Lactiplantibacillus plantarum strain 84-3 and Staphylococcus aureus phages alleviate type 2-diabetes-induced S. aureus and BCAAs increases by PI3K/AKT/GLUT4 signaling pathway

Epidemiological studies have indicated that branched-chain amino acids (BCAAs) increased and gut microbiota disordered in type 2 diabetes mellitus (T2DM). This study aimed to investigate the mechanism of Lactiplantibacillus plantarum strain 84-3 (Lp84-3) combined with Staphylococcus aureus bacteriophage on ameliorating T2DM. Here we perform a case-control study and identify that Staphylococcus_phage was inversely correlated with fasting blood glucose (FBG). It revealed that Lp84-3 could inhibit the growth of S. aureus, and Lp84-3 contains BCAAs degradation enzymes in its genome. Furthermore, Lp84-3 alone or combined with S. aureus bacteriophage interventions can improve blood glucose, insulin resistance, triglycerides, interleukin-1β, tumor necrosis factor-α (TNF-α), BCAAs, and acetyllactate synthase (ALS) in db/db mice. Lp84-3 and S. aureus bacteriophage decreased S. aureus, Malacoplasma iowae, and Oscillibacter sp., and increased some beneficial such as L. plantarum and Muribaculaceae bacterium. Transcriptomic analyses revealed that Lp84-3 and S. aureus bacteriophage activated the PI3K/AKT/GLUT4 signaling pathway and upregulated key genes of Il22, Hgf, Col6a1, Gh, Itga10, Fgf23, and Prl involved in glucose metabolism in hypothalamus. Collectively, Lp84-3 and S. aureus bacteriophage alleviate T2DM by modulating gut microbiota and enhancing glucose metabolism in hypothalamus, supporting its potential use as a promising functional compound microecological agent for alleviating T2DM.