Ergosterol Regulates Visceral Hypersensitivity and Intestinal Motility in Irritable Bowel Syndrome Through Microbiota–Metabolites–AhR Signaling Axis

Irritable bowel syndrome (IBS), a globally prevalent disorder, is characterized by visceral hypersensitivity and gut dysmotility. Ergosterol, which is a fungal sterol found in food, has been reported to alleviate metabolic disorders and colitis. However, the underlying role and precise mechanism of ergosterol in managing IBS remain elusive. Here, we identified that ergosterol contributes to IBS-alleviating symptoms by regulating intestinal motility, visceral pain, colonic inflammation, gut barrier function, and mast cell activation. Moreover, we demonstrated that ergosterol modulated gut microbiota, enhanced tryptophan metabolism, and promoted the production of tryptophan-derived metabolite indole-3-lactate (ILA), thus activating the aryl hydrocarbon receptor (AhR) signaling. Additionally, antibiotic treatment abolished the beneficial effects of ergosterol. Supplementation with ILA also regulated visceral hypersensitivity, intestinal motility, and AhR activity. Collectively, these findings elucidate the mechanism by which ergosterol attenuates IBS symptoms via the microbiota-metabolites-AhR signaling axis and highlight its potential as a microbial-based nutritional intervention for promoting intestinal health.