肠道微生物对对乙酰氨基酚诱导多器官功能衰竭的调控及机制研究

The mutiple organ dysfunction induced by drug abuse is an important scientific problem in critical care medicine. Acetaminophen (APAP) is one of the most common used drug that cause organ injury. However, the detailed mechanism by which APAP caused organ damage is still unclear and the therapeutic approaches are still limited. Recent reports, together with our previous findings indicated that gut microbiota played a key role in APAP induced organ injury development. By focusing on this topic, we plan to perform a series of experiments. First, we will clarify the phenotype of the modulation of gut microbiota on organ injury induce by APAP. Then perform the omics analysis for gut microbiota, including 16s rDNA, metagenomics, metabolomics and metaprotomics to explore the key molecules that regulate APAP associated organ injury. The detail mechanism of these molecules will also be studied. Finally, by screening the best interventional method, our project will provide some novel therapeutic approaches. Our work is not only for the novel mechanism exploration, but also with translational significance.

药物滥用导致的多脏器功能衰竭是急危重症领域内的研究重点。其中对乙酰氨基酚（acetaminophen, APAP）是导致器官损伤最主要的药物之一。APAP诱导多器官损伤的机制很不清楚且防治手段也十分匮乏，我们前期的工作及近期的报导明确指向肠道微生物是调控APAP诱导外周器官损伤的核心因素，围绕这一全新方向，我们拟深入开展一系列原创性工作。首先，我们将在动物水平明确肠道菌群对APAP诱导多器官损伤调控的表型，并进一步系统的开展针对肠道菌群的各种组学分析以找出关键的肠道微生物来源调控分子，包括：16S多样性分析；宏基因组学分析；宏代谢组学分析；宏蛋白质组学分析等。我们还将深入探究这些关键分子调控外周器官损伤的机制。最后筛选出干预效果最佳的若干分子并优化干预条件为开发新型有效的防治手段打下基础。本工作不仅是APAP诱导多器官损伤机制的全新探索，也具有较高的转化意义。

本项目主要的研究内容是探究肠道及肠道菌群在对乙酰氨基酚诱导器官损伤中的作用。申请人团队运用动物疾病模型，多组学分析，分子及细胞生物学实验等手段，深入研究了相关重要调控表型及其机制，重要结果包括：（1）发现肠道关键趋化因子CCL7在对乙酰氨基酚器官损伤中早期肠道屏障功能破化的重要作用，我们率先发现对乙酰氨基酚可以显著上调肠道通透性，促进细菌产物移位至肝脏，加剧肝脏损伤，这可能是对乙酰氨基酚器官损伤的新机制，其中肠道趋化因子CCL7高表达可能是这一病理学进展的关键诱因（Am J Pathol, 2区）；（2）发现肠道菌群对于二型大豆皂苷的代谢差异可能诱发肝脏衰竭，在肝脏急性衰竭的早期，肠道菌群对二型大豆皂苷的分解代谢增强，导致该活性物质水平下降，进一步实验发现二型大豆皂苷可以显著削弱炎症小体的激活并保护肝脏损伤的发生（Theranostics, 1区）；（3）我们还在该项目资助下发表了肠道菌群与脓毒症的综述（Burns & Trauma, 1区）。本项目成果拓展了人们对对乙酰氨基酚及其他诱因所致器官损伤机制的新认识，也挖掘了若干新的潜在干预方式，具有一定的临床转化价值。