DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk.

Animals Dual Oxidases / genetics Female Gastrointestinal Microbiome / immunology Genetic Variation HEK293 Cells Homeostasis / genetics Humans Inflammatory Bowel Diseases / genetics Interleukin-17 / genetics Male Mice Mice, Knockout
Gastroenterology Genetic variation Inflammatory bowel disease Innate immunity

Journal

The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877

Informations de publication

Date de publication:
03 05 2021
Historique:
received: 26 06 2020
accepted: 25 02 2021
pubmed: 3 3 2021
medline: 6 10 2021
entrez: 2 3 2021
Statut: ppublish

Résumé

A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multiomic analyses using 2872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance. We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C, which is induced also in mucosal biopsies of patients with IBD. DUOX2-deficient mice replicated increased IL-17C induction in the intestine, with outlier high Il17c expression linked to the mucosal expansion of specific Proteobacteria pathobionts. Integrated microbiota/host gene expression analyses in patients with IBD corroborated IL-17C as a marker for epithelial activation by gram-negative bacteria. Finally, the impact of DUOX2 variants on IL-17C induction provided a rationale for variant stratification in case control studies that substantiated DUOX2 as an IBD risk gene. Thus, our study identifies an association of deleterious DUOX2 variants with a preclinical hallmark of disturbed microbiota-immune homeostasis that appears to precede the manifestation of IBD.

Identifiants

DOI: 10.1172/JCI141676 PMID: 33651715 PMC: PMC8087203
pubmed: 33651715
pii: 141676
doi: 10.1172/JCI141676
pmc: PMC8087203
doi:
pii:

Substances chimiques

IL17C protein, human 0
Il17c protein, mouse 0
Interleukin-17 0
Dual Oxidases EC 1.11.1.-
DUOX2 protein, human EC 1.6.3.1
Duox2 protein, mouse EC 1.6.3.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : BLRD VA
ID : I01 BX001245
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA210967
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK124779
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034933
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117565
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES017885
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002240
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK054221
Pays : United States

Commentaires et corrections

Type : CommentIn

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Auteurs

Helmut Grasberger (H)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Andrew T Magis (AT)

Institute for Systems Biology, Seattle, Washington, USA.
Arivale Inc., Seattle, Washington, USA.

Elisa Sheng (E)

Arivale Inc., Seattle, Washington, USA.

Matthew P Conomos (MP)

Arivale Inc., Seattle, Washington, USA.
Department of Biostatistics, University of Washington, Seattle, Washington, USA.

Min Zhang (M)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Lea S Garzotto (LS)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Guoqing Hou (G)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Shrinivas Bishu (S)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Hiroko Nagao-Kitamoto (H)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Mohamad El-Zaatari (M)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Sho Kitamoto (S)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Nobuhiko Kamada (N)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Ryan W Stidham (RW)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Yasutada Akiba (Y)

West Los Angeles VA Medical Center and Departments of Medicine and Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Jonathan Kaunitz (J)

West Los Angeles VA Medical Center and Departments of Medicine and Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Yael Haberman (Y)

Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Subra Kugathasan (S)

Departments of Pediatrics and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

Lee A Denson (LA)

Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Gilbert S Omenn (GS)

Departments of Computational Medicine & Bioinformatics, Internal Medicine, Human Genetics, and School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

John Y Kao (JY)

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › NADPH oxidase › Dual oxydases › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Environnement et santé publique › Environnement › Écosystème › Biodiversité › Biote › Microbiote › Microbiome gastro-intestinal › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Phénomènes génétiques › Variation génétique › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Cellules › Cellules épithéliales › Cellules HEK293 › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Phénomènes physiologiques › Homéostasie › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies inflammatoires intestinales › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-17 › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › DUOX2 variants associate with preclinical...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › DUOX2 variants associate with preclinical...