Gut microbial ammonia enhances colonic acetylcholine levels to regulate intestinal motility.

Intestinal motility is a function of the enteric nervous system involving secretion of the excitatory neurotransmitter acetylcholine (ACh). Although gut commensal bacteria are key regulators of intestinal physiology, the molecular mechanisms underlying microbial influence on intestinal peristalsis and constipation remain unclear. Here we report a link between microbial nitrogen metabolism and intestinal motility regulation via ammonia production. We observed compensatory elevation of intestinal ammonia levels and urease activity in mouse models of intestinal dysmotility, induced by ACh deficiency, and in patients with constipation. Ammonia supplementation or intervention in mice with the urease-positive Lysinibacillus fusiformis isolated from patient stool, or engineered urease-expressing bacteria, effectively restored colonic ACh levels. In vitro, ammonia upregulated the expression of voltage-gated calcium channels on enteric neurons, driving Ca2+ influx to potentiate ACh secretion. Our study reveals a microbial compensatory mechanism that responds to fluctuating ACh levels in the intestine and provides microbial targets for intestinal motility disorders.