Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine

Abstract

Endogenous circadian clocks regulate 24-h rhythms of physiology and behavior. Circadian rhythm disruption (CRD) is suggested as a risk factor for inflammatory bowel disease. However, the underlying molecular mechanisms remain unknown. Intestinal biopsies from Per1/2 mutant and wild-type (WT) mice were investigated by electron microscopy, immunohistochemistry, and bromodeoxyuridine pulse-chase experiments. TNF-α was injected intraperitoneally, with or without necrostatin-1, into Per1/2 mice or rhythmic and externally desynchronized WT mice to study intestinal epithelial cell death. Experimental chronic colitis was induced by oral administration of dextran sodium sulfate. , caspase activity was assayed in Per1/2-specific small interfering RNA-transfected cells. was overexpressed to study antiapoptosis and the cell cycle. Genetic ablation of circadian clock function or environmental CRD in mice increased susceptibility to severe intestinal inflammation and epithelial dysregulation, accompanied by excessive necroptotic cell death and a reduced number of secretory epithelial cells. Receptor-interacting serine/threonine-protein kinase (RIP)-3-mediated intestinal necroptosis was linked to increased mitotic cell cycle arrest Per1/2-controlled Wee1, resulting in increased antiapoptosis cellular inhibitor of apoptosis-2. Together, our data suggest that circadian rhythm stability is pivotal for the maintenance of mucosal barrier function. CRD increases intestinal necroptosis, thus rendering the gut epithelium more susceptible to inflammatory processes.-Pagel, R., Bär, F., Schröder, T., Sünderhauf, A., Künstner, A., Ibrahim, S. M., Autenrieth, S. E., Kalies, K., König, P., Tsang, A. H., Bettenworth, D., Divanovic, S., Lehnert, H., Fellermann, K., Oster, H., Derer, S., Sina, C. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine.

Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats

“…Circadian disruption has been reported to dysregulate inflammatory responses (Castanon-Cervantes et al 2011), impair tissue homeostasis and exacerbate chronic inflammation, such as in the intestine (Pagel et al 2017). However, little is known about circadian disruption in chronic LPS-induced neuroinflammation.…”

Effects of Psychological, Environmental and Physical Stressors on the Gut Microbiota

“…Within the GI tract, variable feeding schedules and diet composition have been shown to disrupt circadian rhythms as well ( Asher and Sassone-Corsi, 2015 ). The health effects of circadian disruption are increasingly recognized, and include both short and long term health decrements such as increased GI permeability ( Summa et al, 2013 ; Voigt et al, 2016b ), altered immune responses ( Curtis et al, 2014 ), increased susceptibility to inflammation and GI epithelium damage ( Pagel et al, 2017 ), and multiple chronic inflammation-associated diseases including irritable bowel syndrome and inflammatory bowel disease ( Hoogerwerf, 2009 ; Voigt et al, 2016a ; James et al, 2017 ). Increasingly, evidence suggests that these effects may be mediated in part by the gut microbiota.…”

Reserve Stem Cells in Intestinal Homeostasis and Injury

“…The ability of putative quiescent þ4 ISC to convert to and from aISCs suggests that each population of ISCs can sense and adapt to fluctuations in physiologic demand for stem cell activity 58 ( Figure 1B, Figure 2). Such fluctuations might occur during homeostatic conditions such as during periods of nutrient deprivation or during circadian cycles, [59][60][61] or alternatively under conditions of extreme injury and stress. The concept that þ4 ISCs are dedicated to the reserve function of replacing lost or compromised aISCs to support epithelial regeneration is of great interest.…”