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

膳食胆固醇通过肠道微生物群的作用在非酒精性脂肪肝中的作用

• 批准号: 10751526
• 负责人: Jake Brenner Hermanson
• 金额: $ 3.56万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751526
• 关键词: 16S ribosomal RNA sequencing; Affect; Alkynes; Animal Model; Automobile Driving; Bifidobacterium; Bile Acids; Bioinformatics; Biological Assay; Chemistry; Cholesterol; Clinical Trials; Colony-forming units; Communication; Communities; Complex; Coupled; Critical Thinking; Cues; Data; Development; Diet; Dietary Cholesterol; Dietary Component; Disease; Disease Outcome; Dose; Dyes; Elements; Environment; Exhibits; Extinction; FDA approved; Fatty Liver; Fatty acid glycerol esters; Feces; Fibrosis; Flow Cytometry; Fluorescence; Functional disorder; Gallbladder; Genes; Genomics; Germ-Free; Goals; Growth; Healthcare; Hepatic; In Vitro; Incidence; Individual; Inflammatory; Institution; Intake; Intervention; Knowledge; Libraries; Life Style; Liver; Liver Cirrhosis; Liver Dysfunction; Liver Fibrosis; Massive Parallel Sequencing; Measures; Mediating; Membrane; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Microbe; Microbiology; Molecular; Mus; Mutagenesis; Mutation; Onset of illness; Optics; Oral; Organism; Outcome; Pathogenesis; Persons; Population; Prevalence; Primary carcinoma of the liver cells; Principal Investigator; Proliferating; Role; Shotguns; Small Intestines; Techniques; Testing; Therapeutic; Time; Training; Writing; beneficial microorganism; candidate identification; career; cost; density; dietary; dysbiosis; epidemiology study; feeding; fitness; gene function; germ free condition; gut dysbiosis; gut microbes; gut microbiome; gut microbiota; host-microbe interactions; improved; in vivo; insight; liquid chromatography mass spectrometry; liver injury; liver transplantation; loss of function; member; metagenomic sequencing; microbial; microbial community; microbiome; microbiome research; microbiota; mortality risk; mutant; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutics; prevent; probiotic therapy; rRNA Genes; saturated fat; skills; sugar; uptake; western diet

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.

项目摘要 非酒精性脂肪性肝病（NAFLD）的患病率在全球范围内不断增加，影响了四分之一的 全球人口。NAFLD可能发展为更严重的形式，非酒精性脂肪性肝炎（NASH）， 将成为肝脏移植的头号适应症。虽然有超过400个正在进行的NAFLD相关的 临床试验，没有FDA批准的治疗方法。目前迫切需要制定战略， NAFLD/NASH的发展和进展在世界各地。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，部分由肠道微生物介导。 流行病学研究表明，膳食胆固醇与晚期NAFLD的发病率密切相关。 然而，西方饮食成分，如胆固醇，对肠道微生物群的影响在很大程度上是 未知在知识上存在相当大的差距， 离散的西方饮食成分，肠道微生物群和NAFLD/NASH的发展。初步 研究表明，含有高水平胆固醇的西方饮食会导致肠道微生物失衡， 并且是无特定病原体（SPF）小鼠中NAFLD/NASH的先决条件，但无菌（GF）小鼠缺乏 保护肠道微生物免受疾病的侵害。双歧杆菌是有益的关键微生物 并且通常在代谢紊乱如NAFLD/NASH中下调。然而，在这方面， 导致双歧杆菌减少的环境因素仍然难以捉摸。初步研究表明，它们是从 肠道对高胆固醇喂养的剂量依赖性的方式和他们的相对丰度是负的 与肝损伤有关。这些数据有力地表明，饮食会导致双歧杆菌的损失， 它是NAFLD/NASH发病机制的一部分。关键是要定义基本机制， 将开发针对NAFLD/NASH的基于微生物组的治疗策略。这项提案的目的是 目的是确定饮食胆固醇在NAFLD/NASH发病机制中驱动肠道微生物失衡的作用。我 假设饮食胆固醇驱动肠道双歧杆菌消除，其促进促炎微生物 在NAFLD/NASH的发病过程中的环境。为了验证这一假设，我将利用体外、体内 体内，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 在单独存在高膳食胆固醇的情况下与在复杂的肠道微生物群中维持生态位的能力 2）阐明饮食胆固醇介导的NAFLD/NASH发展的间接作用 通过改变胆汁酸谱，从一个复杂的肠道微生物群群落中损失双歧杆菌， NAFLD/NASH发展。通过让我了解微生物组研究的核心方面，这些研究提供了 这是我训练的完美工具，将推动我实现成为校长的目标。 在R1机构研究饮食，肠道微生物和代谢疾病之间相互作用的研究者。