Sleep Deprivation Impairs Intestinal Mucosal Barrier by Activating Endoplasmic Reticulum Stress in Goblet Cells

Sleep deficiency is frequently associated with intestinal inflammatory conditions and has been increasingly recognized as a public health concern worldwide. However, the effects of sleep deficiency on intestinal goblet cells (GCs), which play a major role in intestinal barrier formation, remain elusive. Herein, we determined the effects of sleep deprivation on intestinal GCs using a sleep-deprivation mouse model. Sleep deprivation impaired the intestinal mucosal barrier and decreased the expression of tight junction proteins. According to single-cell RNA sequencing and histological assessments, sleep deprivation significantly reduced GC numbers and Mucin protein levels in intestinal tissues. Furthermore, sleep deprivation initiated endoplasmic reticulum stress by activating transcription factor 6 (ATF6) and binding immunoglobulin protein (BIP). Treatment with melatonin (MT), an endoplasmic reticulum stress regulator, significantly alleviated endoplasmic reticulum stress responses in intestinal GCs. In addition, MT increased the villus length, reduced the crypt depth, and restored intestinal barrier function in mice with sleep deprivation. Overall, our findings revealed that sleep deprivation could impair intestinal mucosal barrier integrity and GC function. Targeting endoplasmic reticulum stress could represent an ideal strategy for treating sleep deficiency-induced gastrointestinal disorders.

goblet cells; gut barrier; melatonin; single-cell RNA sequencing; sleep deprivation.