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 focus on circadian-oscillating SIEC MHCII, which is modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating SI barrier function. Disruption of this diurnally-regulated diet-microbiome-MHCII-IL10 axis by circadian clock disarrangement, dietary alterations, or epithelial-specific MHCII depletion leads to commensal-dependent impairment of SI barrier function and 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.