title: Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients.
abstract: Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short-chain fatty acids (SCFAs), induce regulatory T cells (Tregs). We tested whether SCFAs contribute to poor TB control in a longitudinal cohort of ART-treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-γ and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M. tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes, such as Prevotella in the lung, and with M. tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may, therefore, increase TB susceptibility by suppressing IFN-γ and IL-17A production during the cellular immune response to M. tuberculosis.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, New York University, New York, NY 10016, USA.
authors.forename: Leopoldo N
authors.initials: LN
authors.lastname: Segal
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Clemente
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, New York University, New York, NY 10016, USA.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Metabolomics Core, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA.
authors.forename: Chunhai
authors.initials: C
authors.lastname: Ruan
authors.affiliation: Metabolomics Core, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Cao
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, New York University, New York, NY 10016, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Danckers
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Morris
authors.affiliation: Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tapyrik
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, New York University, New York, NY 10016, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Wu
authors.affiliation: Division of Pulmonary, Critical Care & Sleep Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Diaz
authors.affiliation: Division of Pulmonology, Department of Medicine & UCT Lung Institute, University of Cape Town, Cape Town 7925, South Africa.
authors.forename: Gregory
authors.initials: G
authors.lastname: Calligaro
authors.affiliation: Division of Pulmonology, Department of Medicine & UCT Lung Institute, University of Cape Town, Cape Town 7925, South Africa.
authors.forename: Rodney
authors.initials: R
authors.lastname: Dawson
authors.affiliation: Division of Pulmonology, Department of Medicine & UCT Lung Institute, University of Cape Town, Cape Town 7925, South Africa.
authors.forename: Richard N
authors.initials: RN
authors.lastname: van Zyl-Smit
authors.affiliation: Division of Pulmonology, Department of Medicine & UCT Lung Institute, University of Cape Town, Cape Town 7925, South Africa.
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, New York University, New York, NY 10016, USA.
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, New York University, New York, NY 10016, USA. Electronic address: michael.weiden@nyumc.org.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weiden
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D001421:Bacteria, Anaerobic / Q000254:growth & development / Q000378:metabolism*; D004198:Disease Susceptibility; D005232:Fatty Acids, Volatile / Q000097:blood* / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007155:Immunologic Factors / Q000097:blood* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008137:Longitudinal Studies; D008168:Lung / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D013019:South Africa; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000453:epidemiology / Q000276:immunology*
chemical_list: D044966:Anti-Retroviral Agents; D005232:Fatty Acids, Volatile; C508717:IL17A protein, human; D007155:Immunologic Factors; D020381:Interleukin-17; D007371:Interferon-gamma
keywords: FoxP1; FoxP3; HIV; dysbiosis; lung; short-chain fatty acids; tuberculosis