Weintraub Y¹, Cohen S¹, Chapnik N², Ben-Tov A¹, Yerushalmy-Feler A¹, Dotan I³, Tauman R⁴, Froy O⁵. Clin Gastroenterol Hepatol. 2019 Apr 10. pii: S1542-3565(19)30373-8. doi: 10.1016/j.cgh.2019.04.013. [Epub ahead of print]

Author information

1 Pediatric Gastroenterology Unit, Dana-Dwek Children's Hospital, Sourasky Tel-Aviv Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

2 Institute of Biochemistry, Food Science and Nutrition, the Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel.

3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.

4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Sleep Disorders Center, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.

5 Institute of Biochemistry, Food Science and Nutrition, the Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel. Electronic address: oren.froy@mail.huji.ac.il.

Abstract

BACKGROUND & AIMS: Sleep disruption modifies the immune system and can trigger flares of inflammatory bowel diseases (IBD). Changes in expression of clock genes have been reported in patients with IBD. We investigated whether a change in the circadian clock is an early event in development of IBD.

METHODS: We performed a prospective study of patients younger than 21 years old who underwent diagnostic endoscopies at the pediatric and adult gastroenterology units at the Tel Aviv Sourasky Medical Center from August 2016 through August 2017. Questionnaires were completed by 32 patients with IBD (8-21 years old) and 18 healthy individuals (controls) that provided data on demographics, sleep, disease activity scores. We also obtained data on endoscopic scores, anthropometric parameters, blood level of C-reactive protein (CRP), and fecal level of calprotectin. Peripheral blood and intestinal mucosa samples were analyzed for expression levels of clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1, and PER2).

RESULTS: Levels of CRP and fecal calprotectin were significantly higher in patients with IBD compared to controls (P<.05). Expression levels of clock genes (CLOCK, CRY1, CRY2, PER1, and PER2) were significantly lower in inflamed intestinal mucosa from patients compared to intestinal mucosa from controls (P<.05). Expression levels of all clock genes except for PER2, were also significantly lower in non-inflamed intestinal mucosal tissues from patients compared with controls (P<.05). Expression levels of clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) were lower in white blood cells from patients with IBD compared with controls. This reduction was greater in white blood cells from patients with ulcerative colitis than in patients with Crohn's disease.

CONCLUSION: Young, newly diagnosed, untreated patients with IBD have reduced expression of clock genes in inflamed and non-inflamed intestinal mucosal samples, and also in blood cells, compared to healthy individuals. Alterations in expression of clock genes might be an early event in IBD pathogenesis. ClinicalTrials.gov Identifier: NCT03662646.