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The Gut-Liver Axis in HIV-Related Non-Alcoholic Fatty Liver Disease

HIV 相关非酒精性脂肪肝中的肠肝轴

基本信息

批准号：
10762284
负责人：
Curtis Lee Gabriel
金额：
$ 18.4万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2023-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762284
关键词：
AIDS clinical trial group Academic Medical Centers Acquired Immunodeficiency Syndrome Address Adipose tissue Aging Alcohol abuse Alcohol consumption Alcohols Bacteria Biological Markers Butyrates Cardiovascular system Clinical Clinical Research Clinical Trials Cohort Studies Data Deposition Development Diagnostic Disparity Enrollment Environment Evaluation Fatty Liver Fiber Foundations Functional disorder Funding Goals Grant HIV HIV Infections HIV Seronegativity Health Heavy Drinking Hepatic Immunology Impairment Inflammatory Infrastructure Intestines Lead Leaky Gut Lecithin Link Lipids Liver Liver diseases Mass Spectrum Analysis Measures Mentored Clinical Scientist Development Program Mentors Metabolism Participant Pathogenesis Patients Persons Plasma Probiotics Publications Recording of previous events Research Research Infrastructure Research Personnel Resources Sampling Studies Scientist Specimen Strategic Planning Tennessee Testing Training United States National Institutes of Health Universities Veterans Viral hepatitis Viremia antiretroviral therapy bacterial community cardiometabolism career career development co-infection cohort comorbidity design dysbiosis fatty liver disease feasibility testing gut bacteria gut microbiome gut-liver axis high risk imaging study improved intestinal barrier metabolic fitness metabolome metabolomics microbiome microbiome composition microbiome research mortality multidisciplinary non-alcoholic fatty liver disease pilot trial prebiotics prevent probiotic supplementation prospective recruit secondary analysis trimethyloxamine

项目摘要

Project Summary/Abstract Liver disease is a leading cause of mortality in persons with HIV (PWH), and PWH suffer a disproportionate burden of non-alcoholic fatty liver disease (NAFLD). While the mechanisms underlying this disparity are not well understood, intestinal dysbiosis and intestinal barrier dysfunction are implicated in the pathogenesis of NAFLD in HIV-negative persons. HIV infection has been shown to alter the intestinal microbiome, change the plasma metabolome and impair intestinal barrier function; however, there are few data on the microbiome and metabolome among PWH with NAFLD. My pilot preliminary data show that hepatic steatosis is associated with differences in the intestinal bacterial community (reduction in butyrate-producing bacteria), bacteria-related metabolites (including phosphatidylcholine), and markers of intestinal barrier dysfunction among PWH on long- term ART. I hypothesize that intestinal dysbiosis in PWH promotes NAFLD through 1) impairment of intestinal barrier function and 2) alteration of the plasma metabolome to promote hepatic lipid deposition. In Aim 1 I will determine whether differences in plasma levels of NAFLD- and bacteria-related metabolites, including phosphatidylcholine and trimethylamine N-oxide, are associated with hepatic steatosis in PWH. In Aim 2 I will determine whether decreased abundance of butyrate-producing gut bacteria and markers of impaired intestinal barrier function are associated with hepatic steatosis in PWH. In Aim 3 I will test the feasibility and limited efficacy of a multi-strain probiotic and prebiotic fiber on NAFLD biomarkers in a prospective trial in PWH. Aims 1 and 2 will leverage existing data and specimens from 134 PWH in the NIH-supported HIV, Adipose Tissue Immunology and Metabolism (HATIM) cohort, which includes metabolomic, microbiome, and imaging studies from participants with a spectrum of metabolic fitness and in the absence of viral hepatitis or excessive alcohol use. Secondary analyses will compare the findings from the HATIM cohort with both HIV-negative controls and PWH with viral hepatitis and heavy alcohol use. The Aim 3 pilot trial will leverage the well-developed infrastructure and large recruitment pool of the Tennessee Center for AIDS Research. Collectively, these Aims address the call for research related to HIV-associated comorbidities, coinfections and complications described in NIH Strategic Plan for HIV and HIV-related Research, and have the potential to inform new microbiome- based diagnostics and treatments that will reduce the burden of NAFLD in PWH. My research and training plan will be supported a multi-disciplinary team of scientists who have a strong record of mentoring young investigators and the world-class training environment and resources available at Vanderbilt University Medical Center. In addition to the benefits to the health of PWH, the proposed K23 studies and training plan will allow me to further my expertise in patient-facing research and generate the data and publication track record necessary to develop a self-sustaining research career in the field of HIV-related liver disease.

项目总结/文摘