title: Escherichia coli heme oxygenase modulates host innate immune responses.
abstract: Induction of mammalian heme oxygenase (HO)-1 and exposure of animals to carbon monoxide (CO) ameliorates experimental colitis. When enteric bacteria, including Escherichia coli, are exposed to low iron conditions, they express an HO-like enzyme, chuS, and metabolize heme into iron, biliverdin and CO. Given the abundance of enteric bacteria residing in the intestinal lumen, our postulate was that commensal intestinal bacteria may be a significant source of CO and those that express chuS and other Ho-like molecules suppress inflammatory immune responses through release of CO. According to real-time PCR, exposure of mice to CO results in changes in enteric bacterial composition and increases E. coli 16S and chuS DNA. Moreover, the severity of experimental colitis correlates positively with E. coli chuS expression in IL-10 deficient mice. To explore functional roles, E. coli were genetically modified to overexpress chuS or the chuS gene was deleted. Co-culture of chuS-overexpressing E. coli with bone marrow-derived macrophages resulted in less IL-12p40 and greater IL-10 secretion than in wild-type or chuS-deficient E. coli. Mice infected with chuS-overexpressing E. coli have more hepatic CO and less serum IL-12 p40 than mice infected with chuS-deficient E. coli. Thus, CO alters the composition of the commensal intestinal microbiota and expands populations of E. coli that harbor the chuS gene. These bacteria are capable of attenuating innate immune responses through expression of chuS. Bacterial HO-like molecules and bacteria-derived CO may represent novel targets for therapeutic intervention in inflammatory conditions.
authors.affiliation: Department of Medicine and Center for GI Biology and Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.|Department of Gastroenterology and Liver Diseases, Tel Aviv Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel.
authors.forename: Nitsan
authors.initials: N
authors.lastname: Maharshak
authors.affiliation: Department of Medicine and Center for GI Biology and Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.
authors.forename: Hyungjin Sally
authors.initials: HS
authors.lastname: Ryu
authors.affiliation: Department of Medicine and Center for GI Biology and Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.
authors.forename: Ting-Jia
authors.initials: TJ
authors.lastname: Fan
authors.affiliation: Department of Medicine and Center for GI Biology and Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.|Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado, Aurora, CO and Denver VA Medical Center, Denver, Colorado, 80220.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Onyiah
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California, 94305.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schulz
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02115, USA.
authors.forename: Sherrie L
authors.initials: SL
authors.lastname: Otterbein
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California, 94305.
authors.forename: Ron
authors.initials: R
authors.lastname: Wong
authors.affiliation: Department of Medicine and Center for GI Biology and Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hansen
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California, 94305.
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.affiliation: Department of Medicine and Center for GI Biology and Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carroll
authors.affiliation: Department of Medicine and Center for GI Biology and Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.|Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Plevy
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004269:DNA, Bacterial / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D004926:Escherichia coli / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D057131:Immune Evasion; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D012336:RNA, Ribosomal, 16S / Q000235:genetics
chemical_list: D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D053762:Interleukin-12 Subunit p40; D012336:RNA, Ribosomal, 16S; D016753:Interleukin-10; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing)
keywords: carbon monoxide; chuS; enteric microbiota; heme oxygenase