The role of dietary cholesterol in Nonalcoholic fatty liver disease through the action of gut microbiota

项目总结 非酒精性脂肪性肝病(NAFLD)在全球范围内的患病率正在上升，影响到四分之一的 全球人口。NAFLD可能会进展为更严重的形式，非酒精性脂肪性肝炎(NASH)，这是 将成为肝脏移植的头号适应症。虽然目前有400多个与NAFLD相关的 临床试验，目前还没有FDA批准的治疗方法。迫切需要制定战略来抵消 NAFLD/NASH在世界各地的发展和进步。然而，人们对其知之甚少 病理生理学。西方饮食有助于疾病的发病机制，部分是由肠道微生物群介导的。 流行病学研究表明，饮食中的胆固醇与晚期非酒精性脂肪肝的发病密切相关。 然而，西方饮食成分，如胆固醇，对肠道微生物区系的影响很大 未知。在关于机械关系的认识上存在着相当大的差距 离散的西方饮食成分，肠道微生物区系，以及NAFLD/NASH的发展。初步 研究表明，含有高胆固醇的西方饮食会导致肠道微生物失衡 在无特定病原体(SPF)的小鼠中是NAFLD/NASH的先决条件，但在缺乏 肠道微生物群受到保护，免受疾病侵袭。双歧杆菌是有益的关键共生生物。 在NAFLD/NASH等代谢紊乱中通常被下调。然而， 导致双歧杆菌丧失的环境线索仍然难以捉摸。初步研究表明，它们是从 肠道对高胆固醇喂养的影响呈剂量依赖关系，其相对丰度为负。 与肝脏损伤有关。这些数据强烈地表明，饮食会导致双歧杆菌的流失，这会损害 宿主并参与NAFLD/NASH的发病。在以下情况下，定义基本机制至关重要 针对NAFLD/NASH的基于微生物组的治疗策略有待开发。这项提案的目标是 目的是明确膳食胆固醇在NAFLD/NASH发病机制中推动肠道微生物失衡中的作用。我 假设饮食中的胆固醇驱动肠道双歧杆菌的清除，从而促进促炎微生物 NAFLD/NASH发病过程中的环境。为了验证这一假设，我将使用体外、体内 活体和生物信息学技术以1)确定影响双歧杆菌的关键功能元件 仅在高胆固醇饮食中维持生态位的能力与在复杂的肠道微生物区系中的能力 社区在NAFLD/NASH发展中的作用和2)阐明膳食胆固醇介导的间接影响 通过改变胆汁酸对肠道微生物群落中双歧杆菌丧失的影响 NAFLD/NASH开发。通过让我了解微生物组研究的中心方面，这些研究提供了 这是我培训的完美工具，将推动我实现成为校长的目标 在R1研究所研究饮食、肠道微生物和代谢性疾病之间相互作用的研究员。

PROJECT SUMMARY The prevalence of Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, affecting a quarter of the global population. NAFLD may progress to its more severe form, Nonalcoholic steatohepatitis (NASH), which will become the number one indication for liver transplant. While there are over 400 ongoing NAFLD-related clinical trials, there are no FDA-approved therapies. There is an immediate need for strategies to counteract NAFLD/NASH development and progression throughout the world. However, little is known about its pathophysiology. Western diet contributes to disease pathogenesis, mediated in part by the gut microbiome. Epidemiological studies indicate dietary cholesterol closely associates with the incidence of late-stage NAFLD. However, the influences of Western dietary components, such as cholesterol, on gut microbiota are largely unknown. There is a considerable gap in knowledge regarding the mechanistic relationships between discrete Western dietary components, gut microbiota, and the development of NAFLD/NASH. Preliminary studies show Western diets containing high levels of cholesterol induce gut microbial imbalances that precede and are a prerequisite for NAFLD/NASH in Specific pathogen-free (SPF) mice, yet germ-free (GF) mice that lack a gut microbiome are protected from disease. Bifidobacteria are key commensal organisms that are beneficial to the host and are commonly downregulated in metabolic disorders such as NAFLD/NASH. However, environmental cues that drive a loss of Bifidobacteria remain elusive. Preliminary studies show they are lost from the gut upon high-cholesterol feeding in a dose-dependent manner and their relative abundance is negatively correlated with liver damage. These data strongly suggest diet drives a loss of Bifidobacteria which compromises the host and contributes to NAFLD/NASH pathogenesis. It is critical to define the underlying mechanisms if microbiome-based therapeutic strategies against NAFLD/NASH are to be developed. The goal of this proposal is to define the role of dietary cholesterol in driving gut microbial imbalances in NAFLD/NASH pathogenesis. I hypothesize dietary cholesterol drives gut Bifidobacteria elimination which promotes a proinflammatory microbial milieu during the pathogenesis of NAFLD/NASH. To test this hypothesis, I will utilize a combination of in vitro, in vivo, and bioinformatics techniques to 1) Determine critical functional elements that impact Bifidobacteria’s capacity to sustain a niche in the presence of high dietary cholesterol alone vs. within a complex gut microbiota community in NAFLD/NASH development and 2) Elucidate the indirect effect of dietary cholesterol mediated through altered bile acid profile on loss of Bifidobacteria from a complex gut microbiota community in NAFLD/NASH development. By exposing me to central aspects of microbiome research, these studies provide the perfect vehicle for my training and will propel me toward achieving my goal of becoming a Principal Investigator studying interactions between diet, gut microbes, and metabolic disease at a R1 institution.