肠道微生物群诱导的琥珀酸升高通过促进巨噬细胞极化加剧糖尿病心肌缺血/再灌注损伤
Gut microbiota-induced elevation of succinate exacerbates diabetic myocardial ischemia/reperfusion injury by promoting macrophage polarization.
摘要(中文译文)
糖尿病患者对心肌缺血/再灌注（IR）损伤的易感性增加。越来越多的证据强调，肠道微生物群衍生的微生物代谢物是肠-心轴的关键调节因子。本研究探讨了琥珀酸（一种来源于微生物群的关键代谢物）在糖尿病心肌IR损伤进展中的病理作用。研究分析了糖尿病小鼠的肠道微生物群组成和琥珀酸水平。随后评估了抗生素诱导肠道微生物群耗竭后琥珀酸水平的变化。对Sucnr1基因敲除的糖尿病小鼠在诱导IR前给予外源性琥珀酸补充。在体外，利用条件培养基转移系统将巨噬细胞与经受缺氧/复氧损伤的心肌细胞共培养，并评估心肌细胞损伤程度。糖尿病进展过程中心脏琥珀酸蓄积与肠道微生物群失调相关，后者以产琥珀酸细菌和消耗琥珀酸细菌之间的失衡为特征。抗生素介导的肠道微生物群耗竭逆转了这种琥珀酸蓄积，表明微生物群落是心脏琥珀酸的主要来源。此外，琥珀酸驱动心脏巨噬细胞极化并加重糖尿病相关心肌IR损伤。相反，在体外和体内模型中基因敲低Sucnr1均改善了琥珀酸的有害效应。心脏琥珀酸蓄积发生在糖尿病进展过程中，并与特定的肠道微生物群失调相关，后者以产琥珀酸细菌和消耗琥珀酸细菌之间平衡被破坏为特征。这种琥珀酸的病理性蓄积通过激活SUCNR1信号通路驱动巨噬细胞极化，从而加重糖尿病相关心肌IR损伤。
Abstract
Patients with diabetes exhibit increased susceptibility to myocardial ischemia/reperfusion (IR) injury. Emerging evidence highlights gut microbiota-derived microbial metabolites as critical modulators of the gut-heart axis. This study examined the pathological role of succinate, a crucial metabolite derived from the microbiota, in the progression of diabetic myocardial IR injury. The gut microbiota composition and succinate levels in diabetic mice were analyzed. Changes in succinate levels were subsequently assessed following the depletion of the gut microbiota induced by antibiotics. Diabetic mice with genetic ablation of Sucnr1 were administered exogenous succinate supplementation prior to IR induction. In vitro, conditioned medium transfer systems were utilized to coculture macrophages with cardiomyocytes subjected to hypoxia/reoxygenation injury, and the extent of cardiomyocyte damage was evaluated. Cardiac succinate accumulation during diabetes progression is linked to gut microbial dysbiosis, which is characterized by an imbalance between succinate-producing and succinate-consuming bacteria. Antibiotic-mediated depletion of the gut microbiota reversed this succinate accumulation, demonstrating that microbial communities constitute a major source of cardiac succinate. Furthermore, succinate drove the polarization of cardiac macrophages and exacerbated diabetes-associated myocardial IR injury. Conversely, genetic knockdown of Sucnr1 in both in vitro and in vivo models ameliorated the detrimental effects of succinate. Cardiac succinate accumulation occurs during diabetes progression and is associated with specific gut microbial dysbiosis, which is characterized by a disrupted equilibrium between succinate-producing and succinate-consuming bacteria. This pathological accumulation of succinate exacerbates diabetes-associated myocardial IR injury by driving macrophage polarization through activation of the SUCNR1 signaling pathway.
如何引用
AMA
Yang Wu, Juan Dou, Min Liu, Song Peng, Wenyuan Li. Gut microbiota-induced elevation of succinate exacerbates diabetic myocardial ischemia/reperfusion injury by promoting macrophage polarization.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1749185.
APA
Yang Wu, Juan Dou, Min Liu, Song Peng, Wenyuan Li (2026). Gut microbiota-induced elevation of succinate exacerbates diabetic myocardial ischemia/reperfusion injury by promoting macrophage polarization.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1749185
GB/T 7714
Yang Wu, Juan Dou, Min Liu, Song Peng, Wenyuan Li. Gut microbiota-induced elevation of succinate exacerbates diabetic myocardial ischemia/reperfusion injury by promoting macrophage polarization.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1749185.
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