Bidirectional Regulation of Circadian Disturbance and Inflammation in Inflammatory Bowel Disease

Tight crosstalk between the circadian and immune systems has been reported in several inflammatory diseases. We hypothesized that circadian timekeeping was perturbed in inflammatory bowel disease (IBD), and that the bidirectional regulation of circadian disturbance and inflammation may be involved in the pathogenesis of IBD.

Patients with ulcerative colitis (51) and Crohn's disease (39) and 42 healthy controls were recruited and their circadian gene expression levels evaluated. Dextran sodium sulfate/2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse models, and lipopolysaccharide-stimulated macrophages, were examined to detect the influence of inflammation on circadian gene expression, both in vivo and in vitro. Light/dark shift and time-restricted feeding models were also used to evaluate the influence of circadian disturbance on a mouse colitis model.

We found that (1) almost all circadian genes were reduced in both intestinal biopsies and the peripheral blood mononuclear cells of patients with IBD, especially in patients with ulcerative colitis. Nearly all circadian genes of biopsy tissues showed negative correlations with a Mayo score or a simplified endoscopic activity score for Crohn's disease. Circadian genes of peripheral blood mononuclear cells correlated well with erythrocyte sedimentation rate and C-reactive protein levels in IBD. (2) Exposure to dextran sodium sulfate/2,4,6-trinitrobenzene sulfonic acid and lipopolysaccharide-induced marked changes in circadian gene expression profiles. (3) A phase shift exacerbated colitis in mice, with the increased secretion of proinflammatory cytokines and activation of inflammatory-related signaling pathways.

Our results suggested that inflammation and circadian genes showed complex bidirectional regulations that were relevant to IBD. Consequently, the circadian clock seems to be a potential target for IBD therapy.