title: Enhancement of Microbiota in Healthy Macaques Results in Beneficial Modulation of Mucosal and Systemic Immune Function.
abstract: Given the critical role of mucosal surfaces in susceptibility to infection, it is imperative that effective mucosal responses are induced when developing efficacious vaccines and prevention strategies for infection. Modulating the microbiota in the gastrointestinal (GI) tract through the use of probiotics (PBio) is a safe and well-tolerated approach to enhance mucosal and overall health. We assessed the longitudinal impact of daily treatment with the VSL#3 probiotic on cellular and humoral immunity and inflammation in healthy macaques. PBio therapy resulted in significantly increased frequencies of B cells expressing IgA in the colon and lymph node (LN), likely because of significantly increased LN T follicular helper cell frequencies and LN follicles. Increased frequencies of IL-23(+) APCs in the colon were found post-PBio treatment, which correlated with LN T follicular helper cells. Finally, VSL#3 significantly downmodulated the response of TLR2-, TLR3-, TLR4-, and TLR9-expressing HEK293 cells to stimulation with Pam3CSK4, polyinosinic-polycytidylic acid, LPS, and ODN2006, respectively. These data provide a mechanism for the beneficial impact of PBio on mucosal health and implicates the use of PBio therapy in the context of vaccination or preventative approaches to enhance protection from mucosal infection by improving immune defenses at the mucosal portal of entry.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98121; Washington National Primate Research Center, Seattle, WA 98121;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Manuzak
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98121; Washington National Primate Research Center, Seattle, WA 98121;
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hensley-McBain
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98121; Washington National Primate Research Center, Seattle, WA 98121;
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Zevin
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98121; Washington National Primate Research Center, Seattle, WA 98121;
authors.forename: Charlene
authors.initials: C
authors.lastname: Miller
authors.affiliation: Genentech, South San Francisco, CA 94080;
authors.forename: Rafael
authors.initials: R
authors.lastname: Cubas
authors.affiliation: Washington National Primate Research Center, Seattle, WA 98121;
authors.forename: Brian
authors.initials: B
authors.lastname: Agricola
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98121; Washington National Primate Research Center, Seattle, WA 98121;
authors.forename: Jill
authors.initials: J
authors.lastname: Gile
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98121; Washington National Primate Research Center, Seattle, WA 98121;
authors.forename: Laura
authors.initials: L
authors.lastname: Richert-Spuhler
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98121;
authors.forename: Gabriela
authors.identifier: http://orcid.org/0000-0002-5795-0547
authors.initials: G
authors.lastname: Patilea
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195;
authors.forename: Stanley
authors.identifier: http://orcid.org/0000-0002-6833-271X
authors.initials: S
authors.lastname: Langevin
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; and.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Reeves
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Drexel University, Philadelphia, PA 19104.
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98121; Washington National Primate Research Center, Seattle, WA 98121; klattnr@uw.edu.
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Klatt
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003106:Colon / Q000276:immunology / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000276:immunology; D006801:Humans; D007109:Immunity; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D053759:Interleukin-23 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008251:Macaca; D064307:Microbiota; D009092:Mucous Membrane / Q000276:immunology* / Q000382:microbiology*; D019936:Probiotics / Q000008:administration & dosage; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D053759:Interleukin-23; D051193:Toll-Like Receptors
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