Gut Mycobiota‐Associated Tryptophan Catabolites Protect Against Metabolic Dysfunction‐Associated Steatotic Liver Disease

ABSTRACT Accumulating evidence suggests that the intestinal microbiota participates in the progression of metabolic dysfunction‐associated steatotic liver disease (MASLD) through microbiota‐host interaction. However, the beneficial role of commensal mycobiota in MASLD progression remains poorly understood. By comparing the gut microbiome differences, we demonstrated that the deficiency of Caspase Recruitment Domain‐containing protein 9 (CARD9), an adaptor protein for a microbiota recognition receptor, exacerbated high‐fat diet (HFD)‐induced MASLD in a gut fungi‐dependent manner. CARD9 deficiency reduced the abundance of Saccharomyces cerevisiae ( S. cerevisiae ), which was a probiotic alleviating MASLD progression. S. cerevisiae promoted a significantly greater abundance of 5‐hydroxyindoleacetic acid (5‐HIAA) in the intestine through Toll‐like receptor 1 (TLR1), which reduced body weight in mice and alleviated MASLD phenotypes via the “gut‐liver” axis. Particularly, 5‐HIAA directly binds to aryl‐hydrocarbon receptor (AhR) and stimulates its nuclear translocation, subsequently inducing fatty acid oxidation via carnitine palmitoyltransferase 1A (CPT1A) and acyl‐CoA oxidase 1 (ACOX1) transactivation. MASLD patients exhibited decreased levels of S. cerevisiae and 5‐HIAA, and S. cerevisiae effectively reduced hepatic steatosis and improved glucose homeostasis in patients with MASLD. In summary, our findings identified a novel pathway of fungi‐ S. cerevisiae stimulating intestinal 5‐HIAA production and indicated that S. cerevisiae and 5‐HIAA might alleviate MASLD progression, highlighting that the mycobiota‐dependent gut‐liver axis was a promising target for the prevention of MASLD.