Lacticaseibacillus rhamnosus B6 alleviates metabolic dysfunction-associated fatty liver disease by suppressing intestinal LPS synthesis and regulating lipid metabolism

Danqi Wang^1,2Jin Han^1,2Xiaohua Wang^1,2Jing Wang^1,2Chunping You^1,2Zhengjun Wu^1,2*

• ¹Bright Dairy and Food Co Ltd, Shanghai, China
• ²State Key Laboratory of Dairy Biotechnology, Shanghai, China

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) has become a global epidemic with unclear etiology and no effective therapeutic options. Disruption of the gut-liver axis driven by intestinal dysbiosis is closely implicated in MAFLD pathogenesis, making gut microbiota-targeted probiotic interventions a promising preventive strategy. Methods: Lacticaseibacillus rhamnosus B6, a probiotic strain isolated from homemade Bulgarian fermented milk, synthesizes immunomodulatory macromolecules and regulates intestinal flora. In the present study, we comprehensively investigated the colonization ability and MAFLD-alleviating effects of L. rhamnosus B6 in a high-fat diet (HFD)-induced murine MAFLD model, using an integrated approach encompassing metagenomics, untargeted metabolomics, serum biochemical assays, and liver histopathological analysis. Results: Supplementation with L. rhamnosus B6 markedly decreased the relative abundance of Cupriavidus, Desulfovibrionaceae, and Enterobacteriacea, inhibited the predicted lipopolysaccharide (LPS) synthesis pathway, and thereby suppressed the inflammatory response. Furthermore, L. rhamnosus B6 intervention elevated unsaturated fatty acids levels by modulating lipid metabolic pathways—specifically mitochondrial β-oxidation of long chain saturated fatty acids, as well as α-linolenic acid, linoleic acid, and sphingolipids metabolism—while downregulating predicted myo-inositol degradation pathways, collectively contributing to MAFLD alleviation. In vitro, metabolites of L. rhamnosus B6 exerted potent inhibitory activity against LPS-producing bacteria (e.g., Escherichia coli and Salmonella enterica). Discussion: These findings demonstrate that L. rhamnosus B6 is a promising probiotic for MAFLD alleviation, via dual mechanisms of attenuating inflammation and regulating lipid metabolism. This study provides compelling evidence for the specific protective effects of L. rhamnosus B6 against MAFLD and offers a novel probiotic-based therapeutic regimen for MAFLD.