Aspergillus ruber, a Candidate Beneficial Gut Fungus, Alleviates Colitis by Secreting 3-Methyldioxyindole, a Metabolite Linked to Aryl Hydrocarbon Receptor Signaling.

Inflammatory bowel disease (IBD) is closely associated with intestinal microecological imbalance, and the role of gut fungi in its pathogenesis has attracted increasing attention. Our previous study showed that polyphenols from foxtail millet bran (BPIS) alleviated experimental colitis while increasing the abundance of Aspergillus ruber. Here, we found that gavage with A. ruber ameliorated dextran sodium sulfate (DSS)-induced colitis, as reflected by reduced body weight loss, disease activity index, colon shortening, and tissue injury. Metabolomics analysis identified 3-methyldioxyindole as a major candidate metabolite, which was further verified in the liquid culture metabolite extract of A. ruber and functionally validated in vivo using the purified compound. Mechanistically, the anti-inflammatory effect of 3-methyldioxyindole was aryl hydrocarbon receptor (AhR)-dependent, blocked by the AhR antagonist CH-223191, and associated with suppressed p65 and IκBα phosphorylation in the NF-κB pathway. These findings support fungal-derived postbiotic strategies for colitis intervention.