基于肠道黏膜免疫调控流感病毒诱导肺-肠组织损伤的肺与大肠表里反馈与干预机制研究

The theory of lung and gut being interior exterior is the important part of the theory of visceral outward manifestation, but how to being pathogenesis transmission from lung to gut in the infectious disease, is not clear. The results had showed that lung injury and gut injury could be induced by influenza A virus simultaneously. Lung and gut have a common embryonic development, and gut microbiota and intestinal mucosal immunity would regulate the relationship between the lung and gut in physical and pathological process. So, we speculated that intestinal mucosal immunity exert the crucial effect on the lung and gut injury. We aims to study the mechanism on lung-gut injury induced by influenza A virus based on gut microbiota and intestinal mucosal immunity. So, Houttuynia cordata and decoction of xuan-bai-cheng-qi as tool medicine, would be verified the protective mechanism on lung-gut injury induced by influenza A virus, which under the guidance of the theory of lung and gut being interior exterior. The research would reveal that the mechanism on pathogenesis transmission from lung to gut in influenza, which would clarify that modern connotative definition on the theory. The prospective results would provide the evidence on the superiority of the treating infectious diseases intensively with Chinese medicine.

肺与大肠相表里是藏象中脏腑相关理论的重要内容，在外感热病的疾病传变中，肺与大肠相关联以及反馈调节机制的现代内涵尚不明确。本课题组已证实流感病毒感染不仅引起肺损伤，同时也造成了肠道损伤。由于肺与肠在胚胎发育上有共同起源，肠道菌及肠道粘膜免疫系统在肺肠疾病相互作用中扮演重要角色，因此推测肠道粘膜免疫系统在流感的多组织损伤机制中发挥了关键作用。本研究拟从肠道菌群及肠道免疫两个角度来探求流感病毒诱导肺-肠损伤的作用机制，并运用肺经药鱼腥草以及肺肠同治验方宣白承气汤作为工具药验证以肺肠表里理论为指导的药物对流感病毒诱导的肺肠组织损伤的保护机制，揭示流感中肺与肠在疾病传变中的反馈及药物干预机制，阐明肺肠表里理论的现代内涵，为中医药在病毒性疾病中广谱治疗优势提供现代依据。

病毒性肺炎发病率高，危害严重。针对宿主免疫调控是中药治疗感染性疾病不拘泥于病原微生物的有优势的治疗策略。临床流感产生肺系症状的同时，也常伴随胃肠道表现，我们研究证实流感病毒感染鼠肺及肠道的黏膜屏障同时出现损伤，印证了肺与肠之间共有黏膜免疫相互调控的机制，与传统医学“肺与大肠相表里”存在相关性。本研究借助甲流病毒H1N1感染急性肺损伤小鼠模型，以黏膜免疫调控为切入点，揭示了肠-肺轴中CCR6+Th17/CCR6+Treg的迁移介导了病毒性肺炎诱导的黏膜免疫损伤的病理机制，并阐释了肺经中药鱼腥草及肺肠同治宣白承气汤治疗肺损伤的肠-肺轴相关的干预机制。结果表明：急性流感肺损伤模型中，肠道是黏膜免疫调控起始点，鱼腥草多糖（HCP）下调肠-肺轴中CCR6+Th17/ CCR6+Treg细胞的比例，抑制CCL20在肺部的基因表达，通过CCR6-CCL20轴，调控Th17/Treg平衡而减轻了肺部炎症。并进一步借助肠道菌清除ABX小鼠以及粪菌移植的手段证实多糖大分子药效发挥依赖肠道菌及调控代谢产物发挥治疗作用。借助DSS小鼠肠炎模型证实了HCP能抑制肠上皮细胞凋亡、调整巨噬细胞极化，具有直接保护肠道上皮屏障活性。本研究是对多糖作用机制研究的新发现，为难以吸收入血却具有全身治疗效果的多糖类药效成分的作用机制研究提供了突破口，丰富了传统医学理论“肺病从肠论治”的科学内涵。宣白承气汤是“肺肠同治”法的代表方，本课题证实了其保护药效并运用网络药理学推测了药物分子机制，通过去大黄的拆方试验，比较分析肠道菌的菌群变化，证实宣白承气汤治疗病毒性肺炎的靶标主要富集于TNF、T cell receptor、NF-κB 等信号通路上。“治肠”药大黄是主要调控肠道菌群的中药，间接影响黏膜免疫而发挥的作用机制。该复方研究深化了“肺肠同治法”的生物机制，为肠肺轴现代机制的阐释提供佐证。