@article{2c93c9c07ccf4d45bcdd8af45b784c58,
title = "Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota",
abstract = "The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.",
author = "Hiroko Nagao-Kitamoto and Leslie, {Jhansi L.} and Sho Kitamoto and Chunsheng Jin and Thomsson, {Kristina A.} and Gillilland, {Merritt G.} and Peter Kuffa and Yoshiyuki Goto and Jenq, {Robert R.} and Chiharu Ishii and Akiyoshi Hirayama and Seekatz, {Anna M.} and Martens, {Eric C.} and Eaton, {Kathryn A.} and Kao, {John Y.} and Shinji Fukuda and Higgins, {Peter D.R.} and Karlsson, {Niclas G.} and Young, {Vincent B.} and Nobuhiko Kamada",
note = "Funding Information: Source data for all Figures and Extended Data Figures are provided with the paper. The microbiome data in this study are available at the NCBI Sequence Read Archive under BioProject PRJNA594915. The metabolome data are available at the NIH Common Fund{\textquoteright}s Data Repository and Coordinating Center website (supported by NIH grant, U01-DK097430), the Metabolomics Workbench (http://www.metabolomicsworkbench.org) where it has been assigned project ID PR000882 (anti-IL-22 antibody experiment in Fig. 2b and Extended Data Fig. 4), PR000881 (FMT experiment in Fig. 6f and Extended Data Fig. 9) and PR000869 (Phascolarctobacterium administration in Fig. 6i). Funding Information: The authors thank A. B. Shreiner for technical assistance, the University of Michigan Center for Gastrointestinal Research (DK034933), Host Microbiome Initiative, the GF Animal Facility and the Michigan Regional Comprehensive Metabolomics Resource Core (MRC2) (DK097153) for core services and I. L. Bergin from the In Vivo Animal Core at the University of Michigan Unit for Laboratory Animal Medicine for histological assessment. This work was supported by the National Institutes of Health (NIH) DK110146 and DK108901 (N.K.), Crohn{\textquoteright}s and Colitis Foundation of America (N.K and H.N.-K.), Young Investigator Grant from the Global Probiotics Council (N.K.), University of Michigan Center for Gastrointestinal Research (DK034933) (N.K.), Joint Usage/Research Program of Medical Mycology Research Center Chiba University 18-1 (N.K. and Y.G.), Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad (H.N.-K. and S.K.), the Uehara Memorial Foundation Postdoctoral Fellowship Award (S.K.), Clinical and Translational Science Awards Program (S.K.), Prevent Cancer Foundation (S.K.), Japan Society for the Promotion of Science KAKENHI grants 16H04901, 17H05654 and 18H04805 (S.F.), Japan Science and Technology Agency PRESTO grant JPMJPR1537 (S.F.), Japan Science and Technology Agency ERATO grant JPMJER1902 (S.F.), Advanced Research and Development Programs for Medical Innovation CREST program grant JP19gm1010009 (S.F.), the Takeda Science Foundation (S.F.) and the Food Science Institute Foundation (S.F.). MS analysis of glycans was performed by the Swedish Infrastructure for Biological Mass Spectrometry, supported by the Swedish Research Council. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = apr,
day = "1",
doi = "10.1038/s41591-020-0764-0",
language = "English",
volume = "26",
pages = "608--617",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",
}
