical role of MCP-1 in the development of colonic inflammation in this model in the context of immune and enteric endocrine cells.

Ghia J-E, Blennerhassett P, El-Sharkawy RT, Collins SM. The protective effect of the vagus nerve in a murine model of chronic relapsing colitis. Am J Physiol Gastrointest Liver Physiol 293: G711-G718, 2007. First published August 2, 2007; doi:10.1152/ajpgi.00240.2007.-The vagus nerve inhibits the response to systemic administration of endotoxin, and we have recently extended this observation to show that the vagus attenuates acute experimental colitis in mice. The purpose of the present study was to determine whether there is a tonic counterinflammatory influence of the vagus on colitis maintained over several weeks. We assessed disease activity index, macroscopic and histological damage, myeloperoxidase (MPO) activity, and Th1 and Th2 cytokine profiles in chronic colitis induced by administration of dextran sodium sulfate (DSS) in drinking water for three cycles during 5 days with 11 days of rest between each cycle (DSS 3, 2, 2%) in healthy and vagotomized C57BL/6 mice and in mice deficient in macrophage-colony stimulating factor (M-CSF). A pyloroplasty was performed in vagotomized mice. Vagotomy accelerated the onset and the severity of inflammation during the first and second but not the third cycle. Although macroscopic scores were not significantly changed, histological scores as well as MPO activity and colonic tissue levels of IL-1␣, TNF-␣, IFN-␥, and IL-18 but not IL-4 were significantly increased in vagotomized mice compared with shamoperated mice that received DSS. In control mice (without colitis), vagotomy per se did not affect any inflammatory marker. Vagotomy had no effect on the colitis in M-CSF-derived macrophage-deficient mice. These results indicate that the vagus protects against acute relapses on a background of chronic inflammation. Identification of the molecular mechanisms underlying the protective role of parasympathetic nerves opens a new therapeutic avenue for the treatment of acute relapses of chronic inflammatory bowel disease. vagotomy; chronic experimental colitis; inflammatory bowel disease; cytokine; macrophages INFLAMMATORY BOWEL DISEASES (IBD), including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract that result in significant morbidity. The pathogenesis of IBD is unknown but is thought to reflect an interaction of genetic and environmental factors; chronic inflammation results from immune dysregulation and an intolerance of commensal bacteria in the gut (25,34,35). Clinical observations also suggest that the nervous system influences the clinical course of IBD. This is supported by the beneficial effects of lidocaine (40) or nicotine (28) in at least a subset of IBD patients. More direct evidence of a neural modulation is from a case study in which spinal cord stimulation, a therapeutic strategy for treating neuropathic pain, induced relapses of ulcerative colitis (23).The autonomic nervous system is altered both structurally and functionally in IBD; structural changes in autonomic nerves in the gut include changes in ga...