Diet Diurnally Regulates Small Intestinal Microbiome-Epithelial-Immune Homeostasis and Enteritis

Cell. 2020 Sep 17;182(6):1441-1459.e21. doi: 10.1016/j.cell.2020.08.027. Epub 2020 Sep 3.


Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.

Keywords: Crohn disease; HFD; IBD; IL-10; MHC class II; SFB; circadian clock; epithelial cell; high-fat diet; inflammatory bowel disease; interleukin-10; major histocompatibility complex; microbiome; segmented filamentous bacteria; small intestine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Circadian Clocks / physiology
  • Crohn Disease / immunology
  • Crohn Disease / metabolism
  • Crohn Disease / microbiology*
  • Diet
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism*
  • Flow Cytometry
  • Gastrointestinal Microbiome* / drug effects
  • Gastrointestinal Microbiome* / genetics
  • Gene Expression Profiling
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism*
  • Homeostasis
  • In Situ Hybridization, Fluorescence
  • Interleukin-10 / metabolism
  • Interleukin-10 / pharmacology
  • Intestine, Small / immunology*
  • Intestine, Small / microbiology*
  • Intestine, Small / physiology
  • Lymphocytes
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Periodicity
  • T-Lymphocytes / immunology
  • Transcriptome / genetics*
  • Transcriptome / physiology


  • Anti-Bacterial Agents
  • Histocompatibility Antigens Class II
  • IL10 protein, mouse
  • Interleukin-10