Multi-omics analysis reveals the mechanism of Lactobacillus plantarum in alleviating metabolic disorders in type 2 diabetic mice through the gut-liver axis.

Type 2 diabetes mellitus (T2DM) mainly induced by high-fat diets (HFD) is becoming a prevalent and serious metabolic disease worldwide. Although probiotics are considered a treatment for T2DM, the underlying mechanisms and therapeutic effects of the specific strain remain unclear. Thus, elucidating the strain-dependent mechanisms and identifying effective probiotic strains for T2DM management are critically needed. In this study, Lactobacillus plantarum was administered to HFD-induced T2DM mice to evaluate its effects on fasting blood glucose (FBG), body weight (BW), gut microbiota (GM) composition, gut metabolites, and liver gene expression. We found that L. plantarum supplementation significantly reduced FBG, insulin levels, and BW, while ameliorating liver and pancreatic damage in T2DM mice. Furthermore, shifts in gut microbial composition were observed following L. plantarum intervention, characterized by the suppression of Lactobacillus johnsonii, Bacteroides acidifaciens, Alistipes sp., and bacterium D1676, along with enrichment of beneficial strains, such as L. acidophilus, Enterorhabdus sp. P55, and Bacteroides caecimuris. Besides, L. plantarum administration significantly increased the concentrations of glycocholic acid, arachidonic acid, L-tryptophan, and palmitic acid while decreasing chenodeoxycholic acid concentration. This modulation is accompanied by the upregulation of Hmgcr and Ugt1a5 mRNA expression, leading to increased levels of TGR5 (G protein-coupled bile receptor) and GLP1R (Glucagon-like peptide-1 receptor). Transcriptomic and metabolomic analyses confirmed that L. plantarum alleviates T2DM caused by HFD through upregulating the bile acid secretion pathway. The results demonstrate that L. plantarum ameliorates symptoms in T2DM mice through the gut-liver axis. IMPORTANCE: T2DM is becoming a global health problem linked to poor diet and metabolic disorders. The probiotic L. plantarum offers a promising natural approach by targeting two key factors: gut bacteria balance and bile acid function. In HFD-fed mice, this treatment helps restore healthy gut microbes and improves bile acid signaling, which together lower blood glucose, reduce inflammation, and protect against liver damage. Unlike many diabetes medications, L. plantarum works with the body's natural systems, potentially providing a safer, long-term solution. This research highlights how probiotics could complement existing therapies, offering novel therapeutic strategies for diabetes treatment through the gut-liver axis.