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

• 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
• 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

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.

项目摘要/摘要 肝病是艾滋病毒（PWH）患者死亡的主要原因，而PWH遭受不相称的 非酒精性脂肪肝病（NAFLD）的负担。而这种差异的基础机制不是 知情人士，肠道营养不良和肠道屏障功能障碍与 艾滋病毒阴性人的nafld。 HIV感染已被证明会改变肠道微生物组，改变 血浆代谢组和障碍肠屏障功能；但是，微生物组和 与Nafld的PWH中的代谢组。我的飞行员初步数据表明，肝脂肪变性与 肠道细菌群落的差异（减少丁酸细菌），与细菌有关 代谢产物（包括磷脂酰胆碱），以及长期PWH中肠道屏障功能障碍的标记 术语艺术。我假设PWH中的肠道营养不良促进NAFLD通过1）肠道损害 屏障功能和2）血浆代谢组的改变以促进肝脂质沉积。在目标1中我会 确定NAFLD和细菌相关代谢产物血浆水平的差异，包括 磷脂酰胆碱和三甲胺N氧化物与PWH中的肝脂肪变性有关。在目标2我会 确定是否减少了产生丁酸酯的肠道细菌的丰度和肠道受损的标记 屏障功能与PWH中的肝脂肪变性有关。在AIM 3中，我将测试可行性并有限 在PWH的一项前瞻性试验中，多应变益生菌和益生元纤维对NAFLD生物标志物的功效。目标 1和2将利用NIH支持的HIV，脂肪组织中的134 PWH的现有数据和标本 免疫学和代谢（Hatim）队列，包括代谢组，微生物组和成像研究 来自具有代谢健康的参与者，在没有病毒肝炎或过量酒精的情况下 使用。次级分析将将Hatim队列的发现与HIV阴性控制和 病毒肝炎和大量酒精的PWH。 AIM 3试点试验将利用发达的 田纳西州艾滋病研究中心的基础设施和大型招聘池。总的来说，这些目标 解决与与HIV相关的合并症，共同感染和并发症有关的研究的呼吁 在NIH艾滋病毒和艾滋病毒相关研究的NIH战略计划中，并有可能告知新的微生物组 - 基于诊断和治疗将减轻PWH中NAFLD的负担。我的研究和培训计划 将支持一个多学科的科学家团队 研究人员以及范德比尔特大学医学的世界一流培训环境和资源 中心。除了对PWH健康的好处外，拟议的K23研究和培训计划还将允许 我要进一步在面向患者的研究方面的专业知识，并生成数据和出版记录 在HIV相关肝病领域发展自我维持的研究职业所必需的。