Probiotic-driven gut-liver redox crosstalk modulates hepatic Nrf2 signaling pathway and attenuates metabolic dysfunction-associated steatohepatitis

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by persistent inflammation, oxidative stress, and progressive fibrosis. There is currently no effective pharmacological therapy for MASH. We investigated whether two defined probiotic bacteria strains, Lactobacillus delbrueckii subsp. lactis (L. lactis) CKDB001 and Lactiplantibacillus plantarum (L. plantarum) Q180, attenuate MASH pathology in association with modulation of gut-liver redox signaling. Using diet-induced preventive and therapeutic mouse models of MASH, we showed that oral administration of these strains significantly improved hepatic steatosis, robustly attenuates fibrosis, and reduced inflammatory and oxidative stress markers. Probiotic treatment was associated with increased intestinal glutathione availability, and was accompanied by activation of hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and upregulation of canonical antioxidant enzymes, consistent with improved hepatic redox homeostasis and reduced hepatocellular injury. Microbiome profiling revealed successful intestinal persistence of the administered strains and enrichment of other bacterial taxa associated with gut barrier integrity and metabolic resilience, including Akkermansia muciniphila, Parabacteroides goldsteinii, and Mediterraneibacter butyricigenes. Functional prediction analysis further suggested enhancement of microbial glutathione metabolism pathways, supporting a potential role for microbiota-driven redox modulation in host protection. Therapeutic efficacy was maintained after disease establishment and under conditions recapitulating features of a lean MASH-like phenotype, highlighting obesity-independent mechanisms of action. Collectively, our findings support a probiotic-driven association between intestinal glutathione dynamics and hepatic Nrf2 activation within the gut-liver axis, providing a mechanistically informed and translationally relevant framework for MASH intervention.