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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE318635 | GEO | 2026/07/15

REPOSITORIES: GEO

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Project description:Background: The etiology of Inflammatory Bowel Disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3 and Reg3 independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that five weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or healthy microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for the host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.

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

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