title: Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism.
abstract: Mercaptopurine (MP) and pro-drug azathioprine are 'first-line' oral therapies for maintaining remission in IBD. It is believed that their pharmacodynamic action is due to a slow cumulative decrease in activated lymphocytes homing to inflamed gut. We examined the role of host metabolism, lymphocytes and microbiome for the amelioration of colitis by the related thioguanine (TG).
  
  
  
  C57Bl/6 mice with or without specific genes altered to elucidate mechanisms responsible for TG's actions were treated daily with oral or intrarectal TG, MP or water. Disease activity was scored daily. At sacrifice, colonic histology, cytokine message, caecal luminal and mucosal microbiomes were analysed.
  
  
  
  Oral and intrarectal TG but not MP rapidly ameliorated spontaneous chronic colitis in Winnie mice (point mutation in Muc2 secretory mucin). TG ameliorated dextran sodium sulfate-induced chronic colitis in wild-type (WT) mice and in mice lacking T and B lymphocytes. Remarkably, colitis improved without immunosuppressive effects in the absence of host hypoxanthine (guanine) phosphoribosyltransferase (Hprt)-mediated conversion of TG to active drug, the thioguanine nucleotides (TGN). Colonic bacteria converted TG and less so MP to TGN, consistent with intestinal bacterial conversion of TG to so reduce inflammation in the mice lacking host Hprt. TG rapidly induced autophagic flux in epithelial, macrophage and WT but not Hprt-/-fibroblast cell lines and augmented epithelial intracellular bacterial killing.
  
  
  
  Treatment by TG is not necessarily dependent on the adaptive immune system. TG is a more efficacious treatment than MP in Winnie spontaneous colitis. Rapid local bacterial conversion of TG correlated with decreased intestinal inflammation and immune activation.
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Oancea
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.|School of Pharmacy, Griffith University, Brisbane, Queensland, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Movva
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Das
authors.affiliation: Division of Livestock Industries, CSIRO Preventative Health National Research Flagship, Brisbane, Queensland, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Aguirre de Cárcer
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Schreiber
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Purdon
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Harrington
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Proctor
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Inflammatory Diseases Biology & Therapeutics Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Lobb
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Lourie
authors.affiliation: Translational Research Institute, Woolloongabba, Queensland, Australia.|Diamantina Institute-University of Queensland, Brisbane, Queensland, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Ó Cuív
authors.affiliation: Division of Livestock Industries, CSIRO Preventative Health National Research Flagship, Brisbane, Queensland, Australia.|Inflammatory Diseases Biology & Therapeutics Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Duley
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.|School of Medicine-University of Queensland, St Lucia, Queensland, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Begun
authors.affiliation: Immunity Infection and Inflammation Program, Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.|Translational Research Institute, Woolloongabba, Queensland, Australia.|School of Medicine-University of Queensland, St Lucia, Queensland, Australia.
authors.forename: T H J
authors.initials: TH
authors.lastname: Florin
mesh_terms: D000284:Administration, Oral; D000285:Administration, Rectal; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000070077:Bacteroides thetaiotaomicron / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000382:microbiology; D016207:Cytokines / Q000235:genetics; D016264:Dextran Sulfate; D013293:Enterococcus faecalis / Q000378:metabolism; D004847:Epithelial Cells; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D054884:Host-Pathogen Interactions; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000382:microbiology*; D008264:Macrophages; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055262:Mucin-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013866:Thioguanine / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; C524626:Muc2 protein, mouse; D055262:Mucin-2; D012333:RNA, Messenger; D016264:Dextran Sulfate; D015122:Mercaptopurine; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine
keywords: AZATHIOPRINE; COLONIC BACTERIA; DRUG METABOLISM; IBD MODELS