Longitudinal Study of Early NAFLD Progression and the Gut Microbiome in Asian Americans, Native Hawaiians and Whites

亚裔美国人、夏威夷原住民和白人早期 NAFLD 进展和肠道微生物组的纵向研究

• 批准号: 10607981
• 负责人: Meredith Hullar
• 金额: $ 70.04万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607981
• 关键词: 16S ribosomal RNA sequencing; Address; Affect; Asian Americans; Bacteria; Behavioral; Bile Acids; Biological; Biological Markers; Blood; C-reactive protein; Cancer Burden; Carbohydrates; Clinic; Communities; Data; Deposition; Diet; Dietary Component; Dietary Factors; Dietary Practices; Disease; Disease Progression; Elderly; Endotoxins; Ethnic group; Etiology; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Fusobacterium; Gold; Hawaiian population; Image; Inflammation; Inflammatory; Intervention; Investigation; Japanese American; Knowledge; Laboratories; Life Style; Liver; Liver Fibrosis; Liver diseases; Longitudinal Studies; Magnetic Resonance Imaging; Malignant neoplasm of liver; Measures; Mediating; Mediation; Metabolic Pathway; Metabolism; Metagenomics; Methods; Native Hawaiian; Native Hawaiian or Other Pacific Islander; Obesity; Participant; Pathway interactions; Pharmacology; Phenotype; Plasma; Population; Sampling; Secondary to; Severities; Structure; Testing; Time; Toll-like receptors; Viral hepatitis; aged; base; biomarker panel; blood-based biomarker; burden of illness; carbohydrate metabolism; chronic liver disease; cohort; dysbiosis; effective therapy; elastography; epidemiology study; follow up assessment; follow-up; gut bacteria; gut microbiome; gut microbiota; high risk; high risk population; improved; indexing; lipopolysaccharide-binding protein; liver cancer prevention; liver development; liver stiffness; longitudinal design; metagenomic sequencing; microbial; mortality; multi-ethnic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel strategies; phenotypic data; population based; prevent; prospective; racial and ethnic; stool sample; systemic inflammatory response; trend; 16S ribosomal RNA sequencing; Address; Affect; Asian Americans; Bacteria; Behavioral; Bile Acids; Biological; Biological Markers; Blood; C-reactive protein; Cancer Burden; Carbohydrates; Clinic; Communities; Data; Deposition; Diet; Dietary Component; Dietary Factors; Dietary Practices; Disease; Disease Progression; Elderly; Endotoxins; Ethnic group; Etiology; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Fusobacterium; Gold; Hawaiian population; Image; Inflammation; Inflammatory; Intervention; Investigation; Japanese American; Knowledge; Laboratories; Life Style; Liver; Liver Fibrosis; Liver diseases; Longitudinal Studies; Magnetic Resonance Imaging; Malignant neoplasm of liver; Measures; Mediating; Mediation; Metabolic Pathway; Metabolism; Metagenomics; Methods; Native Hawaiian; Native Hawaiian or Other Pacific Islander; Obesity; Participant; Pathway interactions; Pharmacology; Phenotype; Plasma; Population; Sampling; Secondary to; Severities; Structure; Testing; Time; Toll-like receptors; Viral hepatitis; aged; base; biomarker panel; blood-based biomarker; burden of illness; carbohydrate metabolism; chronic liver disease; cohort; dysbiosis; effective therapy; elastography; epidemiology study; follow up assessment; follow-up; gut bacteria; gut microbiome; gut microbiota; high risk; high risk population; improved; indexing; lipopolysaccharide-binding protein; liver cancer prevention; liver development; liver stiffness; longitudinal design; metagenomic sequencing; microbial; mortality; multi-ethnic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel strategies; phenotypic data; population based; prevent; prospective; racial and ethnic; stool sample; systemic inflammatory response; trend

