title: Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen.
abstract: Our intestinal microbiota harbors a diverse microbial community, often containing opportunistic bacteria with virulence potential. However, mutualistic host-microbial interactions prevent disease by opportunistic pathogens through poorly understood mechanisms. We show that the epithelial interleukin-22 receptor IL-22RA1 protects against lethal Citrobacter rodentium infection and chemical-induced colitis by promoting colonization resistance against an intestinal opportunistic bacterium, Enterococcus faecalis. Susceptibility of Il22ra1(-/-) mice to C. rodentium was associated with preferential expansion and epithelial translocation of pathogenic E. faecalis during severe microbial dysbiosis and was ameloriated with antibiotics active against E. faecalis. RNA sequencing analyses of primary colonic organoids showed that IL-22RA1 signaling promotes intestinal fucosylation via induction of the fucosyltransferase Fut2. Additionally, administration of fucosylated oligosaccharides to C. rodentium-challenged Il22ra1(-/-) mice attenuated infection and promoted E. faecalis colonization resistance by restoring the diversity of anaerobic commensal symbionts. These results support a model whereby IL-22RA1 enhances host-microbiota mutualism to limit detrimental overcolonization by opportunistic pathogens.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Tu Anh N
authors.initials: TA
authors.lastname: Pham
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: David
authors.initials: D
authors.lastname: Goulding
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Arasteh
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stares
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Hilary P
authors.initials: HP
authors.lastname: Browne
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Keane
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Page
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Natsuhiko
authors.initials: N
authors.lastname: Kumasaka
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Leanne
authors.initials: L
authors.lastname: Kane
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Lynda
authors.initials: L
authors.lastname: Mottram
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Harcourt
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Hale
authors.affiliation: Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gaffney
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK. Electronic address: tl2@sanger.ac.uk.
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Lawley
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D044082:Citrobacter rodentium / Q000276:immunology* / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000517:prevention & control*; D004198:Disease Susceptibility; D064806:Dysbiosis; D013293:Enterococcus faecalis / Q000276:immunology* / Q000502:physiology; D005647:Fucosyltransferases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D056265:Microbial Interactions; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D005647:Fucosyltransferases; D018123:Receptors, Interleukin; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C415369:interleukin-22 receptor