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

GAA supplementation restored intestinal motility in IBS-like mice.

• IBS-like phenotype was induced in C57BL/6 mice by combining Citrobacter rodentium challenge with water avoidance stress.
• GAA treatment markedly alleviated intestinal dysmotility as part of IBS-like symptom reversal.
• The model recapitulates key features of IBS including visceral hypersensitivity and intestinal dysmotility.

GAA supplementation regulated enteric nNOS+ and ChAT+ neurons in IBS-like mice.

• Both nitrergic (nNOS+) and cholinergic (ChAT+) enteric neuron populations were modulated by GAA treatment.
• Enteric neuron regulation is identified as a key component of GAA's mechanism of action in IBS.
• This finding links GAA's effects on gut microbiota to neuronal modulation within the enteric nervous system.

GAA reduced visceral hypersensitivity in IBS-like mice.

• Visceral hypersensitivity is a hallmark feature of IBS that was ameliorated by GAA supplementation.
• Reduction of visceral hypersensitivity occurred alongside inhibition of colonic inflammation and normalization of mast cell activity.
• Mast cell activity normalization was identified as part of the mechanism underlying reduced visceral sensitivity.

GAA reinforced epithelial barrier integrity and inhibited colonic inflammation in IBS-like mice.

• Epithelial barrier integrity was restored as part of the broader intestinal homeostasis effects of GAA.
• Colonic inflammation was inhibited by GAA supplementation in the IBS mouse model.
• These effects occurred in conjunction with normalization of mast cell activity.

GAA reshaped gut microbiota composition and altered key tryptophan-metabolizing bacterial taxa.

• GAA supplementation changed the abundance of key tryptophan-metabolizing bacterial taxa.
• Changes in microbiota composition were associated with increased production of indole-3-aldehyde (IAld).
• IAld production led to activation of aryl hydrocarbon receptor (AhR) signaling as a downstream mechanistic pathway.

Antibiotic treatment abolished the therapeutic benefits of GAA, confirming that its effects are microbiota-dependent.

• Antibiotic-treated mice did not benefit from GAA supplementation.
• This finding establishes that gut microbiota sensing is essential to GAA's mechanism of action.
• The result supports a mechanistic model in which GAA acts through microbial intermediaries rather than directly on host tissues alone.

GAA promoted indole-3-aldehyde (IAld) production and activated aryl hydrocarbon receptor (AhR) signaling as a key mechanistic pathway.

• IAld is a tryptophan-derived metabolite produced by gut bacteria that serves as an AhR ligand.
• AhR signaling activation was identified as the downstream effector linking microbiota changes to intestinal homeostasis and enteric neuron modulation.
• This microbiota-sensing mechanism connects GAA's effects on bacterial communities to host physiological responses in IBS.