Pyridostigmine Protects Against Diabetic Cardiomyopathy by Regulating Vagal Activity, Gut Microbiota, and Branched-Chain Amino Acid Catabolism in Diabetic Mice.
Pyridostigmine Protects Against Diabetic Cardiomyopathy by Regulating Vagal Activity, Gut Microbiota, and Branched-Chain Amino Acid Catabolism in Diabetic Mice.
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吡斯的明通过调节糖尿病小鼠迷走神经活动、肠道微生物群和支链氨基酸分解代谢来预防糖尿病心肌病
DOI：
10.3389/fphar.2021.647481
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zang WJ
中科院分区：
文献类型：
--
作者：
Yang Y;Zhao M;He X;Wu Q;Li DL;Zang WJ
肠道微生物的破坏与糖尿病性心肌病有关，但肠道微生物影响心脏损伤的机制仍不清楚。我们探索了糖尿病心肌病小鼠的肠道微生物和支链氨基酸 (BCAA) 代谢物分解代谢，并研究了吡斯的明的心脏保护作用。实验采用高脂饮食+链脲佐菌素诱导的C57BL/6小鼠糖尿病心肌病模型进行。高通量测序结果显示，糖尿病心肌病小鼠肠道微生物多样性下降，糖尿病相关微生物丰度改变，产生支链氨基酸的梭菌目和毛螺菌科微生物丰度增加。此外，糖尿病会下调紧密连接蛋白（ZO-1、occludin 和 claudin-1）并增加肠道通透性，从而损害肠道屏障。这些损伤伴随着迷走神经活动的减少，表现为乙酰胆碱酯酶水平升高、乙酰胆碱水平降低和心率变异性，最终导致心脏损伤。吡啶斯的明增强迷走神经活性，恢复肠道微生物群稳态，减少产生 BCAA 的微生物丰度，并改善肠道屏障以降低循环 BCAA 水平。吡斯的明还上调 BCAT2 和 PP2Cm 并下调 p-BCKDHA/BCKDHA 和 BCKDK，以改善心脏 BCAA 分解代谢。此外，吡斯的明可以缓解线粒体结构异常；增加 ATP 产量；减少活性氧和线粒体相关的细胞凋亡；并减轻糖尿病心肌病小鼠的心脏功能障碍、肥大和纤维化。总之，糖尿病心肌病小鼠的肠道微生物群、支链氨基酸分解代谢和迷走神经活动受损，但吡斯的明得到改善。这些结果为开发针对肠道微生物和支链氨基酸分解代谢的糖尿病引起的心脏损伤的治疗策略提供了新的见解。
The disruption of gut microbes is associated with diabetic cardiomyopathy, but the mechanism by which gut microbes affect cardiac damage remains unclear. We explored gut microbes and branched-chain amino acid (BCAA) metabolite catabolism in diabetic cardiomyopathy mice and investigated the cardioprotective effect of pyridostigmine. The experiments were conducted using a model of diabetic cardiomyopathy induced by a high-fat diet + streptozotocin in C57BL/6 mice. The results of high-throughput sequencing showed that diabetic cardiomyopathy mice exhibited decreased gut microbial diversity, altered abundance of the diabetes-related microbes, and increased abundance of the BCAA-producing microbes Clostridiales and Lachnospiraceae. In addition, diabetes downregulated tight junction proteins (ZO-1, occludin, and claudin-1) and increased intestinal permeability to impair the intestinal barrier. These impairments were accompanied by reduction in vagal activity that manifested as increased acetylcholinesterase levels, decreased acetylcholine levels, and heart rate variability, which eventually led to cardiac damage. Pyridostigmine enhanced vagal activity, restored gut microbiota homeostasis, decreased BCAA-producing microbe abundance, and improved the intestinal barrier to reduce circulating BCAA levels. Pyridostigmine also upregulated BCAT2 and PP2Cm and downregulated p-BCKDHA/BCKDHA and BCKDK to improve cardiac BCAA catabolism. Moreover, pyridostigmine alleviated abnormal mitochondrial structure; increased ATP production; decreased reactive oxygen species and mitochondria-related apoptosis; and attenuated cardiac dysfunction, hypertrophy, and fibrosis in diabetic cardiomyopathy mice. In conclusion, the gut microbiota, BCAA catabolism, and vagal activity were impaired in diabetic cardiomyopathy mice but were improved by pyridostigmine. These results provide novel insights for the development of a therapeutic strategy for diabetes-induced cardiac damage that targets gut microbes and BCAA catabolism.
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影响因子：
9.3
作者：
Lee DM;Battson ML;Jarrell DK;Hou S;Ecton KE;Weir TL;Gentile CL
通讯作者：
Gentile CL
影响因子：
29
作者：
Li T;Zhang Z;Kolwicz SC Jr;Abell L;Roe ND;Kim M;Zhou B;Cao Y;Ritterhoff J;Gu H;Raftery D;Sun H;Tian R
通讯作者：
Tian R
小檗碱减轻 2 型糖尿病大鼠的肠粘膜屏障功能障碍
影响因子：
5.6
作者：
Gong J;Hu M;Huang Z;Fang K;Wang D;Chen Q;Li J;Yang D;Zou X;Xu L;Wang K;Dong H;Lu F
通讯作者：
Lu F
影响因子：
4.5
作者：
Johnson RL;Wilson CG
通讯作者：
Wilson CG
影响因子：
5.7
作者：
Androne, AS;Hryniewicz, K;Katz, SD
通讯作者：
Katz, SD