Enteric Neuronal Density Contributes to the Severity of Intestinal Inflammation

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 141; no. 2; pp. 588 - 598.e2
• Main Authors: Margolis, Kara Gross, Stevanovic, Korey, Karamooz, Nima, Li, Zi Shan, Ahuja, Ankur, D'Autréaux, Fabien, Saurman, Virginia, Chalazonitis, Alcmene, Gershon, Michael David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2011
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Carrier Proteins - metabolism; Colitis; Colitis - chemically induced; Colitis - genetics; Colitis - metabolism; Colitis - pathology; Crohn's Disease; Dextran Sulfate; Dinitrofluorobenzene; Enteric Nervous System - metabolism; Enteric Nervous System - pathology; Female; Gastroenterology and Hepatology; Hypersensitivity, Delayed - chemically induced; Hypersensitivity, Delayed - metabolism; IBD; Interferon-gamma - metabolism; Interleukin-1beta - metabolism; Leukocyte Elastase - metabolism; Male; Mice; Neurons - metabolism; Neurons - pathology; Neutrophils - metabolism; NF-kappa B p50 Subunit - metabolism; Severity of Illness Index; Signaling; Survival; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha - metabolism; nuclear factor κB; IBD; 2,4-dinitro-1-fluorobenzene; ENS; TNF; IFN; NF-κB; analysis of variance; ANOVA; glyceraldehyde-3-phosphate dehydrogenase; interleukin; WT; polymerase chain reaction; IL; DSS; DNFB; dextran sulfate sodium; interferon; TNBS; trinitrobenzene sulfonic acid; Signaling; delayed-type hypersensitivity; Crohn's Disease; tumor necrosis factor; enzyme-linked immunosorbent assay; DTH; Colitis; enteric nervous system; wild-type; GAPDH; PCR; ELISA
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2011.04.047

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-1β, 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.