Fiber- and acetate-mediated modulation of MHC-II expression on intestinal epithelium protects from Clostridioides difficile infection

Cell Host Microbe. 2025 Feb 12;33(2):235-251.e7. doi: 10.1016/j.chom.2024.12.017. Epub 2025 Jan 17.

Abstract

Here, we explore the relationship between dietary fibers, colonic epithelium major histocompatibility complex class II (MHC-II) expression, and immune cell interactions in regulating susceptibility to Clostridioides difficile infection (CDI). We find that a low-fiber diet increases MHC-II expression in the colonic epithelium, which, in turn, worsens CDI by promoting the development of pathogenic CD4+ intraepithelial lymphocytes (IELs). The influence of dietary fibers on MHC-II expression is mediated by its metabolic product, acetate, and its receptor, free fatty acid receptor 2 (FFAR2). While acetate activation of FFAR2 on epithelial cells helps resist CDI, it does not directly regulate MHC-II expression. Instead, MHC-II is regulated by FFAR2 in type 3 innate lymphoid cells (ILC3s). Acetate enhances interleukin-22 (IL-22) production by ILC3s, which then suppresses MHC-II expression on the colonic epithelium. In conclusion, a low-fiber diet reduces acetate-induced IL-22 production by ILC3s, leading to increased MHC-II on the colonic epithelium. This change affects recovery from CDI by expanding the population of pathogenic CD4+ IELs.

Keywords: Clostridioides difficile; MHC-II; diet; fibers; group 3 innate lymphoid cells; gut microbiota; interleukin-22; intestinal epithelial cells; intraepithelial lymphocytes; short-chain fatty acids.

MeSH terms

  • Acetates* / metabolism
  • Acetates* / pharmacology
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Clostridioides difficile* / immunology
  • Clostridium Infections* / immunology
  • Clostridium Infections* / prevention & control
  • Colon / immunology
  • Colon / microbiology
  • Dietary Fiber* / administration & dosage
  • Dietary Fiber* / metabolism
  • Epithelial Cells
  • Histocompatibility Antigens Class II* / genetics
  • Histocompatibility Antigens Class II* / metabolism
  • Humans
  • Interleukin-22
  • Interleukins / metabolism
  • Intestinal Mucosa* / drug effects
  • Intestinal Mucosa* / immunology
  • Intestinal Mucosa* / metabolism
  • Intestinal Mucosa* / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Receptors, G-Protein-Coupled / metabolism

Substances

  • Dietary Fiber
  • Acetates
  • Receptors, G-Protein-Coupled
  • Histocompatibility Antigens Class II
  • Interleukins
  • Interleukin-22
  • Ffar2 protein, mouse