Abstract
Sleep deprivation (SD) is an epidemic phenomenon in modern countries, and its harmful effects are well known. SD acts as an aggravating factor in inflammatory bowel disease. Melatonin is a sleep-related neurohormone, also known to have antioxidant and anti-inflammatory effects in the gastrointestinal tract; however, the effects of melatonin on colitis have been poorly characterized. Thus, in this study, we assessed the measurable effects of SD on experimental colitis and the protective effects of melatonin. For this purpose, male imprinting control region (ICR) mice (n=24) were used; the mice were divided into 4 experimental groups as follows: the control, colitis, colitis with SD and colitis with SD and melatonin groups. Colitis was induced by the administration of 5% dextran sulfate sodium (DSS) in the drinking water for 6 days. The mice were sleep-deprived for 3 days. Changes in body weight, histological analyses of colon tissues and the expression levels of pro-inflammatory cytokines and genes were evaluated. SD aggravated inflammation and these effects were reversed by melatonin in the mice with colitis. In addition, weight loss in the mice with colitis with SD was significantly reduced by the injection of melatonin. Treatment with melatonin led to high survival rates in the mice, in spite of colitis with SD. The levels of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-17, interferon-γ and tumor necrosis factor-α, in the serum of mice were significantly increased by SD and reduced by melatonin treatment. The melatonin-treated group showed a histological improvement of inflammation. Upon gene analysis, the expression of the inflammatory genes, protein kinase Cζ (PKCζ) and calmodulin 3 (CALM3), was increased by SD, and the levels decreased following treatment with melatonin. The expression levels of the apoptosis-related inducible nitric oxide synthase (iNOS) and wingless-type MMTV integration site family, member 5A (Wnt5a) genes was decreased by SD, but increased following treatment with melatonin. Treatment with melatonin reduced weight loss and prolonged survival in mice with colitis with SD. Melatonin exerted systemic anti-inflammatory effects. Gene analysis revealed a possible mechanism of action of melatonin in inflammation and sleep disturbance. Thus, melatonin may be clinically applicable for patients with inflammatory bowel disease, particulary those suffering from sleep disturbances.
Highlights
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic recurrent inflammatory disorders of the gastrointestinal tract characterized by abdominal pain, chronic diarrhea and weight loss
Experimental colitis in the imprinting control region (ICR) mice was induced by the addition of 5% dextran sulfate sodium (DSS) to their drinking water for 6 days
There was a significant increase in the levels of IL-1β, IL-6, IL-17, tumor necrosis factor-α (TNF-α) and INF-γ in the plasma of the mice with colitis
Summary
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic recurrent inflammatory disorders of the gastrointestinal tract characterized by abdominal pain, chronic diarrhea and weight loss. Known environmental factors for IBD, such as smoking, exacerbate the diseases in individuals with genetic susceptibility [4]. Chronic stress is a well-known factor that increases the progression and recurrence of IBD, and decreased immunity, caused by stress, may affect individuals who are more susceptible to IBD [5]. A physiological stressor, has been clinically shown to aggravate IBD in patients [6]. Sleep disturbance affects symptoms in patients with IBD and can aggravate intestinal inflammation. Even patients with inactive IBD had more sleep disturbances, prolonged sleep latency, sleep fragmentation, were prone to use a greater amount of sleeping pills, had decreased activity during the day, increased fatigue and lower sleep quality compard with the healthy control group [8]
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