肠道菌群移位：心肌梗死后单核细胞活化的新机制

Recent studies provide evidence indicating that monocyte subsets play an important role in post-infarction healing process. The expansion of pro-inflammatory monocyte subset and subsequent enhancement of local inflammatory response in infarct region could lead to an impaired healing and adverse left ventricular remodeling. Our recent work in patients with ST segment elevation myocardial infarction (STEMI) revealed that there is a temporal coincidence of the transient expansion of intermediate “pro-inflammatory” subset (CD14++CD16+) and increased circulating lipopolysaccharide (LPS) level, as well as up-regulation of CD14 expression on monocytes. These evidence indicate that STEMI induced acute stress response could lead to a transient increase of intestinal permeability, i.e., intestinal microbial translocation, which contributes to elevated circulating LPS level. Thus, LPS via interaction with its receptor, CD14, may trigger Toll-like receptor 4 (TLR4) downstream signal pathway, leading to an accelerated transition from CD14++CD16- monocytes to CD14++CD16+ subset. This gut-origin expansion of circulating pro-inflammatory monocyte subset may ultimately contribute to exacerbation of post-infarction healing. Our aim was to test this hypothesis in murine models of myocardial infarction using CD14-/- mice as well as LPS-target approach, and to investigate the pathophysiological mechanism leading to the dynamics of microbial translocation, and to explore the molecular mechanism underlying microbial translocation induced monocyte subset expansion. In addition, we would using the high throughput sequencing approach to investigate the specific microbiral strains that translocated into circulating after STEMI. Our work would provide novel evidence linking gut microbiota, innate immunity and post-infarction inflammatory response, which might be of therapeutic potential for post-infarction ventricular remodeling and heart failure.

促炎症单核细胞亚群增多加重的炎症反应可导致心肌梗死后组织修复障碍。我们新近的研究显示，ST段抬高心肌梗死（STEMI）引起的中间群促炎症单核细胞亚群（CD14++CD16+）增多伴随着一过性脂多糖（LPS）增高（内毒素血症），提示STEMI可引起一过性肠道通透性增加和菌群移位，并通过LPS与CD14的配体/受体相互作用单核细胞的活化和动员。本项目拟通过对心肌梗死动物模型肠道通透性动态变化及病理学研究，以及以LPS为靶点的研究（LPS拮抗剂和CD14-/-小鼠）的干预研究，和STEMI患者外周血16srRNA高通量测序，阐明STEMI所致肠道菌群移位与单核细胞亚群平衡和心肌梗死后心室重塑的关系、明确LPS/CD14通路作为潜在治疗靶点的干预效果，并发现STEMI后移位微生物的种属。本项目可从一个新的角度揭示心肌梗死后炎症反应的机制及其干预靶点。

促炎症单核细胞亚群增多加重的炎症反应可导致心肌梗死后组织修复障碍。我们新近的研究显示，ST段抬高心肌梗死（STEMI）引起的中间群促炎症单核细胞亚群（CD14++CD16+）增多伴随着一过性脂多糖（LPS）增高（内毒素血症），提示STEMI可引起一过性肠道通透性增加和菌群移位，并通过LPS与CD14的配体/受体相互作用单核细胞的活化和动员。本项目通过对心肌梗死动物模型肠道通透性动态变化及病理学研究，以及以LPS为靶点的研究的干预研究，和STEMI患者外周血16srRNA高通量测序等技术平台，首先阐明了心肌梗死后肠道菌群移位的病理生理学机制；然后阐明了心肌梗死后肠道菌群移位引起单核细胞活化/动员的分子机制，并探讨以LPS 拮抗为靶点干预方法对心肌梗死后心室重塑的潜在治疗作用；最后，明确了STEMI 后进入循环的肠道微生物种属，为STEMI 后肠道菌群移位的潜在的微生物学干预靶点提供了证据。从而探索一种以肠道通透性增加和肠道微生物移位为靶点的心肌梗死后心室重塑干预新方法。