Colitis-induced small intestinal hypomotility is dependent on enteroendocrine cell loss in mice

Background & Aims The abdominal discomfort experienced by patients with colitis may be attributable in part to the presence of small intestinal dysmotility, yet mechanisms linking colonic inflammation with small bowel motility remain largely unexplored. We hypothesize that colitis results in small intestinal hypomotility due to a loss of enteroendocrine cells (EECs) within the small intestine that can be rescued using serotonergic-modulating agents. Methods Male C57BL/6J mice, as well as mice that over-express (EECOVER) or lack (EECDEL) NeuroD1+ enteroendocrine cells, were exposed to DSS-colitis (2.5% or 5% for 7 days) and small intestinal motility was assessed by 70kd FITC-dextran fluorescence transit. EEC number and differentiation were evaluated by immunohistochemistry, TUNEL staining, and qRT-PCR. Mice were treated with the 5-HT4 agonist prucalopride (5mg/kg orally, daily) to restore serotonin signaling. Results DSS-induced colitis was associated with a significant small bowel hypomotility that developed in the absence of significant inflammation in the small intestine and was associated with a significant reduction in EEC density. EEC loss occurred in conjunction with alterations in the expression of key serotonin synthesis and transporter genes, including Tph1, Ddc, and Slc6a4. Importantly, mice over-expressing enteroendocrine cells revealed improved small intestinal motility, whereas mice lacking EECs had worse intestinal motility when exposed to DSS. Finally, treatment of DSS-exposed mice with the 5-HT4 agonist prucalopride restored small intestinal motility and attenuated colitis. Conclusions Experimental DSS colitis induces significant small bowel dysmotility in mice due to enteroendocrine loss that can be reversed by genetic modulation of EEC or administering serotonin analogs, suggesting novel therapeutic approaches for patients with symptomatic colitis.