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The gastrointestinal (GI) tract is the largest immune organ; in vertebrates, it is the only organ whose function is controlled by its own intrinsic enteric nervous system (ENS), but it is additionally regulated by extrinsic (sympathetic and parasympathetic) innervation. The GI nervous and immune systems are highly integrated in their common goal, which is to unite digestive functions with protection from ingested environmental threats. This review discusses the physiological relevance of enteric neuroimmune integration by summarizing the current knowledge of evolutionary and developmental pathways, cellular organization, and molecular mechanisms of neuroimmune interactions in health and disease.

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Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:

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BACKGROUND & AIMS: 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. METHODS: 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. 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 nuclear factor κB) 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-1ß, interferon-γ, or tumor necrosis factor-α) induced in the ears using 2,4-dinitro-1-fluorobenzene. Transgene effects on inflammation were therefore restricted to the gastrointestinal tract. CONCLUSIONS: 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.

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PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition, the pathophysiology of which is not well understood. It has, however, become increasingly evident that interactions between the enteric nervous system and the immune system play an important role in the cause of IBD. Both the enteric nervous system and the central nervous system can amplify or modulate the aspects of intestinal inflammation through secretion of neuropeptides or small molecules. The purpose of this study is to present recent data on the role that neuropeptides play in the pathophysiology of IBD. RECENT FINDINGS: The best studied of the neuropeptides thought to play a role in the pathogenesis of IBD include substance P, corticotropin-releasing hormone, neurotensin, and vasoactive intestinal peptide; small molecules include acetylcholine and serotonin. Recently discovered functions of each of these neuropeptides with a discussion of implications of the data for therapy are reviewed. SUMMARY: Although the available data suggest an important role for neuropeptides in the pathophysiology of intestinal inflammation, there does yet not appear to be a function that can be taken as established for any of these molecules. The complexity of neuroimmune-endocrine systems, conflicting study results and dual mechanisms of action, warrant further research in this field. Clarification of the molecular mechanisms of action of neuropeptides and on immune and inflammatory reactions will likely yield new treatment options in the future.

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