The expression of clock genes has been observed to be impaired in biopsies from patients with inflammatory bowel disease(IBD).Disruption of circadian rhythms,which occurs in shift workers,has been linked to an increas...The expression of clock genes has been observed to be impaired in biopsies from patients with inflammatory bowel disease(IBD).Disruption of circadian rhythms,which occurs in shift workers,has been linked to an increased risk of gastrointestinal diseases,including IBD.The peripheral circadian clock in intestinal epithelial cells(IECs)was previously shown to balance gastrointestinal homeostasis by regulating the microbiome.Here,we demonstrated that the intestinal clock is disrupted in an IBD-relevant mouse model(IL-10−/−).A lack of the intestinal clock gene(Bmal1)in intestinal epithelial cells(IECs)in a chemically and a novel genetically induced colitis model(DSS,Bmal1IEC−/−xIL-10−/−)promoted colitis and dramatically reduced survival rates.Germ-free Bmal1IEC−/−mice colonized with disease-associated microbiota from IL-10−/−mice exhibited increased inflammatory responses,highlighting the importance of the local intestinal clock for microbiota-induced IBD development.Targeting the intestinal clock directly by timed restricted feeding(RF)in IL-10−/−mice restored intestinal clock functions,including immune cell recruitment and microbial rhythmicity;improved inflammatory responses;dramatically enhanced survival rates and rescued the histopathological phenotype.In contrast,RF failed to improve IBD symptoms in Bmal1IEC−/−xIL-10−/−mice,demonstrating the significance of the intestinal clock in determining the beneficial effect of RF.Overall,we provide evidence that intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis.Enhancing intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate symptoms in IBD patients.展开更多
基金German Research Foundation(DFG,project KI 19581)European Crohn´s and Colitis Organisation(ECCO,grant 5280024)SK and DH received funding from the Deutsche Forschungsgemeinschaft Fund((DFG,German Research Foundation)-Projektnummer 395357507-SFB 1371).
文摘The expression of clock genes has been observed to be impaired in biopsies from patients with inflammatory bowel disease(IBD).Disruption of circadian rhythms,which occurs in shift workers,has been linked to an increased risk of gastrointestinal diseases,including IBD.The peripheral circadian clock in intestinal epithelial cells(IECs)was previously shown to balance gastrointestinal homeostasis by regulating the microbiome.Here,we demonstrated that the intestinal clock is disrupted in an IBD-relevant mouse model(IL-10−/−).A lack of the intestinal clock gene(Bmal1)in intestinal epithelial cells(IECs)in a chemically and a novel genetically induced colitis model(DSS,Bmal1IEC−/−xIL-10−/−)promoted colitis and dramatically reduced survival rates.Germ-free Bmal1IEC−/−mice colonized with disease-associated microbiota from IL-10−/−mice exhibited increased inflammatory responses,highlighting the importance of the local intestinal clock for microbiota-induced IBD development.Targeting the intestinal clock directly by timed restricted feeding(RF)in IL-10−/−mice restored intestinal clock functions,including immune cell recruitment and microbial rhythmicity;improved inflammatory responses;dramatically enhanced survival rates and rescued the histopathological phenotype.In contrast,RF failed to improve IBD symptoms in Bmal1IEC−/−xIL-10−/−mice,demonstrating the significance of the intestinal clock in determining the beneficial effect of RF.Overall,we provide evidence that intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis.Enhancing intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate symptoms in IBD patients.
