肠道菌群调节的肠黏膜免疫调控病毒性心肌炎发病的机制

The close relationship between Gut-Microbial flora and intestinal mucosal immune system may have critical influence on the development of gut infectious or inflammatory disease. Infections with cardiotropic ssRNA viruses, such as Coxsackievirus B3 (CVB3), can result in myocarditis and dilated cardiomayopathy, mechanism not fully clarified. Our preliminary data have demonstrated that CVB3 vividly replicates in the intestine and induces innate TLR3/7/8/9/13 response locally before the entry into the heart accompanied by infiltration of macrophages, neutrophils and IL-17+IL-22+ILC3. There is a distinct gender-biased differential susceptibility of mice to CVB3 which is related with distinct microbiota profile analogous, differential PRR stimulation profiles and intestinal cytokine profiles demonstrated by us. Depletion of intestinal Th17-related SFB by gavages of Vankomycin significantly reduced motality of mice, the level of cardiac inflammation as well as systemic and intestinal Th1/Th17 response. We speculate that Gut-microbial flora-regulated mucosal innate inflammatory immunity may play important role in the pathogenesis of viral myocarditis. We plan to prove the relationship between intestinal innate inflammatory response pattern and VMC, study the role and TLR-based mechanism of gut-microbiota in the regulation of intestinal inflammatory innate response as well as myocardial inflammation; further, whether the Gut-microbial flora-regulated mucosal innate immunity would modulate sex-biased susceptibility to CVB3 myocarditis would be studied. Our study would provide new insight for the understanding the pathogenesis of viral myocarditis and provide novel target for the treatment of enterovirus-related inflammatory disease.

肠道菌群调控的肠道免疫对肠道疾病发生具有重要影响。肠道病毒柯萨奇病毒B3（CVB3）经肠道感染诱导病毒性心肌炎（VMC）的发病机制尚未阐明。我们发现CVB3在肠道积极复制，诱导肠道局部PRR固有免疫激活和中性粒等细胞浸润，IL-17/Th17和 IL-17+IL-22+ILC3应答显著增高；雌雄鼠对CVB3易感性显著不同，且在肠道生理和病理的PRR激活格局、炎症因子格局、肠道菌群种属丰度均不同，万古霉素清除肠道SFB后Th17降低和心肌炎减轻，提示小鼠对CVB3的性别差异易感性可能与肠道菌群调控的肠道局部免疫差异相关。我们假设：CVB3感染肠道所诱导的肠道黏膜免疫炎症格局受肠道菌群调控，可能影响后续心肌炎的发生和进程。拟明确肠道黏膜免疫炎症格局与心肌炎的相关性、研究SFB调控肠道黏膜免疫炎症格局及心肌炎发生的TLR机制。本研究从肠道免疫角度系统解析心肌炎机制，为VMC防治提供新思路。

柯萨奇病毒B3（CVB3）经肠道感染诱导病毒性心肌炎（VMC）的发病机制尚未阐明。我们在证实CVB3在肠道上皮积极复制、诱导肠道Th17类型免疫及轻微肠炎、雌雄鼠对CVB3易感性不同且肠道菌群种属丰度不同的基础上，提出CVB3感染肠道诱导的肠道菌群和肠道免疫改变，可影响心肌炎进程的假设。通过IL-17A、IL-17RA敲除小鼠和抗生素清除肠道菌群试验，我们发现：1）CVB3感染肠道上皮细胞改变了肠道乳酸杆菌和拟杆菌属丰度和分支节段杆菌SFB的免疫调节能力，使肠道及外周血17 type免疫显著上调；2）IL-17-IL-17RA通路的肠道与全身激活，通过激活下游Th17应答、中性粒和单核细胞浸润显著促进CVB3心肌炎；3）SFB通过促进外周血Th17、中性粒细胞等IL-17 type细胞增殖和上调表达CCR6，并循CCR6-CCL20 axis加速心脏定向迁移，进一步通过后续IL-17A炎症加剧病毒性心肌炎。本研究发现并证实的CVB3改变的肠道菌群及肠道免疫经CCR6-CCL20 axis影响心脏感染及炎症的肠道调控机制，具有创新性，并提供了CCR6等病毒性心肌炎防治的新靶点。