Alcohol-Associated Syndemic and Microbiome Evaluation and Targeted Treatment in Persons Living with HIV

项目总结 四分之一的艾滋病毒携带者(PWH)报告有危险饮酒[例如，每周七(14)杯酒或一周三(4)杯酒 女性(男性)的场合]。在这一人群中，65%的人报告有抑郁症状或吸烟，21%的人报告 这三种情况都构成了酒精相关的综合征(即，2+条件的相互作用会增加穷人的风险 结果)。这种综合征与心血管疾病(CVD)发病风险增加有关。这个 胃肠道(GI)微生物组是联结相关过度的强烈候选机制途径 心血管疾病的风险，通过胃肠道生物失调、微生物易位(MT)和全身炎症。生物失调就是 以有益细菌的减少和促炎细菌的增加为特征。胃肠道菌群失调 导致MT，其中GI管腔的紧密连接受到损害，导致全身炎症-a 心血管疾病的主要原因。艾滋病毒、危险饮酒、吸烟和抑郁与胃肠道感染独立相关 生物失调、MT和炎症。有益的丁酸产生菌，它下调促炎作用 调停者，在危险的饮酒PWH中耗尽。在有酒精使用障碍的人类中，益生菌的使用 减轻MT和炎症。在PWH中，益生菌(例如，生产丁酸的细菌)具有益生菌的用途 (细菌生长的营养物质)，一种被称为“合生素”的组合，有利地改变体内的胃肠道微生物群 4-16周。我们假设与酒精相关的综合征与胃肠道菌群失调有关 随后与心血管疾病相关的生物标志物和靶向补充可恢复胃肠道微生物群 动态平衡，减少炎症。与范德比尔特大学的跨学科指导小组 我的职业发展计划将提升酒精临床研究的技能 共生表型；微生物组结构、功能、多样性和免疫学；临床和翻译 研究；主要数据收集、负责任的研究行为和领导力。目标1将确定 酒精相关综合征患者12个月来胃肠道微生物群的变化，AIM 2将 确定与胃肠道通透性、MT和炎症相关的生物标记物的变化 酒精相关综合征超过12个月，目标3将评估a)实施 丁酸补充丸和多菌种合生菌(益生菌+益生菌)药丸和b)治疗效果 酒精性肝病患者胃肠道微生物群结构及心血管疾病相关标志物的研究 (n=40)。AIMS 1和2利用来自NIAAA资助的200个PWH的微生物组研究的次要数据 现有的胃肠道微生物组数据，血清生物标志物数据，以及酒精使用、吸烟和 抑郁症状。AIM 3利用VUMC田纳西艾滋病研究中心的基础设施， 它有很强的支持早期职业教师的记录。这一奖项将促进我向 具有酒精/心血管疾病流行病学、微生物组结构和功能方面的专业知识的独立调查员，以及 在PWH中的临床试验开发，也将为R01的应用提供信息数据。

PROJECT SUMMARY One in four people with HIV (PWH) report hazardous drinking [i.e., >7 (14) drinks per week or >3 (4) drinks per occasion for women (men)]. Of this population, 65% report depressive symptoms or smoking, and 21% report all three- constituting an alcohol-associated syndemic (i.e., interaction of 2+ conditions to increase risk for poor outcomes). This syndemic is associated with increased risk of incident cardiovascular disease (CVD). The gastrointestinal (GI) microbiome is a strong candidate mechanistic pathway for the syndemic-related excess CVD risk, through GI dysbiosis, microbial translocation (MT), and systemic inflammation. Dysbiosis is characterized as a decrease in beneficial bacteria and increase in pro-inflammatory bacteria. GI dysbiosis leads to MT, in which tight junctions of the GI lumen are compromised, driving systemic inflammation- a leading cause of CVD. HIV, hazardous drinking, smoking and depression are independently associated with GI dysbiosis, MT and inflammation. Beneficial butyrate producing bacteria, which downregulate pro-inflammatory mediators, are depleted in hazardous drinking PWH. In humans with alcohol use disorder, probiotic use attenuates MT and inflammation. Among PWH, probiotic (e.g., butyrate producing bacteria) with prebiotic use (nutrients for bacterial growth), a combination known as “synbiotic”, favorably alters the GI microbiome within 4-16 weeks. We hypothesize that the alcohol-associated syndemic is associated with GI dysbiosis and subsequent CVD related biomarkers and that targeted supplementation may restore GI microbiome homeostasis and reduce inflammation. With a transdisciplinary mentoring panel at Vanderbilt University Medical Center (VUMC), my career development plan will advance skills in clinical investigation of alcohol syndemic phenotypes; microbiome structure, function, diversity and immunology; clinical & translational research; and primary data collection, responsible conduct of research, and leadership. Aim 1 will identify changes in the GI microbiome among PWH with the alcohol-associated syndemic over 12 months, Aim 2 will determine changes in biomarker profiles related to GI permeability, MT, and inflammation among PWH with the alcohol-associated syndemic over 12 months, and Aim 3 will evaluate the a) feasibility of administering a butyrate supplement pill followed by a multi-strain synbiotic (prebiotic + probiotic) pill and b) treatment effects on GI microbiome structures and CVD-related biomarkers among PWH with the alcohol-associated syndemic (n=40). Aims 1 & 2 leverage secondary data from an NIAAA-funded microbiome study of 200 PWH with existing GI microbiome data, sero-biomarker data, and validated self-reports of alcohol use, smoking, and depressive symptoms. Aim 3 utilizes the infrastructure of the Tennessee Center for AIDS Research at VUMC, which has a strong record of supporting Early Career Faculty. This award will facilitate my transition to an independent investigator with expertise in alcohol/CVD epidemiology, microbiome structure and function, and clinical trial development among PWH, and will also provide informative data for an R01 application.