Genetic disruption of the circadian gene Bmal1 in the intestinal epithelium reduces colonic inflammation.

Abstract

Disruption of the circadian clock is associated with the development of inflammatory bowel disease (IBD), but the underlying mechanisms remain unclear. Here, we observe that mice in the early active phase (Zeitgeber time 12, ZT12) of the circadian clock are more tolerant to dextran sodium sulfate (DSS)-induced colitis, compared to those in the early resting phase (ZT0). The expression of the circadian gene Bmal1 peaks in the early resting phase and declines in the early active phase. Bmal1 knockout in the intestinal epithelium reduces DSS-induced inflammatory symptoms. Mechanistically, BMAL1 promotes apoptosis by binding to apoptosis-related genes, including Bax, p53, and Bak1, and promotes their expression. Intriguingly, we observe circadian apoptotic rhythms in the homeostatic intestinal epithelium, while Bmal1 deletion reduces cell apoptosis. Consistently, reducing Bmal1 expression by the REV-ERBα agonist SR9009 has the best therapeutic efficacy against DSS-induced colitis at ZT0. Collectively, our data demonstrate that the Bmal1-centered circadian clock is involved in intestinal injury repair.