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

点击翻译按钮获取中文摘要

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. !