Precision Medicine Approaches for Alcohol and HIV-associated Dysbiosis, Immune Activation and Cardiometabolic Syndrome

项目摘要 过量饮酒和HIV/SIV感染，无论是单独还是共同， 胃肠道生态失调，微生物从肠腔移位到组织和循环中， 免疫激活和心脏代谢合并症。本建议的目的是制定一个 根据个体患者的胃肠道微生物群特征制定精准医疗策略 艾滋病毒感染者（PLWH）与有害的酒精使用，以减少肠道易位，免疫 激活和心脏代谢合并症的风险。这一目标将由 完成两项研究。第一个是UH 2部分，将检验以下假设： 患有心脏代谢综合征的PLWH患者的胃肠道微生物群系统发育谱 酒精的使用与益生元和益生菌的特定组合的能力相关， 免疫激活和肠道易位生物标志物。这一假设将由以下人员进行检验： 进行益生菌和/或益生元的高通量筛选以鉴定试剂的组合 其在体外和体内减弱人类生态失调诱导易位和免疫激活， 异种移植（人-小鼠）模型的基础上的微生物群结构。第二 组件（UH 3阶段）将测试益生菌/益生菌的个性化给药的假设 益生元/组合将减少免疫激活，微生物易位的生物标志物， 改善PLWH中的心脏代谢生物标志物与积极使用酒精。我们将评估 市售产品，评估益生菌制剂中的抗生素抗性基因，以及 确定、解决监管问题，并探索与商业实体的伙伴关系。以下 益生菌和/或益生元的精准医疗策略的安全性和有效性 将通过测量肠粘膜的生物标志物来测试在具有活跃酒精使用的PLWH中的给药。 易位、免疫激活和心脏代谢综合征。 !

PROJECT ABSTRACT Excessive alcohol use and HIV/SIV infection, independently or in concert, are associated with gastrointestinal dysbioss, microbial translocation from the gut lumen into tissues and the circulation, immune activation, and cardiometabolic comorbidities. The objective of this proposal is to develop a precision medicine strategy informed by the individual patient's GI microbiota characteristics in people living with HIV (PLWH) with harmful alcohol use in order to reduce intestinal translocation, immune activation, and risk for cardiometabolic comorbidities. This objective will be accomplished by the completion of two research components. The first, the UH2 component, will test the hypothesis that gastrointestinal microbiota phylogenetic profiles in PLWH with cardiometabolic syndrome with active alcohol use correlate with the capacity of specific combinations of prebiotics and probiotics to reduce immune activation and biomarkers of intestinal translocation. This hypothesis will be tested by performing high-throughput screening of probiotics, and/or prebiotics to identify combinations of agents that attenuate human dysbiosis-induced translocation and immune activation in vitro and in xenotransplantation (human-mouse) models based upon the microbiota structure. The second component (UH3 phase) will test the hypothesis that personalized administration of probiotics / prebiotics / combinations will reduce immune activation, biomarkers of microbial translocation, and improved cardiometabolic biomarkers in PLWH with active alcohol use. We will assess the quality of commercially available products, evaluate antibiotic resistance genes in probiotic preparations, and determine, resolve regulatory issues, and explore partnerships with commercial entities. Following these steps the safety and efficacy of the Precision Medicine strategy of probiotics and/or prebiotics administration in PLWH with active alcohol use will be tested by measuring biomarkers of intestinal translocation, immune activation and cardiometabolic syndrome during the intervention. !