R01MD018265

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

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.

University Of Hawaii

TO SUPPORT BASIC, CLINICAL, SOCIAL, AND BEHAVIORAL RESEARCH, PROMOTE RESEARCH INFRASTRUCTURE AND TRAINING, FOSTER EMERGING PROGRAMS, DISSEMINATE INFORMATION, AND REACH OUT TO MINORITY AND OTHER HEALTH DISPARITY COMMUNITIES. THE NATIONAL INSTITUTE ON MINORITY HEALTH AND HEALTH DISPARITIES (NIMHD) HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS: (1) THE CENTERS OF EXCELLENCE PROGRAM PROMOTES RESEARCH TO IMPROVE MINORITY HEALTH AND/OR REDUCE AND ELIMINATE HEALTH DISPARITIES, BUILDS RESEARCH CAPACITY FOR MINORITY HEALTH AND HEALTH DISPARITIES RESEARCH IN ACADEMIC INSTITUTIONS, ENCOURAGES PARTICIPATION OF HEALTH DISPARITY GROUPS AND COMMUNITIES IN BIOMEDICAL AND BEHAVIORAL RESEARCH AND PREVENTION AND INTERVENTION ACTIVITIES, AND BRINGS TOGETHER INVESTIGATORS FROM RELEVANT DISCIPLINES IN A MANNER THAT WILL ENHANCE AND EXTEND THE EFFECTIVENESS OF THEIR RESEARCH, (2) NIMHD RESEARCH ENDOWMENT PROGRAM BUILDS RESEARCH CAPACITY AND INFRASTRUCTURE AT ELIGIBLE NIMHD CENTERS OF EXCELLENCE OR ELIGIBLE SECTION 736 HEALTH PROFESSIONS SCHOOLS (42 U.S.C. 293) TO FACILITATE MINORITY HEALTH AND OTHER HEALTH DISPARITIES RESEARCH TO CLOSE THE DISPARITY GAP IN THE BURDEN OF ILLNESS AND DEATH EXPERIENCED BY RACIAL AND ETHNIC MINORITY AMERICANS AND OTHER HEALTH DISPARITY POPULATIONS, PROMOTES A DIVERSE AND STRONG SCIENTIFIC, TECHNOLOGICAL AND ENGINEERING WORKFORCE, AND EMPHASIZES THE RECRUITMENT AND RETENTION OF UNDERREPRESENTED MINORITIES AND OTHER SOCIO-ECONOMICALLY DISADVANTAGED POPULATIONS IN THE FIELDS OF BIOMEDICAL AND BEHAVIORAL RESEARCH AND OTHER AREAS OF THE SCIENTIFIC WORKFORCE, (3) THE CENTERS OF EXCELLENCE ON ENVIRONMENTAL HEALTH DISPARITIES RESEARCH TO STIMULATE BASIC AND APPLIED RESEARCH ON ENVIRONMENTAL HEALTH DISPARITIES, (4) MINORITY HEALTH AND HEALTH DISPARITIES INTERNATIONAL RESEARCH TRAINING PROGRAM (MHIRT) AWARDS ENABLE U.S. INSTITUTIONS TO TAILOR SHORT-TERM BASIC SCIENCE, BIOMEDICAL AND BEHAVIORAL MENTORED STUDENT INTERNATIONAL RESEARCH TRAINING OPPORTUNITIES TO ADDRESS GLOBAL ISSUES RELATED TO UNDERSTANDING, REDUCING, AND ELIMINATING HEALTH DISPARITIES, (5) SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM INCREASES PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, ENCOURAGES SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTERS AND ENCOURAGES PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (6) SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTERS TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, INCREASES PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTERS AND ENCOURAGES PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (7) HEALTH DISPARITIES RESEARCH PROJECT GRANTS (RPG) SUPPORT INNOVATIVE PROJECTS TO ENHANCE OUR UNDERSTANDING OF BIOLOGICAL MECHANISMS, SOCIAL, BEHAVIORAL, AND HEALTH SERVICES THAT CAN DIRECTLY AND DEMONSTRABLY CONTRIBUTE TO THE IMPROVEMENT IN MINORITY HEALTH AND THE ELIMINATION OF HEALTH DISPARITIES WHICH INCLUDES THE (8) RESEARCH CENTERS IN MINORITY INSTITUTIONS (RCMI) BUILD CAPACITY FOR BASIC BIOMEDICAL AND/OR BEHAVIORAL RESEARCH, CLINICAL AND TRANSLATIONAL RESEARCH (RCTR) AND A NETWORK (RCTN) BY FOCUSING ON INSTITUTIONAL RESOURCE DEVELOPMENT, SUCH AS SUPPORTING CORE RESEARCH FACILITIES AND STAFF, PURCHASING ADVANCED INSTRUMENTATION, AND LABORATORY RENOVATIONS/ALTERATIONS (9) CLINICAL RESEARCH EDUCATION AND CAREER DEVELOPMENT (CRECD) AWARDS PROVIDE DIDACTIC TRAINING AND MENTORED CLINICAL RESEARCH EXPERIENCES TO DEVELOP INDEPENDENT RESEARCHERS WHO CAN LEAD CLINICAL RESEARCH STUDIES, ESPECIALLY THOSE ADDRESSING HEALTH DISPARITIES, (10) PATHWAY TO INDEPENDENCE AWARDS (K99/R00) TO INCREASE AND MAINTAIN A STRONG COHORT OF NEW AND TALENTED, NIH-SUPPORTED, INDEPENDENT INVESTIGATORS. (11) NIH RESEARCH CONFERENCE GRANT AND NIH RESEARCH CONFERENCE COOPERATIVE AGREEMENT PROGRAMS SUPPORT HIGH-QUALITY CONFERENCES THAT ARE RELEVANT TO THE MINORITY HEALTH AND HEALTH DISPARITIES, (12) TRANSDISCIPLINARY COLLABORATIVE CENTERS FOR HEALTH DISPARITIES RESEARCH COMPRISE REGIONAL COALITIONS OF ACADEMIC INSTITUTIONS, COMMUNITY ORGANIZATIONS, SERVICE PROVIDERS AND SYSTEMS, GOVERNMENT AGENCIES AND OTHER STAKEHOLDERS CONDUCTING COORDINATED RESEARCH, IMPLEMENTATION AND DISSEMINATION ACTIVITIES THAT TRANSCEND CUSTOMARY APPROACHES AND SILO ORGANIZATIONAL STRUCTURES TO ADDRESS CRITICAL QUESTIONS AT MULTIPLE LEVELS IN INNOVATIVE WAYS FOCUSED ON PRIORITY RESEARCH AREAS IN MINORITY HEALTH AND HEALTH DISPARITIES, (13) RUTH L. KIRSCHSTEIN NRSA INDIVIDUAL PREDOCTORAL FELLOWSHIP

93.307 - Minority Health and Health Disparities Research

National Institute for Minority Health and Health Disparities (NIMHD) [HHS - NIH]

Honolulu, Hawaii 968135515 United States

Single Zip Code

Research Supplements to Promote Diversity in Health-Related Research (Admin Supp Clinical Trial Not Allowed) (PA-23-189)

Amendment Since initial award the total obligations have increased 366% from $700,437 to $3,263,901.