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.

项目概要/摘要 肝病是艾滋病毒感染者 (PWH) 死亡的主要原因，而 PWH 则遭受着不成比例的痛苦 非酒精性脂肪肝（NAFLD）的负担。虽然造成这种差异的机制并不 众所周知，肠道菌群失调和肠道屏障功能障碍与肠道菌群失调的发病机制有关。 HIV 阴性人群中的 NAFLD。 HIV 感染已被证明会改变肠道微生物群，改变 血浆代谢组和损害肠道屏障功能；然而，关于微生物组的数据很少 患有 NAFLD 的 PWH 的代谢组。我的初步试验数据表明，肝脂肪变性与 肠道细菌群落的差异（产生丁酸的细菌减少），与细菌相关 长期服用 PWH 的代谢物（包括磷脂酰胆碱）和肠道屏障功能障碍标志物 术语“艺术”。我假设感染者肠道菌群失调通过以下方式促进 NAFLD：1) 肠道损伤 屏障功能；2) 改变血浆代谢组以促进肝脏脂质沉积。在目标 1 中我会 确定 NAFLD 和细菌相关代谢物的血浆水平是否存在差异，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 中我会 确定产生丁酸盐的肠道细菌和受损肠道标记物的丰度是否减少 屏障功能与 PWH 中的肝脂肪变性相关。在目标3中我将测试可行性和有限性 在 PWH 的一项前瞻性试验中，研究了多菌株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 134 名 PWH 的现有数据和样本 免疫学和代谢 (HATIM) 队列，包括代谢组学、微生物组和影像学研究 来自具有一系列代谢健康且没有病毒性肝炎或过量饮酒的参与者 使用。二次分析将 HATIM 队列的研究结果与 HIV 阴性对照和 患有病毒性肝炎和大量饮酒的感染者。 Aim 3 试点试验将利用成熟的 田纳西州艾滋病研究中心的基础设施和庞大的人才库。总的来说，这些目标 响应与 HIV 相关合并症、合并感染和并发症相关的研究呼吁 NIH 艾滋病毒和艾滋病毒相关研究战略计划，并有潜力为新的微生物组提供信息 基于诊断和治疗的方法将减轻 PWH 中 NAFLD 的负担。我的研究和培训计划 将获得多学科科学家团队的支持，他们在指导年轻人方面拥有良好的记录 范德比尔特大学医学院提供研究人员以及世界一流的培训环境和资源 中心。除了对感染者健康的益处外，拟议的 K23 研究和培训计划还将允许 我将进一步提升我在面向患者的研究方面的专业知识并生成数据和发表记录 在艾滋病毒相关肝病领域发展自我维持的研究事业是必要的。