Ganoderic Acid A Modulates Enteric Neurons and Intestinal Homeostasis in Irritable Bowel Syndrome by Microbiota Sensing

Irritable bowel syndrome (IBS), a common functional gastrointestinal disorder, is characterized by visceral hypersensitivity and intestinal dysmotility. Ganoderic acid A (GAA), a bioactive triterpenoid from the edible mushroom Ganoderma lucidum, has been reported to exert multiple health-promoting effects; yet, its role in IBS remains unclear. Here, we induced an IBS-like phenotype in C57BL/6 mice by combining the Citrobacter rodentium challenge with water avoidance stress. GAA supplementation markedly alleviated IBS-like symptoms by restoring intestinal motility, regulating enteric nNOS+ and ChAT+ neurons, reducing visceral hypersensitivity, inhibiting colonic inflammation, reinforcing epithelial barrier integrity, and normalizing mast cell activity. Mechanistically, GAA reshaped gut microbiota, changed key tryptophan-metabolizing bacterial taxa, and promoted indole-3-aldehyde (IAld) production, leading to activation of aryl hydrocarbon receptor (AhR) signaling. Additionally, antibiotic treatment abolished the therapeutic benefits of GAA. Collectively, our findings reveal a microbiota-sensing mechanism by which GAA modulates enteric neurons and intestinal homeostasis, providing mechanistic insight and nutritional strategies for managing IBS and related gastrointestinal disorders.