Lactobacillus plantarum 1-2-3 inhibits ferroptosis by regulating dysregulated fatty acid metabolism to protect mice from high-fat diet-induced MAFLD.

Metabolic associated fatty liver disease (MAFLD) has a high global prevalence with limited therapeutic optionsand poor efficacy. Probiotics are characterized by their safety and small side effects, making them an effective and safe option for treating chronic diseases. They help regulate gut microbiota balance, reduce inflammation, and improve liver metabolism. In this study, we isolated several strains of Lactobacillus plantarum and evaluated their potential applications in MAFLD. The results of in vitro probiotic property tests showed that L. plantarum 1-2-3 and L. plantarum D4-2 exhibited high bile salt hydrolase activity, strong stress resistance, and rapid growth advantages. Both strains were selected as candidates for lipid-lowering potential. Functional validation showed that these two strains alleviated obesity, abnormal glycolipid metabolism, liver damage, and inflammation in HFD-induced mice. Given that Lactobacillus plantarum 1-2-3 exhibited superior therapeutic effects, its regulatory mechanisms were further investigated. The strain was found to regulate the expression of liver lipid metabolism-related genes such as fas and srebp2, as well as the metabolism of free fatty acids such as petroselinic acid, tricosanoic acid, arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid. Furthermore, it boosted hepatic antioxidant capacity and suppressed ferroptosis, thereby mitigating the progression of MAFLD. Additionally, L. plantarum 1-2-3 alleviated intestinal inflammation, repaired the intestinal barrier, increased the expression of fxr and cpt1a genes, and alleviated MAFLD symptoms through the gut-liver axis. The 16S rRNA sequencing results showed that L. plantarum 1-2-3 increased the abundance of Ruminococcus and Clostridia microbial communities, while decreasing the abundance of Megamonas and Streptococcus populations, thereby improving the gut microbiota composition to some extent. Overall, the findings of this study suggest that L. plantarum 1-2-3 has significant potential in mitigating the adverse effects of MAFLD, improving fatty acid metabolism, and regulating the gut microbiota.