title: Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature.
abstract: Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.
authors.forename: Yael
authors.initials: Y
authors.lastname: Haberman
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Tickle
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Dexheimer
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Dora
authors.initials: D
authors.lastname: Tang
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.forename: Robert N
authors.initials: RN
authors.lastname: Baldassano
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Noe
authors.forename: Joel
authors.initials: J
authors.lastname: Rosh
authors.forename: James
authors.initials: J
authors.lastname: Markowitz
authors.forename: Melvin B
authors.initials: MB
authors.lastname: Heyman
authors.forename: Anne M
authors.initials: AM
authors.lastname: Griffiths
authors.forename: Wallace V
authors.initials: WV
authors.lastname: Crandall
authors.forename: David R
authors.initials: DR
authors.lastname: Mack
authors.forename: Susan S
authors.initials: SS
authors.lastname: Baker
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.forename: David J
authors.initials: DJ
authors.lastname: Keljo
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Hyams
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Walters
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Dirk
authors.initials: D
authors.lastname: Gevers
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
mesh_terms: D000293:Adolescent; D016632:Apolipoprotein A-I / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics / Q000382:microbiology; D003424:Crohn Disease / Q000235:genetics* / Q000382:microbiology*; D000074623:Dual Oxidases; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007082:Ileum / Q000378:metabolism* / Q000382:microbiology*; D008297:Male; D064307:Microbiota; D019255:NADPH Oxidases / Q000235:genetics*; D020560:Proteobacteria / Q000302:isolation & purification; D059467:Transcriptome
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human