Fecal Microbiota Composition Drives Immune Activation in HIV-infected Individuals

• Published in: EBioMedicine 2018-04, Vol.30, p.192-202
• Main Authors: Neff, Charles Preston, Krueger, Owen, Xiong, Kathy, Arif, Sabrina, Nusbacher, Nichole, Schneider, Jennifer M., Cunningham, Annie W., Armstrong, Abigail, Li, Sam, McCarter, Martin D., Campbell, Thomas B., Lozupone, Catherine A., Palmer, Brent E.
• Format: Article
• Language: English
• Subjects: Bacteria - growth & development; Chronic inflammation; Colony Count, Microbial; Cytokines - metabolism; Fecal bacteria; Feces - microbiology; Female; HIV; HIV Infections - immunology; HIV Infections - microbiology; HIV-1 - physiology; Homosexuality, Male; Humans; Immune activation; Inflammation Mediators - metabolism; Lymphocyte Activation - immunology; Male; Microbiome; Microbiota; Principal Component Analysis; Research Paper; RNA, Ribosomal, 16S - genetics; T-Lymphocytes - immunology; TLR2; Toll-Like Receptors - metabolism; Tumor Necrosis Factor-alpha - metabolism; Viral Load
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2018.03.024

The inflammatory properties of the enteric microbiota of Human Immunodeficiency Virus (HIV)-infected individuals are of considerable interest because of strong evidence that bacterial translocation contributes to chronic immune activation and disease progression. Altered enteric microbiota composition occurs with HIV infection but whether altered microbiota composition or increased intestinal permeability alone drives peripheral immune activation is controversial. To comprehensively assess the inflammatory properties of HIV-associated enteric microbiota and relate these to systemic immune activation, we developed methods to purify whole fecal bacterial communities (FBCs) from stool for use in in vitro immune stimulation assays with human cells. We show that the enteric microbiota of untreated HIV-infected subjects induce significantly higher levels of activated monocytes and T cells compared to seronegative subjects. FBCs from anti-retroviral therapy (ART)-treated HIV-infected individuals induced intermediate T cell activation, indicating an only partial correction of adaptive immune cell activation capacity of the microbiome with ART. In vitro activation levels correlated with activation levels and viral load in blood and were particularly high in individuals harboring specific gram-positive opportunistic pathogens. Blockade experiments implicated Tumor Necrosis Factor (TNF)-α and Toll-Like Receptor-2 (TLR2), which recognizes peptidoglycan, as strong mediators of T cell activation; This may contradict a previous focus on lipopolysaccharide as a primary mediator of chronic immune activation. These data support that increased inflammatory properties of the enteric microbiota and not increased permeability alone drives chronic inflammation in HIV. •The fecal microbiomes of HIV positive subjects induce higher levels of activated monocytes and T cells in vitro.•Levels of induced activation in vitro correlate with activation levels and viral load in the blood.•HIV-associated microbiome immune activation is linked to the pathways involving the inflammatory cytokine TNF-α, and TLR-2. Chronic immune activation is a hallmark of HIV infection. Although many studies defined gut microbiome dysbiosis with HIV, we have little understanding of whether a pro-inflammatory microbiome underlies systemic immune activation. Here, we show that fecal microbiomes of individuals with HIV induce higher levels of activated monocytes and T cells in vitro, and these levels correlate w