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

Timur Tuganbaev, Uria Mor, Stavros Bashiardes, Timur Liwinski, Samuel Philip Nobs, Avner Leshem, Mally Dori-Bachash, Christoph A. Thaiss, Elisha Y. Pinker, Karina Ratiner, Lorenz Adlung, Sara Federici, Christian Kleimeyer, Claudia Moresi, Takahiro Yamada, Yotam Cohen, Xiao Zhang, Hassan Massalha, Efi Massasa, Yael KupermanPandelakis A. Koni, Alon Harmelin, Nan Gao, Shalev Itzkovitz, Kenya Honda, Hagit Shapiro, Eran Elinav

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1441-1459.e21
JournalCell
Volume182
Issue number6
DOIs
Publication statusPublished - 2020 Sep 17

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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