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

基本信息

批准号：
10160470
负责人：
Natalie E Chichetto
金额：
$ 16.33万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-25 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160470
关键词：
Academic Medical Centers Acquired Immunodeficiency Syndrome Address Alcohol abuse Alcohol consumption Alcohol or Other Drugs use 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 targeted treatment treatment effect

项目摘要

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.

项目概要四分之一的 HIV 感染者 (PWH) 报告有危险饮酒行为 [即每周 >7 (14) 次饮酒或每次 >3 (4) 次饮酒女性（男性）的场合] 在该人群中，65% 的人报告有抑郁症状或吸烟，21% 的人报告有抑郁症状。所有这三种情况均构成酒精相关综合征（即 2 个以上条件的相互作用会增加贫困的风险）该综合征与心血管疾病 (CVD) 风险增加相关。胃肠道 (GI) 微生物组是与综合征相关的过度代谢的一个强有力的候选机制途径胃肠道生态失调、微生物易位 (MT) 和全身炎症导致 CVD 风险。其特点是有益细菌减少，促炎细菌增加，胃肠道生态失调。导致 MT，其中胃肠道腔的紧密连接受到损害，导致全身炎症 - HIV、有害饮酒、吸烟和抑郁症与胃肠道独立相关。菌群失调、MT 和炎症，产生有益的丁酸盐，可下调促炎性物质。在患有酒精使用障碍、使用益生菌的人类中，危险饮酒中的介质会被耗尽。在 PWH 中，益生菌（例如产生丁酸盐的细菌）与益生元的使用可减轻 MT 和炎症。（细菌生长的营养物质），一种被称为“合生元”的组合，可以有利地改变体内的胃肠道微生物组 4-16 周，我们勇敢地承认酒精相关综合症与胃肠道生态失调有关。随后的 CVD 相关生物标志物以及有针对性的补充可能会恢复胃肠道微生物组与范德比尔特大学的跨学科指导小组一起维持体内平衡并减少炎症。医疗中心 (VUMC)，我的职业发展计划将提高酒精临床调查的技能流行病表型；微生物组结构、功能、多样性和免疫学；目标 1 将确定主要数据收集、负责任的研究行为和领导力。患有酒精相关综合征的感染者胃肠道微生物组在 12 个月内发生变化，目标 2 将确定 PWH 中与胃肠道通透性、MT 和炎症相关的生物标志物谱的变化超过 12 个月的酒精相关综合症，目标 3 将评估 a) 施用丁酸盐补充丸，随后服用多菌株合生元（益生元 + 益生菌）丸和 b) 治疗效果酒精相关综合征感染者中胃肠道微生物组结构和 CVD 相关生物标志物的研究 (n=40) 目标 1 和 2 利用 NIAAA 资助的 200 名 PWH 微生物组研究的二手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过验证的饮酒、吸烟和饮酒的自我报告目标 3 利用 VUMC 田纳西州艾滋病研究中心的基础设施，该奖项在支持早期职业教师方面有着良好的记录，该奖项将有助于我向一名职业教师的过渡。具有酒精/CVD流行病学、微生物组结构和功能专业知识的独立调查员，以及 PWH 中的临床试验开发，还将为 R01 应用提供信息数据。