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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要非酒精性脂肪肝 (NAFLD) 的患病率在全球范围内不断增加，影响了四分之一的人全球人口 NAFLD 可能会发展为更严重的非酒精性脂肪性肝炎 (NASH)。将成为肝移植的第一大适应症，而目前有超过 400 种与 NAFLD 相关的疾病正在进行中。临床试验中，尚无 FDA 批准的治疗方法，迫切需要制定应对策略。然而，人们对 NAFLD/NASH 的发展和进展知之甚少。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介导的。流行病学研究表明膳食胆固醇与晚期 NAFLD 的发病密切相关。然而，西方饮食成分（例如胆固醇）对肠道微生物群的影响在很大程度上是未知。关于之间的机械关系的知识存在相当大的差距。离散的西方饮食成分、肠道微生物群和 NAFLD/NASH 的发展。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，从而导致肠道微生物失衡。是无特定病原体 (SPF) 小鼠发生 NAFLD/NASH 的先决条件，而无菌 (GF) 小鼠缺乏肠道微生物群受到保护，免受疾病侵害。双歧杆菌是有益的关键共生生物。然而，在 NAFLD/NASH 等代谢性疾病中，该蛋白通常被下调。初步研究表明，导致双歧杆菌消失的环境因素仍然难以捉摸。高胆固醇喂养后肠道以剂量依赖性方式表达，其相对丰度呈负值这些数据强烈表明饮食会导致双歧杆菌的损失，从而损害肝脏。确定其潜在机制至关重要。该提案的目标是制定针对 NAFLD/NASH 的基于微生物组的治疗策略。旨在明确膳食胆固醇在 NAFLD/NASH 发病机制中驱动肠道微生物失衡的作用。膳食胆固醇促进肠道双歧杆菌的消除，从而促进促炎微生物为了检验这一假设，我将结合使用体外、体内实验。体内和生物信息学技术，1) 确定影响双歧杆菌的关键功能元素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 NAFLD/NASH 发展中的社区和 2) 阐明膳食胆固醇介导的间接影响通过胆汁酸谱的改变，导致复杂肠道微生物群落中双歧杆菌的损失通过让我了解微生物组研究的核心方面，这些研究提供了 NAFLD/NASH 的发展。这是我培训的完美工具，将推动我实现成为校长的目标研究人员在 R1 机构研究饮食、肠道微生物和代谢疾病之间的相互作用。