Gut microbiota‐mediated branched‐chain amino acid metabolism: A novel mechanism by which Bacteroides uniformis improves type 2 diabetes mellitus

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a global metabolic disorder where gut microbiota plays a causal therapeutic role. Bacteroides uniformis (B. uniformis, Bu) abundance inversely correlates with T2DM progression, but its mechanism remains unclear. METHODS: This study employed T2DM rat models induced by high-fat feeding (HFD), low-dose streptozotocin (STZ), treated with Bu for six weeks. Methods included physiological monitoring, biochemical assays, histopathology, 16S rRNA gut microbiota sequencing, serum metabolomics, and in vitro HepG2 cell experiments under BCAA-deprived conditions to assess therapeutic mechanisms. RESULTS: Bu restored glucose-lipid homeostasis and reduced multi-organ oxidative/inflammatory damage in T2DM rats. 16S rRNA sequencing showed Bu reversed gut dysbiosis, restored microbial diversity, and enriched butyrate-producing bacteria, elevating fecal propionate and butyrate. Integration of non-targeted and targeted metabolomics further demonstrated that Bu specifically decreased circulating branched-chain amino acid (BCAA) levels, including leucine, isoleucine, valine, and their associated metabolites. In vitro validation confirmed that BCAA deprivation enhanced glucose uptake and attenuated lipid deposition in palmitate (PA)-induced insulin resistance (IR) in HepG2 cells. CONCLUSIONS: The present study demonstrates that Bu exerts multi-target modulation of the gut microbiota-metabolic axis, providing experimental evidence for its potential as a next-generation probiotic for T2DM prevention and treatment and associates the improvement with altered BCAA metabolism.