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

HIV 感染者与酒精相关的疾病和微生物组评估及针对性治疗

• 批准号: 10415317
• 负责人: Natalie E Chichetto
• 金额: $ 15.94万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415317
• 关键词: Academic Medical Centers; Acquired Immunodeficiency Syndrome; Address; Alcohol abuse; Alcohol consumption; Alcohols; Attenuated; Automobile Driving; Award; Back; Bacteria; Behavior Therapy; Behavioral; Biodiversity; Biological Markers; Blood Circulation; Butyrates; Cardiovascular Diseases; Clinical Research; Clinical Trials; Competence; Data; Data Collection; Development; Development Plans; Endotoxins; Engraftment; Evaluation; Feasibility Studies; Firmicutes Bacteroidetes ratio; Funding; Growth; HIV; HIV Infections; Health; Health Benefit; Heavy Drinking; Homeostasis; Human; Immunology; Inflammation; Inflammation Mediators; Inflammatory; Infrastructure; Leadership; Link; Mental Depression; Mental disorders; Mentored Research Scientist Development Award; Mentors; Mus; National Institute on Alcohol Abuse and Alcoholism; Nutrient; Outcome; Pathway interactions; Patient Self-Report; Patients; Permeability; Persons; Phenotype; Population; Probiotics; Proteobacteria; Reporting; Research; Research Personnel; Risk; Risk Reduction; Serum; Smoking; Social Work; Structure; Supplementation; Teacher Professional Development; Tennessee; Testing; Therapeutic; Tight Junctions; TimeLine; Training; Translational Research; Visit; Vulnerable Populations; Woman; Work; addiction; alcohol effect; alcohol exposure; alcohol use disorder; behavioral health; cardiovascular disorder epidemiology; cardiovascular disorder risk; cardiovascular disorder therapy; career development; clinical investigation; comorbidity; depressive symptoms; drinking; dysbiosis; early-career faculty; experience; follow-up; gastrointestinal; gut microbiome; hazardous drinking; high risk; member; men; microbial; microbiome; microbiome research; microorganism; mortality; mortality risk; pill; post intervention; prebiotics; prevent; responsible research conduct; skills; substance use; systemic inflammatory response; targeted treatment; treatment effect

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.

项目摘要 四分之一的艾滋病毒感染者（PWH）报告危险饮酒[即，每周饮酒超过7（14）杯或每周饮酒超过3（4）杯 女（男）的场合。在这一人群中，65%的人报告有抑郁症状或吸烟，21%的人报告有抑郁症状或吸烟。 所有这三种疾病构成了与酒精相关的综合征（即，2+条件的相互作用增加穷人的风险 成果）。这种综合征与心血管疾病（CVD）的风险增加有关。的 胃肠道（GI）微生物组是一个强有力的候选机制途径的综合征相关的过度 CVD风险，通过GI生态失调，微生物易位（MT）和全身炎症。生态失调 其特征在于有益细菌的减少和促炎细菌的增加。胃肠道生态失调 导致MT，其中胃肠道腔的紧密连接受损，驱动全身性炎症- CVD的主要原因。HIV、危险饮酒、吸烟和抑郁症与GI独立相关 生态失调、MT和炎症。有益的丁酸产生细菌，其下调促炎因子 介质，在危险的饮用PWH耗尽。在患有酒精使用障碍的人中，益生菌的使用 减弱MT和炎症。在PWH中，益生菌（例如，产丁酸菌）与益生元的应用 （细菌生长的营养素），一种被称为“合生元”的组合，有利地改变了胃肠道内的微生物组。 4-16周我们假设酒精相关的综合征与胃肠道生态失调有关， 随后的CVD相关生物标志物和靶向补充可以恢复GI微生物组 体内平衡和减少炎症。与范德比尔特大学的跨学科指导小组合作 医学中心（VUMC），我的职业发展计划将提高酒精临床研究的技能 症状表型;微生物组结构、功能、多样性和免疫学;临床和转化 研究;和主要数据收集，负责任的研究行为，和领导。目标1将确定 在12个月内，PWH与酒精相关综合征的GI微生物组的变化，Aim 2将 确定PWH中与GI通透性、MT和炎症相关的生物标志物谱的变化， 目标3将评估a）给予一种 丁酸盐补充丸，然后是多菌株合生素（益生元+益生菌）丸，和B）治疗效果 对伴有酒精相关综合征的PWH中GI微生物组结构和CVD相关生物标志物的影响 （n=40）。目标1和2利用来自NIAAA资助的200名PWH微生物组研究的二级数据， 现有的胃肠道微生物组数据、血清生物标志物数据以及经验证的饮酒、吸烟和 抑郁症状目标3利用VUMC田纳西艾滋病研究中心的基础设施， 它在支持早期职业教师方面有着良好的记录。这个奖项将有助于我过渡到一个 具有酒精/CVD流行病学、微生物组结构和功能方面专业知识的独立调查员，以及 PWH的临床试验开发，也将为R 01应用提供信息数据。