Bifidobacterium longum alleviation of metabolic dysfunction-associated steatotic liver disease: A multi-omics landscape of microbiota and metabolome reconfiguration.

The gut microbiome-host metabolism axis plays a critical role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Although the probiotic Bifidobacterium longum (B. longum) shows promise in ameliorating metabolic disorders, its functional impact on the microbiome-metabolome interplay in MASLD remains elusive. Herein, we established a MASLD mouse model using a high-fat, high-fructose (HFHF) diet and conducted integrated multi-omics analyses, including liver transcriptomics, gut metagenomics, and serum metabolomics, following B. longum intervention. B. longum supplementation effectively attenuated systemic metabolic dysfunction, hepatic steatosis, and intestinal barrier impairment in MASLD. This amelioration was driven by a two-pronged functional reorganization: the restoration of intestinal integrity and a profound remodeling of the hepatic transcriptome, featuring the downregulation of crucial mediators within the CD14-TLR4-NF-κB signaling cascade, including Cd14 and Runx1. Such functional reorganization coincided with a reconfigured gut microbiota, characterized by an increased abundance of beneficial taxa (e.g., Parabacteroides distasonis, Muribaculum intestinale) and suppression of opportunistic pathobionts (e.g., Ruminococcus gnavus, Clostridioides difficile). Furthermore, these microbial shifts were intrinsically linked to a reconfigured serum metabolome, highlighted by the enrichment of protective tryptophan-derived metabolites (e.g., indole-3-propionic acid) and the reduction of detrimental ones (e.g., 17α-methyltestosterone, 7-HDoHE). Collectively, our results suggest that B. longum mitigates MASLD through modulation of the gut microbiota and host serum metabolome, supporting its potential as a probiotic candidate for the management of metabolic health.