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) affects >35% of older adults in the US. It is now the primary etiology of chronic liver disease and liver cancer, and the driver of the recent upward trend in these lethal diseases. A dysbiotic gut microbiome has been associated with NAFLD, but mostly in small-scale, cross-sectional or clinic- based studies. Population-based longitudinal studies are needed to provide evidence for the temporal relationship of the gut microbiome with the progression of NAFLD. In the cross-sectional Multiethnic Cohort (MEC) Adiposity Phenotype Study (APS; P01 CA168530), we showed a significant difference in gut microbial composition and inferred microbial function by NAFLD status, including enrichment of Fusobacterium and endotoxin-producing bacteria and altered microbial pathways for bile acid and simple carbohydrate metabolism in NAFLD. We now hypothesize that specific gut bacterial features (genera, metabolic pathways and blood endotoxin biomarker lipopolysaccharide binding protein (LBP)) are associated with increase in liver fat and liver fibrosis over time. We also hypothesize that several dietary factors are associated with NAFLD progression and that fibrosis-promoting gut bacterial features mediate these associations. We propose a longitudinal investigation by efficiently adding a ~10-year follow-up assessment among 300 of the MEC-APS participants, aged 60-77 years at baseline and of three racial/ethnic groups (Japanese American, Native Hawaiian or White), across a wide range of baseline liver fat. We will re-assess liver fat using MRI and measure liver stiffness using MR elastography, gold-standard methods for non-invasive quantification of liver fat and liver stiffness, respectively, and perform 16S rRNA gene sequencing (follow-up stool samples) and metagenomic sequencing (baseline and follow-up stool samples). Specific Aims are to: 1) evaluate the change in specific gut bacterial features (abundance of genera, metabolic pathways, and LBP) over time in relation to the change in liver fat; 2) evaluate the change in gut bacterial features over time in relation to (2a) liver stiffness at follow-up and (2b) change in a blood biomarker panel for liver fibrosis (Enhanced Liver Fibrosis (ELF) score), and (2c) validate the top two bacterial features associated with liver stiffness using ddPCR; and 3) assess the association of diet (3 dietary pattern scores for overall diet quality and 7 key components) with ELF-based change in liver fibrosis and explore the mediation by fibrosis-promoting gut bacterial features from Aim 2, stratified by liver fat level. Our results will identify gut microbial features associated with early NAFLD progression, while specifically addressing the needs of understudied Asian Americans and Native Hawaiians (NOT-HL-23-001), two high-risk populations for NAFLD and liver cancer. The strengths of the proposed longitudinal design and rigorous imaging and laboratory methods will aid in understanding NAFLD progression involving the gut microbiome. These findings may be used to inform novel targeted intervention strategies to prevent NAFLD progression and, ultimately, reduce liver cancer burden in multiple racial/ethnic populations.

项目摘要 非酒精性脂肪肝病（NAFLD）影响> 35％的美国老年人。现在是主要病因 慢性肝病和肝癌，以及这些致命疾病最近上升趋势的驱动力。一个 不植物肠道微生物组与NAFLD有关，但主要是在小型，横截面或临床上 基于研究。需要基于人群的纵向研究来为时间段提供证据 肠道微生物组与NAFLD的进展。在横断面多民族队列中 （MEC）肥胖表型研究（APS; P01 CA168530），我们在肠道微生物中显示出显着差异 NAFLD状态的组成和推断微生物功能，包括富杆菌和 产生内毒素的细菌和胆汁酸和简单碳水化合物代谢的微生物途径改变 在Nafld。现在，我们假设特定的肠道细菌特征（属，代谢途径和血液 内毒素生物标志物脂多糖结合蛋白（LBP）与肝脏脂肪和肝脏的增加有关 纤维化随着时间的流逝。我们还假设几个饮食因素与NAFLD的进展有关 促进纤维化的肠道细菌特征介导了这些关联。我们提出了一个纵向 通过在300名MEC-APS参与者中有效添加约10年的随访评估来调查， 基线和三个种族/族裔的60-77岁（日裔美国人，夏威夷人或 白色），遍布各种基线肝脂肪。我们将使用MRI重新评估肝脏脂肪并测量肝脏 使用MR弹性摄影，金色标准方法的僵硬，用于非侵入性肝脏脂肪和肝脏 刚度分别和执行16S rRNA基因测序（随访粪便样品）和元基因组学 测序（基线和后续粪便样品）。具体目的是：1）评估特定肠道的变化 随着时间的流逝，细菌特征（丰富的属，代谢途径和LBP） 肝脂肪； 2）评估肠道细菌特征随着（2A）随访时的变化 （2B）变化肝纤维化的血液生物标志物面板（肝纤维化增强（ELF）评分）和（2C） 使用DDPCR验证与肝脏刚度相关的顶部两个细菌特征； 3）评估 饮食的关联（总体饮食质量的3个饮食图案得分和7个关键成分）与基于ELF的饮食分数 肝纤维化的变化并通过AIM 2的促进纤维化肠道细菌特征探索介导 由肝脏脂肪水平分层。我们的结果将确定与早期NAFLD相关的肠道微生物特征 进步时，专门满足了正在研究的亚裔美国人和夏威夷原住民的需求 （非HL-23-001），两个用于NAFLD和肝癌的高风险人群。提议的优势 纵向设计以及严格的成像和实验室方法将有助于理解NAFLD的进步 涉及肠道微生物组。这些发现可用于告知新颖的目标干预策略 防止NAFLD进展，并最终减轻多个种族/种族人群中的肝癌负担。