Abstract |
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.
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Authors | Helmut Grasberger, Andrew T Magis, Elisa Sheng, Matthew P Conomos, Min Zhang, Lea S Garzotto, Guoqing Hou, Shrinivas Bishu, Hiroko Nagao-Kitamoto, Mohamad El-Zaatari, Sho Kitamoto, Nobuhiko Kamada, Ryan W Stidham, Yasutada Akiba, Jonathan Kaunitz, Yael Haberman, Subra Kugathasan, Lee A Denson, Gilbert S Omenn, John Y Kao |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 131
Issue 9
(05 03 2021)
ISSN: 1558-8238 [Electronic] United States |
PMID | 33651715
(Publication Type: 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.)
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Chemical References |
- IL17C protein, human
- Il17c protein, mouse
- Interleukin-17
- Dual Oxidases
- DUOX2 protein, human
- Duox2 protein, mouse
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Topics |
- Animals
- Dual Oxidases
(genetics, immunology)
- Female
- Gastrointestinal Microbiome
(immunology)
- Genetic Variation
- HEK293 Cells
- Homeostasis
(genetics, immunology)
- Humans
- Inflammatory Bowel Diseases
(genetics, immunology, microbiology)
- Interleukin-17
(genetics, immunology)
- Male
- Mice
- Mice, Knockout
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