Multi-omics analysis reveals microbiota-metabolite crosstalk in MASLD pathogenesis in a non-obese murine model

The rising global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), including its severe form metabolic dysfunction-associated steatohepatitis (MASH), underscores the urgency to elucidate disease pathophysiology. To investigate key metabolic interactions central to MASLD progression between the gut microbiota and the host, this study employed a mouse model based on a choline-deficient, amino acid-defined, high-fat diet (CDAHFD). CDAHFD-fed mice rapidly developed severe MASLD, evidenced by hepatomegaly, inflammation and fibrosis, accompanied with significant shifts in certain gut microbial taxa. Metagenomic analysis revealed functional shifts towards pathways involving aromatic amino acid metabolism, particularly tryptophan metabolism. Targeted analysis of circulating metabolites further demonstrated that these shifts correlated with decreased microbial indole derivatives and increased host-derived kynurenine, strongly associated with disease severity. Bile acid profiling identified substantial increases in conjugated primary bile acids, particularly tauro-ß-muricholic acid, linked to impaired gut-liver signaling pathways. Multi-omics network analysis suggested a critical role of Clostridia in metabolizing aromatic amino acids, associated with reducing microbial diversity and exacerbating metabolic disruptions. These findings emphasize the integral role of the microbiota in MASLD pathogenesis, proposing microbiome-derived secondary metabolites and altered bile acid metabolism as potential diagnostic and therapeutic targets for managing MASLD.