Dysfunctional gut microbiota drives chronic immune activation in HIV-treated individuals

An altered interplay between gut mucosa and gut microbiota during treated HIV infection possibly contributes to increased bacterial translocation and chronic immune activation, which are predictors of morbidity and mortality. In a cohort of HIV-infected individuals on succesful antiretroviral therapy (ART) without comorbidities and in healthy controls we determined a number of systemic markers of innate and adaptive immunity. DNA was extracted from stool samples and amplicons of 16S rRNA and whole genome shot-gun sequences were analyzed, and the genus and pathways that characterized the microbiota of HIV-infected individuals were determined. HIV-infected subjects harbored a dysbiotic fecal microbiota, characterized by high levels of disease-associated bacteria, an increment of Gram-negative species and particularly by an abundance of Prevotella and Succinibivrio genera and a depletion of Bacteriodes and Faecalibaterium. This dysbiosis was related to an altered functional profile, including LPS biosynthesis –a source for systemic inflammation–, glutathione metabolism, –a bacterial mechanism to neutralize local oxidative stress–, and several inflammatory pathways. Using Bayesian network modeling, we determined that the dysbiotic bacterial community and the correlated altered metabolic pathways was associated with markers of immune dysfuntion, including impaired thymic output, heightened bactericidal-permeability increasing protein –a marker of bacterial translocation and a severe predictor of severe coronary atherosclerosis-, soluble CD14 –a marker of monocyte activation- and T-cell activation. Hence, the HIV-mediated breakdown of the gut mucosa is associated to a shift in the composition and function of gut microbiota that is not reverted by ART, even in subjects without comorbidities and optimal immunovirological response. This dysbiotic microbiota likely contributes to chronic innate and adaptive immune activation. Hence, strategies aimed at shaping the gut microbiota deserve further attention in the setting of treated HIV infection.