title: Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism.
abstract: Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART), and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan catabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to catabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection that is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease.
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California, San Francisco UCSF, San Francisco, CA 94110, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Vujkovic-Cvijin
authors.forename: Richard M
authors.initials: RM
authors.lastname: Dunham
authors.forename: Shoko
authors.initials: S
authors.lastname: Iwai
authors.forename: Michael C
authors.initials: MC
authors.lastname: Maher
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Albright
authors.forename: Mara J
authors.initials: MJ
authors.lastname: Broadhurst
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Hernandez
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Ma
authors.initials: M
authors.lastname: Somsouk
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.forename: Susan V
authors.initials: SV
authors.lastname: Lynch
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McCune
mesh_terms: D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D001419:Bacteria / Q000254:growth & development; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D018450:Disease Progression; D064806:Dysbiosis / Q000150:complications / Q000382:microbiology*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology* / Q000821:virology; D006801:Humans; D051379:Mice; D064307:Microbiota; D010802:Phylogeny; D014364:Tryptophan / Q000378:metabolism*; D014766:Viremia / Q000150:complications / Q000821:virology
chemical_list: D015415:Biomarkers; D014364:Tryptophan