de Macedo Juliane Colombo Carrer, Guadagnini Dioze, Assalin Heloisa B, Oliveira Emília Sousa, Magro Daniela O, Alborghetti Marcos R, Sforça Maurício L, Rocco Silvana A, Santos Andrey, Saad Mario J A
Department of Internal Medicine, School of Medical Sciences, State University of Campinas, Rua Vital Brasil, 80, Cidade Universitária, Campinas, SP, CEP 13083-888, Brazil.
Brazilian Biosciences National Laboratory and Brazilian Center for Research in Energy and Materials, Campinas, 13083-100, Brazil.
Sci Rep. 2025 Jul 31;15(1):27932. doi: 10.1038/s41598-025-12990-9.
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 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 metabolite), and inosine were significantly reduced after vildagliptin was introduced. Additionally, choline, dimethylamine, and betaine levels were significantly higher, which may contribute to 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 contribute to explain DPP-4i's neuroprotective effects.
二肽基肽酶4（DPP-4）抑制剂（DPP-4i）被广泛用于治疗2型糖尿病（T2D），并以其心血管和肾脏安全性而闻名。系统评价也表明，DPP-4i通过未知机制与降低痴呆风险有关。为了研究维格列汀（DPP-4i）对T2D患者肠道微生物群的影响，进行了血浆代谢组学分析并收集了炎症谱，以研究与潜在神经保护作用的相关性。我们对29例T2D患者（二甲双胍控制不佳）在引入维格列汀之前、之后30天和60天进行了检查，并调查了肠道微生物群、血浆代谢组学和炎症谱。在2个月后的患者中，维格列汀引起了轻微的微生物群变化，表现为肥胖杆菌属、丁酸单胞菌属和海栖菌科（短链脂肪酸产生菌）显著增加，胰岛素、HOMA-IR、MCP1和干扰素（IFN）-γ水平降低，白细胞介素（IL）-4和IL-10水平升高，所有这些都代表了抗炎谱。代谢组学结果显示，引入维格列汀后，亮氨酸、2-氧代异己酸（支链氨基酸代谢物）和肌苷显著减少。此外，胆碱、二甲胺和甜菜碱水平显著升高，这可能有助于解释DPP-4i对痴呆的保护作用，因为这些代谢物具有神经保护作用。在我们的T2D患者队列（二甲双胍控制不佳）中，维格列汀除了改善血糖控制和胰岛素抵抗外，还调节了肠道微生物群、抗炎细胞因子谱和代谢组学，综合起来可能有助于解释DPP-4i的神经保护作用。
