title: Colitis susceptibility in p47(phox-/-) mice is mediated by the microbiome.
abstract: BACKGROUND
  Chronic granulomatous disease (CGD) is caused by defects in nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) complex subunits (gp91(phox) (a.k.a. Nox2), p47(phox), p67(phox), p22(phox), p40(phox)) leading to reduced phagocyte-derived reactive oxygen species production. Almost half of patients with CGD develop inflammatory bowel disease, and the involvement of the intestinal microbiome in relation to this predisposing immunodeficiency has not been explored.
  
  
  RESULTS
  Although CGD mice do not spontaneously develop colitis, we demonstrate that p47(phox-/-) mice have increased susceptibility to dextran sodium sulfate colitis in association with a distinct colonic transcript and microbiome signature. Neither restoring NOX2 reactive oxygen species production nor normalizing the microbiome using cohoused adult p47(phox-/-) with B6Tac (wild type) mice reversed this phenotype. However, breeding p47(phox+/-) mice and standardizing the microflora between littermate p47(phox-/-) and B6Tac mice from birth significantly reduced dextran sodium sulfate colitis susceptibility in p47(phox-/-) mice. We found similarly decreased colitis susceptibility in littermate p47(phox-/-) and B6Tac mice treated with Citrobacter rodentium.
  
  
  CONCLUSIONS
  Our findings suggest that the microbiome signature established at birth may play a bigger role than phagocyte-derived reactive oxygen species in mediating colitis susceptibility in CGD mice. These data further support bacteria-related disease in CGD colitis.
authors.affiliation: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. emilia.falcone@nih.gov.
authors.forename: E Liana
authors.identifier: http://orcid.org/0000-0002-5486-1549
authors.initials: EL
authors.lastname: Falcone
authors.affiliation: Oral Immunity and Inflammation Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Loreto
authors.initials: L
authors.lastname: Abusleme
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Muthulekha
authors.initials: M
authors.lastname: Swamydas
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
authors.affiliation: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.affiliation: Microbiology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Zelazny
authors.affiliation: Oral Immunity and Inflammation Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Niki M
authors.initials: NM
authors.lastname: Moutsopoulos
authors.affiliation: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Clay
authors.initials: C
authors.lastname: Deming
authors.affiliation: Bioinformatics and Computational Bioscience Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Quiñones
authors.affiliation: Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Segre
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Bryant
authors.affiliation: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D000328:Adult; D000818:Animals; D044082:Citrobacter rodentium / Q000472:pathogenicity / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D003433:Crosses, Genetic; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D015870:Gene Expression; D006105:Granulomatous Disease, Chronic / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D064307:Microbiota / Q000235:genetics*; D009249:NADP / Q000378:metabolism; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D009249:NADP; D016264:Dextran Sulfate; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: Chronic granulomatous disease; Colitis; Dextran sodium sulfate; Inflammatory bowel disease; Microbiome; NADPH; Reactive oxygen species; p47 phox