Zhang Jingfan, Chen Yu, Li Ling, Liu Ruiqi, Li Ping
Department of Endocrinology, Shengjing Hospital Affiliated to China Medical University, Shenyang, China.
Department of Endocrinology, Shengjing Hospital Affiliated to China Medical University, Shenyang, China.
Biochem Pharmacol. 2024 Dec;230(Pt 2):116593. doi: 10.1016/j.bcp.2024.116593. Epub 2024 Oct 23.
This study investigated the therapeutic effects of N-Methylnicotinamide (MNAM), a metabolic derivative, on T2DM mice induced by a high-fat diet and streptozotocin (STZ), focusing on its impact on the gut microbiome and immune modulation. MNAM significantly reduced hyperglycemia and enhanced insulin secretion, effects that were dependent on the presence of gut microbiota. It also mitigated STZ-induced weight loss and improved islet cell morphology, reducing islet cell mortality and increasing insulin (INS) levels. Flow cytometry analysis showed a decrease in T helper 17 cells (Th17) and an increase in Treg cells after MNAM treatment, corresponding to the upregulation of Treg markers [interleukin (IL)-10, forkhead box P3 (FOXP3)] and downregulation of Th17 markers [IL17A, RAR-related orphan receptor gamma (RORγt)]. Additionally, MNAM raised anti-inflammatory IL-10 levels while reducing pro-inflammatory cytokines [IL-17α, tumor necrosis factor (TNF-α), IL-6]. Microbiome analysis revealed decreased diversity and increased Blautia abundance post-MNAM administration. Treatment with Blautia not only reversed diabetes indicators but also modulated the Th17/Treg balance and reduced inflammation, with its metabolite sodium acetate mimicking these effects through the G protein-coupled receptor 43 (GPR43) pathway. These findings suggest that MNAM's mitigation of diabetes operates through modulation of the gut microbiota and immune regulation, highlighting Blautia and its metabolite as potential therapeutic agents and providing a theoretical foundation for novel treatment strategies in T2DM.
本研究调查了代谢衍生物N-甲基烟酰胺（MNAM）对高脂饮食和链脲佐菌素（STZ）诱导的2型糖尿病（T2DM）小鼠的治疗作用，重点关注其对肠道微生物群和免疫调节的影响。MNAM显著降低了高血糖并增强了胰岛素分泌，这些作用依赖于肠道微生物群的存在。它还减轻了STZ诱导的体重减轻并改善了胰岛细胞形态，降低了胰岛细胞死亡率并提高了胰岛素（INS）水平。流式细胞术分析显示，MNAM治疗后辅助性T细胞17（Th17）减少，调节性T细胞（Treg）增加，这与Treg标志物[白细胞介素（IL）-10、叉头框P3（FOXP3）]的上调和Th17标志物[IL17A、视黄酸相关孤儿受体γ（RORγt）]的下调相对应。此外，MNAM提高了抗炎性IL-10水平，同时降低了促炎性细胞因子[IL-17α、肿瘤坏死因子（TNF-α）、IL-6]。微生物组分析显示，MNAM给药后微生物多样性降低，布劳特氏菌丰度增加。用布劳特氏菌治疗不仅逆转了糖尿病指标，还调节了Th17/Treg平衡并减轻了炎症，其代谢产物乙酸钠通过G蛋白偶联受体43（GPR43）途径模拟了这些作用。这些发现表明，MNAM对糖尿病的缓解作用是通过调节肠道微生物群和免疫调节来实现的，突出了布劳特氏菌及其代谢产物作为潜在治疗剂的作用，并为T2DM的新型治疗策略提供了理论基础。
