Journal
NATURE MEDICINE
Volume 26, Issue 4, Pages 608-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-020-0764-0
Keywords
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Funding
- University of Michigan Center for Gastrointestinal Research [DK034933]
- Michigan Regional Comprehensive Metabolomics Resource Core (MRC2) [DK097153]
- National Institutes of Health (NIH) [DK110146, DK108901]
- Crohn's and Colitis Foundation of America
- Global Probiotics Council
- Joint Usage/Research Program of Medical Mycology Research Center Chiba University 18-1
- Japan Society for the Promotion of Science
- Uehara Memorial Foundation
- Clinical and Translational Science Awards Program
- Prevent Cancer Foundation
- Japan Society for the Promotion of Science KAKENHI grants [16H04901, 17H05654, 18H04805]
- Japan Science and Technology Agency PRESTO grant [JPMJPR1537]
- Japan Science and Technology Agency ERATO grant [JPMJER1902]
- Advanced Research and Development Programs for Medical Innovation CREST program grant [JP19gm1010009]
- Takeda Science Foundation
- Food Science Institute Foundation
- Swedish Research Council
- Grants-in-Aid for Scientific Research [16H04901, 18H04805, 17H05654] Funding Source: KAKEN
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In germ-free mice colonized with human microbiota, mucosal IL-22 signaling promotes the growth of succinate-consuming commensal bacteria via host mucus glycosylation, and transplantation of these bacteria limits Clostridioides difficile infection. 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.
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