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.

项目摘要非酒精性脂肪肝病（NAFLD）的患病率在全球范围内增加，影响了四分之一全球人口。 NAFLD可能会发展到更严重的非酒精性脂肪性肝炎（NASH），这可能会发展为将成为肝移植的第一指示。虽然有400多个正在进行的NAFLD相关临床试验，没有FDA批准的疗法。立即需要策略来抵制 NAFLD/NASH在全球范围内的发展和发展。但是，对它的知之甚少病理生理学。西方饮食有助于疾病发病机理，部分由肠道微生物组介导。流行病学研究表明，饮食胆固醇与后期NAFLD的事件紧密相关。但是，西方饮食成分（例如胆固醇）对肠道菌群的影响很大未知。了解有关的机械关系存在很大的差距离散的西方饮食成分，肠道菌群和NAFLD/NASH的发展。初步的研究表明，西方饮食中含有高水平的胆固醇会诱导先前的肠道微生物失衡并且是特定无病原体（SPF）小鼠NAFLD/NASH的先决条件，但缺乏细菌（GF）小鼠肠道微生物组免受疾病的保护。双歧杆菌是有益的关键共生生物到宿主，通常在NAFLD/NASH等代谢疾病中被下调。然而，驱动双歧杆菌损失的环境线索仍然难以捉摸。初步研究表明，他们从高胆固醇以剂量依赖性的方式进行的肠道，其相对丰度是负面的与肝损伤相关。这些数据强烈表明饮食驱动了损害双歧杆菌的损失宿主并有助于NAFLD/NASH发病机理。定义基本机制至关重要将开发基于微生物组的基于微生物组的治疗策略。该提议的目标是为了定义饮食胆固醇在驱动NAFLD/NASH发病机理中肠道微生物失衡中的作用。我假设饮食胆固醇驱动肠道双歧杆菌消除促进促炎微生物 NAFLD/NASH发病机理期间的环境。为了检验这一假设，我将利用体外的组合体内和生物信息学技术至1）确定影响双歧杆菌的关键功能元素仅饮食中的胆固醇与在复杂的肠道菌群中相比，维持利基市场的能力 NAFLD/NASH开发的社区和2）阐明饮食胆固醇介导的间接影响通过改变复杂肠道菌群群体丧失双歧杆菌社区的胆汁酸轮廓。 NAFLD/NASH开发。通过使我了解微生物组研究的中心方面，这些研究提供了我训练的理想工具，将推动我实现成为校长的目标研究人员研究了R1机构的饮食，肠道微生物和代谢疾病之间的相互作用。