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

项目摘要/摘要 肝脏疾病是艾滋病毒携带者(PWH)死亡的主要原因，而PWH患者的 非酒精性脂肪性肝病负担(NAFLD)。虽然这种差异背后的机制并不是 众所周知，肠道生物失调和肠道屏障功能障碍与糖尿病的发病机制有关。 HIV阴性人群中的非酒精性脂肪肝。艾滋病毒感染已被证明会改变肠道微生物群，改变 血浆代谢组并损害肠道屏障功能；然而，关于微生物组和 非酒精性脂肪肝患者的代谢组学研究。我的初步数据显示，肝脏脂肪变性与 肠道细菌群落的差异(丁酸盐产生菌的减少)，细菌相关 代谢产物(包括磷脂酰胆碱)和肠道屏障功能障碍的标志物在慢性重型肝炎中的作用。 术语艺术。我假设PWH的肠道生态失调通过1)肠道损害促进NAFLD 屏障功能和2)血浆代谢产物的改变，以促进肝脏脂肪沉积。在《目标1》中我会 确定血浆NAFLD和细菌相关代谢物水平的差异是否包括 磷脂酰胆碱和三甲胺N-氧化物与PWH的肝脏脂肪变性有关。在《目标2》中我会 确定产生丁酸的肠道细菌和受损肠道标志物的丰度是否降低 屏障功能与PWH的肝脏脂肪变性有关。在目标3中，我将测试可行性和局限性 在威斯康星医院的一项前瞻性试验中，多菌株益生菌和益生菌纤维对NAFLD生物标记物的有效性。目标 1和2将利用NIH支持的HIV，脂肪组织中134个PWH的现有数据和样本 免疫学和新陈代谢(HATIM)队列，包括代谢学、微生物组和成像研究 来自代谢健康且无病毒性肝炎或过量饮酒的参与者 使用。二次分析将比较来自Hatim队列的结果与HIV阴性对照和 病毒性肝炎和酗酒的威斯康星医院。Aim 3的试点试验将利用开发良好的 田纳西州艾滋病研究中心的基础设施和庞大的招聘池。总而言之，这些目标 呼吁开展与艾滋病毒相关的共病、合并感染和并发症有关的研究 在美国国立卫生研究院艾滋病毒和艾滋病毒相关研究战略计划中，并有可能告知新的微生物组- 基于诊断和治疗，将减轻非酒精性脂肪肝在PWH中的负担。我的研究和培训计划 将支持一个由多学科科学家组成的团队，他们在指导年轻人方面有很好的记录 范德比尔特大学医学院提供的研究人员和世界级的培训环境和资源 中心。除了对威尔斯亲王医院的健康有益外，拟议的K23研究和培训计划还将使 我要进一步提高我在面向患者的研究方面的专业知识，并生成数据和出版跟踪记录 在艾滋病毒相关肝病领域发展自给自足的研究事业是必要的。

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.