Probiotic-derived strain-specific metabolites ameliorate metabolic dysfunction-associated steatotic liver disease through modulation of the gut-liver axis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition lacking approved treatments, where the gut-liver axis is a key therapeutic target. This study aimed to identify novel probiotic strains and elucidate their strain-specific mechanisms by profiling their functional metabolites. We first investigated gut microbiota alterations in a human cohort (n = 151) and then evaluated six selected lactic acid bacteria strains in a Western diet-induced murine model of MASLD. Untargeted gas chromatography-time-of-flight mass spectrometry (GC-TOF MS) was employed to identify strain-specific metabolic signatures. The human study revealed significant gut dysbiosis in MASH patients. In the animal model, probiotic administration significantly ameliorated hepatic steatosis, inflammation, and improved key serum markers. Crucially, metabolomic analysis demonstrated that each strain possesses a distinct metabolic phenotype; notably, Bifidobacterium breve CKDB002 showed a strong correlation with the antioxidant precursor cysteine, while Pediococcus pentosaceus KID7 was rich in various amino acids. Our findings demonstrate that specific probiotics can alleviate MASLD, and this therapeutic effect is strongly associated with their unique, strain-specific functional metabolites, providing a foundation for developing targeted, evidence-based therapies.