Abstract
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.
Highlights
According to the report released by the International Diabetes Federation in 2019, there were 463 million people with diabetes aged 20–79 years, and that number is estimated to rise to 700 million by 2045 (Saeedi et al, 2019)
(1) Intestinal barrier function and gut microbial homeostasis were impaired in diabetic cardiomyopathy mice, and this impairment was accompanied by reduced vagal activity, which eventually led to cardiac damage
(3) More importantly, branched-chain amino acid (BCAA) catabolism was decreased in cardiac tissue in the context of diabetes, whereas pyridostigmine regulated BCAA catabolism enzymes to decrease cardiac BCAA concentrations and alleviate mitochondrial dysfunction
Summary
According to the report released by the International Diabetes Federation in 2019, there were 463 million people with diabetes aged 20–79 years, and that number is estimated to rise to 700 million by 2045 (Saeedi et al, 2019). The chronic and systemic influences of hyperglycemia, hyperlipidemia, reactive oxygen species (ROS) overproduction, inflammatory cytokine activation, and concomitant metabolic changes associated with diabetes damage multiple organs and tissues, including the eyes, kidneys, blood vessels, nerves, and heart (Hu et al, 2017). Cardiovascular disease is recognized as a major cause of morbidity and mortality among diabetic patients. A major cardiovascular complication in diabetic patients, is defined as structural and functional myocardial impairment without coronary artery disease or hypertension (Cosentino et al, 2020). Diabetic patients and animals exhibit significantly different gut microbiota than their nondiabetic counterparts (Wang and Jia, 2016). Gut microbiota homeostasis is disrupted in the contexts of cardiovascular diseases such as coronary heart disease, hypertension, heart failure, ventricular fibrillation, and vascular dysfunction (Lee et al, 2018). The effects may be mediated partly through metabolome components, especially branched-chain amino acids (BCAAs), and several bacterial species are associated with regulation of BCAA biosynthesis (Pedersen et al, 2016)
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