Gut mycobiota-associated tryptophan catabolites protect against metabolic dysfunction-associated steatotic liver disease

Accumulating evidence suggests that the intestinal microbiota participates in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) through metabolite-host interaction. However, the beneficial role of commensal mycobiota in MASLD progression remains poorly understood. 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 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 intestine through TLR1, which then alleviated MASLD phenotypes via “gut-liver” axis. Particularly, 5-HIAA directly bond to aryl-hydrocarbon receptor (AhR) and stimulated its nuclear translocation, subsequently inducing fatty acid oxidation via carnitine palmitoyl transferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1) transactivation. MASLD patients exhibited decreased levels of S. cerevisiae and 5-HIAA, and S.cerevisiae effectively ameliorated 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 mycobiota-dependent gut-liver axis was a promising target for the prevention of MASLD.