Diet diurnally regulates SI microbiome-epithelial-immune homeostasis and enteritis

Throughout a 24-hour 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’s 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 MHCII, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream circadian activity of intra-epithelial IL-10+ lymphocytes regulating SI barrier function. Disruption of this diurnally-regulated diet-microbiome-MHCII-IL10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHCII depletion leads to an extensive microbial product influx, driving Crohn’s-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’s disease interventions.