Vildagliptin modulates the microbiota and induces an immunometabolic neuroprotective profile in type 2 diabetes

Dipeptidyl peptidase 4 ( DPP-4) inhibitors (DPP-4i) are widely used to treat Type 2 diabetes (T2D) and are known for their cardiovascular and renal safety profiles. Systematic reviews have also shown that DPP-4i are associated with reduced dementia risk via unknown mechanisms. To examine vildagliptin (DPP-4i) effects on the intestinal microbiota in T2D patients, plasma metabolomics were conducted and inflammatory profiles collected to investigate correlations with potential neuroprotective effects. We examined 29 patients with T2D (not well controlled with metformin) before, and at 30 and 60 days after vildagliptin was introduced, and investigated intestinal microbiota, plasma metabolomic, and inflammatory profiles. In patients after 2 months, vildagliptin induced mild microbiota changes, represented by significant increases in Bariatricus and Butyricimonas genera and the Marinifilaceae family (short-chain fatty acids (SCFA) producers), reduced insulin, HOMA-IR, MCP1, and interferon (IFN)-γ levels, and elevated interleukin (IL)-4 and IL-10 levels, all of which represented an anti-inflammatory profile. Metabolomics results showed that leucine, 2-oxoisocaproate (branched-chain amino acid (BCAA) metabolite), and inosine were significantly reduced after vildagliptin was introduced. Additionally, choline, dimethylamine, and betaine levels were significantly higher, which may explain DPP-4i protective effects against dementia, as these metabolites are neuroprotective. In our T2D patient cohort (not well controlled with metformin), vildagliptin, in addition to improved glucose control and improved insulin resistance, modulated the intestinal microbiota, anti-inflammatory cytokine profiles, and metabolomics, and when combined, may explain DPP-4i’s neuroprotective effects.