Clock gene disruption may contribute to inflammatory bowel disease (IBD), and medical therapy might improve both gene expression and disease activity, suggest the results of a first-in-kind study.
Expression levels of five clock genes were significantly lower in inflamed intestinal mucosa from young, newly diagnosed, untreated patients with IBD, compared with intestinal mucosa from controls (P less than .05), wrote Yael Weintraub, MD, of Sourasky Tel-Aviv (Israel) Medical Center and associates in Clinical Gastroenterology and Hepatology. Uninflamed intestinal mucosa and peripheral white blood cells from patients also had significantly less clock gene mRNA, compared with corresponding samples from controls (P less than .05), which suggests that circadian clock disruption factors into the pathogenesis of IBD, the investigators said.
Sleep disturbances and shift work are significant risk factors for IBD and for disease flare. This prospective, 32-participant study assessed sleep patterns and mRNA expression levels for six genes associated with the circadian clock. Validated questionnaires found no significant differences in sleep timing, duration, tendency to snore, and “morningness” versus “eveningness” between patients and controls. However, patients tended to go to bed later and to rise later on weeknights than did controls (P = .08 and .06, respectively). This difference was more pronounced in patients with ulcerative colitis, compared with those with Crohn’s disease, the researchers noted.
In an adjusted analysis, five clock genes (CLOCK, BMAL1, CRY1, CRY2, and PER1) showed 3- to 66-fold lower expression in samples of inflamed intestinal mucosa from patients, compared with intestinal mucosa from controls. Expression of a sixth clock gene (PER2) also was lower but did not reach statistical significance. “Interestingly, noninflamed tissue obtained from IBD patients showed a similar significant reduction in clock gene expression, except for PER2, which showed threefold induction (P less than .001) compared to controls,” the researchers said.
Clock genes were expressed at lower levels in peripheral white blood cells from patients versus controls, and this disparity correlated with higher fecal calprotectin (but not C-reactive protein) levels. “The reduction in clock gene expression was more pronounced in ulcerative colitis compared to Crohn’s disease patients,” the researchers noted. Patients with ulcerative colitis had significantly reduced expression of all six clock genes, compared with controls, whereas patients with Crohn’s disease only had significantly reduced expression of CLOCK.
All 14 patients in the study had newly diagnosed, treatment-naive, endoscopically confirmed IBD. Most were in their early to mid-teens, and eight had Crohn’s disease, five had ulcerative colitis, and one had unclassified IBD. Endoscopic severity was usually mild or moderate. The 18 controls had negative endoscopy and histopathology findings but otherwise resembled patients in terms of age, body mass index, and sex distribution. Both patients and controls were recruited from the same tertiary care center.
“Importantly, a follow-up of a cohort of the IBD patients treated with 5-aminosalicylic acid (5-ASA) or anti-tumor necrosis factor (anti-TNF) revealed that their clinical score improved as well as their clock gene expression,” the investigators wrote. They called for “further research, clarifying the association between the circadian clock and IBD at the genetic and molecular levels, as well as interventional studies investigating the effect of circadian alterations on IBD therapy and course.”
The researchers did not report external funding sources. They reported having no conflicts of interest.
SOURCE: Weintraub Y et al. Clin Gastroenterol Hepatol. 2019 April 10. doi: 10.1016/j.cgh.2019.04.013.