Table 1_Guanxinning attenuates diabetic myocardial ischemia–reperfusion injury by targeting oral Fusobacterium nucleatum and modulating PTEN signaling.xlsx

BackgroundThe incidence and severity of diabetic myocardial ischemia reperfusion injury (DMIRI) are increasing, highlighting the urgent need for effective prevention and treatment. Previous studies have revealed that specific oral microbiota (Fusobacterium nucleatum) are closely involved in DMIRI, potentially serving as therapeutic targets. Guanxinning (GXN) has shown significant efficacy in treating diabetic cardiomyopathy. However, its mechanisms of action regarding DMIRI and its relationship with specific microbiota remain to be elucidated.
ProposalThis study investigates whether GXN alleviates DMIRI by modulating F. nucleatum and host interactions.
MethodsThe effects of GXN on cardiac injury, cardiac protein expression and the abundance of F. nucleatum were evaluated in C57BL/6 mice under both conventional and germ-free conditions. GWAS analysis was employed to identify potential mechanisms linking F. nucleatum and DMIRI. Fusobacterium nucleatum IgG levels were measured, and LC-MS/MS metabolomics along with Metorigin trace-ability analysis were conducted to validate the proposed mechanisms.
ResultsGXN treatment significantly reduced myocardial injury in diabetic mice and decreased oral F. nucleatum abundance, although its effects on other gut microbiota taxa were variable. Importantly, the cardioprotective efficacy of GXN was markedly attenuated under pseudo-germ-free conditions, suggesting that its benefits are at least partly microbiota-dependent. PI3K signaling pathway was identified as a central mediator of the microbiota interaction in DMIRI. Correspondingly, cardiac tissues from diabetic mice exhibited reduced expression of PTEN, consistent with pathway activation. Notably, F. nucleatum exposure elevated plasma levels of specific anti–F. nucleatum IgG antibodies and appeared to influence the host PI3K pathway through modulation of phenylalanine metabolism.
ConclusionGXN may alleviate DMIRI by targeting F. nucleatum and PTEN related pathways, offering new insights into microbiota-based cardio protection.

背景：糖尿病心肌缺血再灌注损伤（diabetic myocardial ischemia reperfusion injury, DMIRI）的发病率与严重程度呈逐年上升趋势，临床亟需开发高效的防治策略。既往研究证实，特定口腔菌群——具核梭杆菌（Fusobacterium nucleatum）与DMIRI的发生发展密切相关，有望成为该病的潜在治疗靶点。冠心宁（Guanxinning, GXN）在糖尿病心肌病的治疗中已展现出显著疗效，但其针对DMIRI的具体作用机制，以及与特定菌群的关联仍有待进一步阐明。
研究目的：本研究旨在探究冠心宁是否通过调控具核梭杆菌与宿主的相互作用，进而缓解DMIRI。
研究方法：本研究分别在常规饲养与无菌饲养的C57BL/6小鼠模型中，评估冠心宁对心脏损伤、心肌蛋白表达水平以及具核梭杆菌丰度的影响。采用全基因组关联分析（Genome-Wide Association Study, GWAS）筛选具核梭杆菌与DMIRI关联的潜在分子机制。同时检测血浆中具核梭杆菌IgG抗体水平，并通过液相色谱-串联质谱（Liquid Chromatography-Tandem Mass Spectrometry, LC-MS/MS）代谢组学结合代谢物溯源分析，验证本研究提出的作用机制。
研究结果：冠心宁给药可显著减轻糖尿病小鼠的心肌损伤，并降低口腔组织中具核梭杆菌的丰度，但对其他肠道菌群类群的影响存在异质性。尤为关键的是，在假无菌饲养条件下，冠心宁的心脏保护作用显著减弱，提示其防治获益至少部分依赖于肠道菌群。本研究鉴定出PI3K信号通路是DMIRI进程中菌群相互作用的核心介导因子。相应地，糖尿病小鼠的心肌组织中PTEN的表达水平显著降低，与该通路的激活状态相符。值得注意的是，具核梭杆菌暴露可升高宿主血浆中特异性抗具核梭杆菌IgG抗体水平，且似乎通过调控苯丙氨酸代谢途径影响宿主PI3K信号通路的活性。
结论：冠心宁可能通过靶向具核梭杆菌及PTEN相关信号通路缓解DMIRI，为基于菌群调控的心脏保护治疗提供了全新的研究视角。