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Abstract
Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Clock genes harmonize circadian rhythms by their periodic expression and regulate several physiological functions. However, the association between clock genes and GERD is still unknown. We investigated whether reflux esophagitis affects circadian variability of clock genes in the esophagus and other organs using a rat reflux esophagitis model. Reflux esophagitis was induced in 7-week-old male Wistar rats. Sham-operated rats were used as controls. Rats were killed at 09:00 (light period) and 21:00 (dark period) 3days (acute phase) and 21days (chronic phase) after induction of esophagitis. The expression levels of clock gene mRNAs such as Per1, Per2, Per3, Cry1, Cry2, Arntl, and Clock in the esophagus were investigated by qPCR. Arntl expression was examined in stomach, small intestine, colon, and liver tissues. Serum melatonin and IL-6 levels were measured by ELISA. Histological examination of reflux esophagitis mainly revealed epithelial defects with marked inflammatory cell infiltration in the acute phase and mucosal thickening with basal cell hyperplasia in the chronic phase. Circadian variability of clock genes, except Cry1, was present in the normal esophagus and was completely disrupted in reflux esophagitis during the acute phase. The circadian variability of Per2, Per3, and Arntl returned to normal, but disruption of Per1, Cry2, and Clock was present in the chronic phase. Disruption of circadian variability of Arntl was observed in the esophagus, as well as in the stomach, small intestine, and liver tissues in reflux esophagitis during the acute phase. There were no significant differences in serum melatonin and IL-6 levels between control and reflux esophagitis animals in both acute and chronic phases. Disruption to circadian variability of clock genes may play a role in the pathogenesis of GERD.
Highlights
Gastroesophageal reflux disease (GERD) is a common gastrointestinal (GI) disorder.GERD is caused by the abnormal reflux of the gastric contents, with reflux symptoms such as heartburn [1]
Disruption of circadian variability of Arntl was observed in the esophagus, as well as in the stomach, small intestine, and liver tissues in reflux esophagitis during the acute phase
There were no significant differences in serum melatonin and IL-6 levels between control and reflux esophagitis animals in both acute and chronic phases
Summary
Gastroesophageal reflux disease (GERD) is a common gastrointestinal (GI) disorder.GERD is caused by the abnormal reflux of the gastric contents, with reflux symptoms such as heartburn [1]. Gastroesophageal reflux disease (GERD) is a common gastrointestinal (GI) disorder. Several clinical studies reported that GERD is strongly associated with sleep disturbances [2,3,4,5]. Our previous animal study confirmed that rat reflux esophagitis is associated with an increase in wakefulness, accompanied by a reduction in non-rapid eye movement (NREM) sleep during light periods, an increase in sleep fragmentation, and more frequent stage transitions [6]. Clock genes induce circadian rhythm by their periodic expression and regulate several physiological functions [7,8,9]. Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Clock genes harmonize circadian rhythms by their periodic expression and regulate several physiological functions. We investigated whether reflux esophagitis affects circadian variability of clock genes in the esophagus and other organs using a rat reflux esophagitis model
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