Bidirectional Regulation of Circadian Disturbance and Inflammation in Inflammatory Bowel Disease

Sep 14, 2017Inflammatory bowel diseases

How Body Clock Disruptions and Inflammation Affect Each Other in Inflammatory Bowel Disease

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Circadian gene expression levels were significantly reduced in patients with inflammatory bowel disease (IBD), especially among those with ulcerative colitis.

Nearly all circadian genes in intestinal biopsies and peripheral blood mononuclear cells of IBD patients were lower compared to healthy controls.
Circadian gene levels in biopsy tissues negatively correlated with disease activity scores in Crohn's disease.
Circadian genes in peripheral blood mononuclear cells were associated with markers of inflammation, such as erythrocyte sedimentation rate and C-reactive protein levels.
Inflammation induced by specific agents led to notable alterations in circadian gene expression profiles.
A shift in circadian rhythm worsened colitis symptoms in mice, increasing proinflammatory cytokine levels and activating inflammatory pathways.

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BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

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Bidirectional Regulation of Circadian Disturbance and Inflammation in Inflammatory Bowel Disease

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