Gut Microbiota-Mediated Inflammatory Interactions Between Alcohol Use Disorders and HIV Infection

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PROJECT SUMMARY. Alcohol use disorder (AUD) has been associated with a high prevalence of inflammation- associated co-morbidities in people living with HIV (PLWH), even those receiving effective antiretroviral therapy (ART). Our preliminary data support a model in which the combined insult of AUD and HIV on the gut, specifically on the microbiota (depletion of the bacteria that produce the anti-inflammatory short-chain fatty acids (SCFAs)) and intestinal barrier integrity, exacerbates inflammation. Our preliminary data using intestinal organoids also suggest a potential mechanism for AUD-mediated changes in the gut barrier function during HIV: the intestines of HIV+ individuals have low resilience to alcohol-induced intestinal barrier disruption caused by high levels of oxidative stress. Finally, our preliminary data also suggest a potential approach to enhance the integrity of the intestinal barrier and reduce gut derived inflammation in PLWH with/without AUD; SCFA-promoting prebiotics. SCFA-promoting prebiotics prevent alcohol-mediated adverse effects on the intestinal barrier and inflammation by preventing oxidative stress. These prebiotics are safe and decrease gut inflammation in humans. Together, our data support our central hypothesis that the intestinal resilience to alcohol-mediated disruption is reduced during HIV infection leading to exaggerated microbial translocation/inflammation, and that SCFA- promoting prebiotics can enhance the resilience of the gut from HIV+ individuals to alcohol-mediated disruption. In Aim 1, we will test the hypothesis that intestines from HIV+ individuals have lower resilience to alcohol- mediated gut barrier disruption than intestines from HIV-negative controls. Blood, urine, stool, and intestinal biopsies will be collected from four groups: (i) HIV- AUD-; (ii) HIV- AUD+, (iii) HIV+ ART+ AUD-; and (iv) HIV+ ART+ AUD+. First, we will compare: (a) intestinal barrier integrity, (b) systemic and gut inflammation, immune activation, and oxidative stress, (c) microbiome and metabolome, and (d) HIV reservoirs. Second, we will generate Ileal/colonic organoids from the HIV- and HIV+ ART+ individuals and examine their resilience to alcohol-induced intestinal barrier disruption. In Aim 2, we will test the hypothesis that SCFA-promoting prebiotics induce the growth and/or activity of beneficial microorganisms that can enhance the resilience of the intestines of HIV+ individuals to alcohol-mediated disruption. We will provide 20 HIV+ ART+ (10 AUD- and 10 AUD+) individuals with commonly used prebiotics fructooligosaccharides (FOS) for 10 days. Stool/blood will be collected before/after the treatment. First, we will examine the impact of FOS on the microbiome, gut-related metabolites, and inflammation. Second, we will examine the impact of pre- and post-FOS microbiome/metabolome (filtered from stool) on the resilience of organoids to alcohol-mediated barrier disruption. The results of this study can build a foundation for: 1) identifying the mechanisms; and 2) designing strategies to prevent the development, of AUD-associated co-morbidities during ART+ HIV infection.