Sleep deprivation exacerbates experimental colitis via down-regulating the clock gene Per2.

Intestinal bowel disease (IBD), prevalent among sleep-deprived populations, is closely associated with circadian rhythm disruptions. Evidence suggests that sleep deprivation (SD) exacerbates colitis; however, the mechanisms remain poorly understood. We subjected mice with Dextran sulfate sodium (DSS) induced acute and chronic colitis to 6 h-SD per day. It was observed that mild SD significantly aggravated both acute and chronic colitis, involving progressive body weight loss, increased Disease Activity Index (DAI), shortened colon length, histopathological deterioration, and elevated levels of inflammatory cytokines. Circadian gene screening identified PER2 as a pivotal mediator in SD aggravating colitis. Both SD and colitis independently suppressed Per2 expression in mice colon. Notably, the inhibitory effect on PER2 was most pronounced in cases of colitis accompanied by SD. Consistent with this, Per2 deficiency heightened the susceptibility of mice to DSS-induced colitis. Furthermore, transcriptomic analysis revealed that the disordered arachidonic acid (AA) metabolism pathway was implicated in the exacerbation of colitis due to Per2 deficiency. Specifically, Ptgs2, a gene coding AA metabolism enzyme COX-2, was significantly upregulated in both Per2 colitis mice and SD colitis mice. The elevated PGE levels in plasma and colon supported the involvement of COX-2 mediated proinflammatory conversion of AA during episodes of SD-related colitis aggravation. Mechanistically, in vitro experiments in CT-26 cells suggested Per2 suppressed COX-2 transcription via BMAL1. In summary, SD inhibited the expression of clock factor PER2 in colon, leading to disorder of COX-2-mediated AA metabolism; this process released more pro-inflammatory mediators thereby aggravating colitis.