Cholinergic drugs reduce metabolic inflammation and diabetic myocardial injury by regulating the gut bacterial component lipopolysaccharide‐induced ERK/Egr‐1 pathway
Cholinergic drugs reduce metabolic inflammation and diabetic myocardial injury by regulating the gut bacterial component lipopolysaccharide‐induced ERK/Egr‐1 pathway
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DOI：
10.1096/fj.202202108r
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发表时间：
2023-04
期刊：
影响因子：
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通讯作者：
Qing Wu;Ming-Yi Zhao;Dong-ling Li;Xi He;W. Zang
中科院分区：
文献类型：
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作者：
Qing Wu;Ming-Yi Zhao;Dong-ling Li;Xi He;W. Zang
自主神经失衡和代谢性炎症是糖尿病心肌病的重要病理过程。肠道微生物区系失调和细菌成分脂多糖(LPS)水平升高与糖尿病心肌损伤有关，但肠道微生物影响代谢性炎症和心脏损伤的机制尚不清楚。我们确定了抑制胆碱酯酶以改善迷走神经活动的吡斯的明(PYR)是否可以调节紊乱的肠道微生物区系，减轻糖尿病患者的肠道屏障功能障碍、代谢性内毒素血症和炎症。Db/db小鼠表现出高血糖水平、胰岛素抵抗、低迷走神经活动和糖尿病心肌损伤。Db/db小鼠还表现出肠道微生物区系紊乱和随后的肠道屏障功能中断，导致内毒素流入、代谢性内毒素血症和炎症。PYR可改善糖和脂代谢紊乱，调节肠道微生物区系的整体结构，选择性地增加抗炎细菌的丰度，降低db/db小鼠的促炎和潜在致病细菌的丰度。重要的是，PYR增强了迷走神经活动，恢复了肠道微生物区系的稳态，并缓解了肠道屏障功能障碍。因此，脂多糖诱导的细胞外信号调节激酶(ERK)/早期生长反应-1(Egr-1)通路和随后的代谢性炎症被抑制，最终改善了db/db小鼠的心肌肥大、纤维化、氧化应激和功能障碍。体外培养乳鼠心肌细胞暴露于高糖(HG)和脂多糖(LPS)诱导心肌细胞损伤。体外分析表明，HG+LPS可诱导ERK1/2磷酸化、Egr-1表达、炎症反应和细胞凋亡，而乙酰胆碱(ACh)对此有抑制作用。α7烟碱型ACh受体而不是M受体在ACh介导的抗炎作用和抑制HG+LPS刺激的新生大鼠心肌细胞ERK/Egr-1通路中起重要作用。PYR和ACh通过抑制脂多糖诱导的ERK/Egr-1途径和代谢性炎症而改善糖尿病心肌损伤。迷走神经-肠道-心轴为糖尿病的复杂机制提供了新的见解，并提供了新的治疗靶点。
Autonomic imbalance and metabolic inflammation are important pathological processes in diabetic cardiomyopathy. Gut microbiota dysbiosis and increased levels of bacterial component lipopolysaccharide (LPS) are associated with diabetic myocardial injury, but the mechanism by which gut microbes affect metabolic inflammation and cardiac injury remains unclear. We determined whether pyridostigmine (PYR), which inhibits cholinesterase to improve vagal activity, could regulate the disordered gut microbiota and attenuate gut barrier dysfunction, metabolic endotoxemia, and inflammation in diabetes. Db/db mice exhibited high blood glucose levels, insulin resistance, low vagal activity, and diabetic myocardial injury. Db/db mice also exhibited gut microbiota perturbations and subsequent disruption of gut barrier function, resulting in an influx of LPS, metabolic endotoxemia, and inflammation. PYR ameliorated the dysregulated glucose and lipid metabolism, modulated the overall structure of the gut microbiota, selectively enhanced the abundance of anti‐inflammatory bacteria, and reduced the abundance of proinflammatory and potentially pathogenic bacteria in db/db mice. Importantly, PYR enhanced vagal activity, restored gut microbiota homeostasis, and alleviated gut barrier dysfunction. Therefore, the LPS‐induced extracellular signal‐regulated kinase (ERK)/early growth response‐1 (Egr‐1) pathway and consequent metabolic inflammation were inhibited, and eventually, cardiac hypertrophy, fibrosis, oxidative stress, and dysfunction were ameliorated in db/db mice. In vitro cardiomyocyte injury was induced by exposing primary neonatal rat ventricular cardiomyocytes to high glucose (HG) and LPS. In vitro analyses showed that HG + LPS induced ERK1/2 phosphorylation, Egr‐1 expression, inflammation, and cell apoptosis, which were inhibited by acetylcholine (ACh). Alpha 7 nicotinic ACh receptor but not muscarinic 2 ACh receptor plays an important role in ACh‐mediated anti‐inflammatory effects and inhibiting the ERK/Egr‐1 pathway in HG + LPS‐administered neonatal rat ventricular cardiomyocytes. PYR and ACh ameliorated diabetic myocardial injury by inhibiting the LPS‐induced ERK/Egr‐1 pathway and metabolic inflammation. The vagus–gut–heart axis has provided new insights into the complex mechanisms of diabetes and offers novel therapeutic targets.