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

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.