Luminal short‐chain fatty acids and 5‐HT acutely activate myenteric neurons in the mouse proximal colon

Abstract Background Gastrointestinal (GI) function is critically dependent on the control of the enteric nervous system (ENS), which is situated within the gut wall and organized into two ganglionated nerve plexuses: the submucosal and myenteric plexus. The ENS is optimally positioned and together with the intestinal epithelium, is well‐equipped to monitor the luminal contents such as microbial metabolites and to coordinate appropriate responses accordingly. Despite the heightened interest in the gut microbiota and its influence on intestinal physiology and pathophysiology, how they interact with the host ENS remains unclear. Methods Using full‐thickness proximal colon preparations from transgenic Villin‐CreERT2;R26R‐GCaMP3 and Wnt1‐Cre;R26R‐GCaMP3 mice, which express a fluorescent Ca 2+ indicator in their intestinal epithelium or in their ENS, respectively, we examined the effects of key luminal microbial metabolites (SCFAs and 5‐HT) on the mucosa and underlying enteric neurons. Key Results We show that the SCFAs acetate, propionate, and butyrate, as well as 5‐HT can, to varying extents, acutely elicit epithelial and neuronal Ca 2+ responses. Furthermore, SCFAs exert differential effects on submucosal and myenteric neurons. Additionally, we found that submucosal ganglia are predominantly aligned along the striations of the transverse mucosal folds in the proximal colon. Conclusions & Inferences Taken together, our study demonstrates that different microbial metabolites, including SCFAs and 5‐HT, can acutely stimulate Ca 2+ signaling in the mucosal epithelium and in enteric neurons.