THE ROLE OF THE CLOCK GENE BMAL1 IN INFLAMMATORY BOWEL DISEASE

The circadian clock is a highly conserved molecular system that drives the oscillation of biological rhythms with a 24 hour period. Disruption of the circadian clock has been shown to cause an increased risk of Inflammatory Bowel Disease (IBD). Patients with IBD experience chronic inflammation along with impaired regeneration of intestinal epithelial cells. Inflammation and regeneration have been shown to be closely linked. Based on previous literature, we can hypothesize that disruption in the circadian clock leads to an increase in IBD severity. In this study, we compared the regenerative response of intestinal epithelial cells in BMAL1+/+ mice (with a functional clock) and BMAL1-/- mice (without a functional clock) who have been given IBD. Dextran Sulfate Sodium (DSS) was applied to induce acute colitis in mice, acting as an effective model for ulcerative colitis: one of the two categories of IBD. We observe a drastic decrease in the survival of mice lacking functional BMAL1 that were treated with 4% DSS over 7 days. Disease activity and cytokine analyses reveal time-dependent severity in inflammatory response that is worse in BMAL1-/- mice. To test the circadian rhythm of IBD, we performed a 24 hour analysis comparing epithelial cell proliferation, cell death, and inflammation in colon tissue. Our results indicate a significant rhythmic expression of mitosis throughout the day in BMAL1+/+ mice while mitosis in BMAL1-/- mice is arrhythmic and at lower levels. Based on these results, poor regeneration during IBD is in part attributed to decreased and arrhythmic regeneration. These data provides insight into how the core clock affects the inflammatory and regenerative abilities of intestinal epithelial cells.