Despite antiretroviral therapy (ART), a substantial number of HIV-infected individuals exhibit chronic systemic inflammation. Chronic inflammation is a major driver of HIV disease progression, excess morbidity (e.g. cardiovascular disease, accelerated liver disease) and mortality. Therefore, addressing persistent inflammation remains a major goal in restoring health of HIV-infected individuals. Our group reported that untreated and many treated HIV-infected individuals exhibit marked alterations in the gut microbiome compared with uninfected individuals, and the degree of dysbiosis correlates positively and strongly with peripheral blood markers of inflammation such as IL-6 and the ratio of kynurenine to tryptophan. Moreover, the bacterial communities overrepresented in HIV-infected individual are more likely to harbor the enzymatic pathway that catabolize tryptophan to kynurenine, a metabolite associated with HIV disease progression and suppresses T cell proliferation, in particular Th17 and Th22 cells, cells important in maintaining the mucosal barrier. Since fecal microbiome transplant (FMT) has been remarkably effective in reconstituting dysbiotic gut microbial communities as highlighted by its efficacy in treating patients with recurrent Clostridium difficile infection, the specific aims of this proposal are to manipulate the gut microbiome in ART treated HIV-infected individuals who are likely to harbor microbial dysbiosis and persistent inflammation by preferentially selecting participants with low CD4 or CD4:CD8 ratio less than one and elevated inflammatory biomarkers. In this study, we will determine the stability of the existing microbiome and use FMT 1) to determine engraftment and durability of the donor microbiome and its safety and 2) to examine whether this intervention can normalize systemic inflammatory markers and mucosal immunity. Stool and mucosal samples will enable high-resolution microbiome profiling, peripheral and gut mononuclear cells for immunophenotyping by flow cytometry, and plasma for assays of inflammatory biomarkers. In addition, asymptomatic HIV-infected ART suppressed individuals undergoing routine screening colonoscopy will be recruited to examine the effects of bowel cleansing on the microbial profile. Should this exploratory study reveal beneficial and sustained effects of microbiome modulation on host immunity and systemic inflammation, FMT or a consortium of bioactive organisms that can reconstitute the microbiome may provide benefit to individuals who exhibit excessive inflammation.
This exploratory study reconstituting the microbiome is relevant to public health for several reasons. First, it would provide proof-of-concept evidence for a gut microbiome that contributes to systemic inflammation. Second, the study may demonstrate that the gut microbiome can be altered such that inflammation can be sustainably reduced, which is a broad goal in restoring health of all individuals.
|Vujkovic-Cvijin, Ivan; Rutishauser, Rachel L; Pao, Montha et al. (2017) Limited engraftment of donor microbiome via one-time fecal microbial transplantation in treated HIV-infected individuals. Gut Microbes 8:440-450|
|Lynch, Susan V; Boushey, Homer A (2016) The microbiome and development of allergic disease. Curr Opin Allergy Clin Immunol 16:165-71|