title: Carbon monoxide and heme oxygenase-1 prevent intestinal inflammation in mice by promoting bacterial clearance.
abstract: OBJECTIVE
  Heme oxygenase-1 (HO-1) and its metabolic by-product, carbon monoxide (CO), protect against intestinal inflammation in experimental models of colitis, but little is known about their intestinal immune mechanisms. We investigated the interactions among CO, HO-1, and the enteric microbiota in mice and zebrafish.
  
  
  METHODS
  Germ-free, wild-type, and interleukin (Il)10(-/-) mice and germ-free zebrafish embryos were colonized with specific pathogen-free (SPF) microbiota. Germ-free or SPF-raised wild-type and Il10(-/-) mice were given intraperitoneal injections of cobalt(III) protoporphyrin IX chloride (CoPP), which up-regulates HO-1, the CO-releasing molecule Alfama-186, or saline (control). Colitis was induced in wild-type mice housed in SPF conditions by infection with Salmonella typhimurium.
  
  
  RESULTS
  In colons of germ-free, wild-type mice, SPF microbiota induced production of HO-1 via activation of nuclear factor erythroid 2-related factor 2-, IL-10-, and Toll-like receptor-dependent pathways; similar observations were made in zebrafish. SPF microbiota did not induce HO-1 in colons of germ-free Il10(-/-) mice. Administration of CoPP to Il10(-/-) mice before transition from germ-free to SPF conditions reduced their development of colitis. In Il10(-/-) mice, CO and CoPP reduced levels of enteric bacterial genomic DNA in mesenteric lymph nodes. In mice with S typhimurium-induced enterocolitis, CoPP reduced the numbers of live S typhimurium recovered from the lamina propria, mesenteric lymph nodes, spleen, and liver. Knockdown of HO-1 in mouse macrophages impaired their bactericidal activity against E coli, E faecalis, and S typhimurium, whereas exposure to CO or overexpression of HO-1 increased their bactericidal activity. HO-1 induction and CO increased acidification of phagolysosomes.
  
  
  CONCLUSIONS
  Colonic HO-1 prevents colonic inflammation in mice. HO-1 is induced by the enteric microbiota and its homeostatic function is mediated, in part, by promoting bactericidal activities of macrophages.
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Onyiah
authors.forename: Shehzad Z
authors.initials: SZ
authors.lastname: Sheikh
authors.forename: Nitsan
authors.initials: N
authors.lastname: Maharshak
authors.forename: Erin C
authors.initials: EC
authors.lastname: Steinbach
authors.forename: Steven M
authors.initials: SM
authors.lastname: Russo
authors.forename: Taku
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Lantz C
authors.initials: LC
authors.lastname: Mackey
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hansen
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Moeser
authors.forename: John F
authors.initials: JF
authors.lastname: Rawls
authors.forename: Luke B
authors.initials: LB
authors.lastname: Borst
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Scott E
authors.initials: SE
authors.lastname: Plevy
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000494:pharmacology*; D003092:Colitis / Q000188:drug therapy / Q000382:microbiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000472:pathogenicity; D005839:Gentamicins / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012486:Salmonella typhimurium / Q000502:physiology*
chemical_list: D005839:Gentamicins; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1