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

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 非酒精性脂肪性肝病（NAFLD）影响美国35%以上的老年人。它现在是主要的病因 慢性肝病和肝癌的发病率，以及这些致命疾病最近上升趋势的驱动因素。一 肠道微生物群失调与NAFLD有关，但主要是在小规模，横断面或临床上， 基于研究。需要进行基于人群的纵向研究，以提供时间相关性的证据。 肠道微生物组与NAFLD进展的关系。在多种族队列中， (MEC)肥胖表型研究（APS; P01 CA 168530）中，我们发现肠道微生物 根据NAFLD状态推断微生物的组成和功能，包括梭杆菌的富集， 产生内毒素的细菌和胆汁酸和简单碳水化合物代谢的改变的微生物途径 在NAFLD。我们现在假设，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））与肝脂肪和肝硬化的增加有关。 随着时间的推移纤维化。我们还假设几种饮食因素与NAFLD进展有关 并且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的 通过在300名MEC-APS参与者中有效增加约10年随访评估进行调查， 基线时年龄为60-77岁，3个人种/种族组（日裔美国人、夏威夷原住民或 白色），跨越广泛的基线肝脏脂肪。我们将使用MRI重新评估肝脏脂肪， 使用MR弹性成像的硬度，用于无创定量肝脏脂肪和肝脏的金标准方法 硬度，并进行16 S rRNA基因测序（后续粪便样本）和宏基因组 测序（基线和随访粪便样本）。具体目的是：1）评估特定肠道的变化 细菌特征（属的丰度、代谢途径和LBP）随时间的变化与 肝脏脂肪; 2）评价肠道细菌特征随时间的变化与（2a）随访时肝脏硬度的关系 和（2b）肝纤维化的血液生物标志物组的变化（增强的肝纤维化（ELF）评分），和（2c） 使用ddPCR验证与肝硬度相关的前两个细菌特征;以及3）评估 饮食（总体饮食质量的3个饮食模式评分和7个关键成分）与基于ELF的 肝纤维化的变化，并探讨促纤维化肠道细菌的功能从目的2， 按肝脏脂肪水平分层。我们的研究结果将确定与早期NAFLD相关的肠道微生物特征 进步，同时专门解决未充分研究的亚裔美国人和夏威夷土著人的需求 （NOT-HL-23-001），NAFLD和肝癌的两个高危人群。建议的优点 纵向设计和严格的成像和实验室方法将有助于了解NAFLD进展 包括肠道微生物组。这些发现可用于提供新的靶向干预策略， 预防NAFLD进展，并最终减少多种族/民族人群的肝癌负担。