Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota

Nat Med. 2020 Apr;26(4):608-617. doi: 10.1038/s41591-020-0764-0. Epub 2020 Feb 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / drug effects
  • Bacteria / growth & development*
  • Bacteria / metabolism*
  • Clostridioides difficile / drug effects
  • Clostridioides difficile / immunology*
  • Clostridium Infections / immunology
  • Clostridium Infections / prevention & control*
  • Enterocolitis, Pseudomembranous / immunology
  • Enterocolitis, Pseudomembranous / metabolism
  • Enterocolitis, Pseudomembranous / microbiology
  • Enterocolitis, Pseudomembranous / prevention & control
  • Female
  • Gastrointestinal Microbiome / drug effects
  • Gastrointestinal Microbiome / physiology*
  • Glycosylation / drug effects
  • Host Microbial Interactions / drug effects
  • Host Microbial Interactions / genetics
  • Host Microbial Interactions / immunology
  • Humans
  • Interleukin-22
  • Interleukins / pharmacology
  • Interleukins / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Veillonellaceae / drug effects
  • Veillonellaceae / growth & development
  • Veillonellaceae / metabolism

Substances

  • Interleukins