Circadian dysregulation induces alterations of visceral sensitivity and the gut microbiota in Light/Dark phase shift mice

Abstract

BackgroundIt is well-established that several features of modern lifestyles, such as shift work, jet lag, and using electronics at night, disturb normal circadian rhythm and increase the risk of suffering from functional gastrointestinal disease. Although substantial evidence demonstrates that shift work is closely correlated with the symptoms of visceral hypersensitivity, few basic studies have revealed the mechanism of visceral hypersensitivity induced by circadian rhythm disturbance, especially light/dark phase shifts. Our study explored the mechanism underlying visceral hypersensitivity caused by light/dark phase shift in mice.MethodsA 6-h delay light/dark phase shift mice model was constructed. Visceral hypersensitivity was assessed by abdominal withdrawal reflex (AWR) score induced by colorectal distention (CRD) in vivo and contraction of colonic muscle strips induced by acetylcholine ex vivo. Intestinal permeability was evaluated by transepithelial resistance (TEER) and FD4 permeability. The expression of tight junction proteins was detected by western blotting and immunofluorescence staining. The gut microbiota was examined by 16S rDNA sequencing. Fecal microbiota transplantation (FMT) was performed to confirm the relationship between the light/dark phase shift, gut microbiota, and visceral hypersensitivity.ResultsWe found that light/dark phase shift increased visceral sensitivity and disrupted intestinal barrier function, caused low-grade intestinal inflammation. Moreover, we found decreased microbial species richness and diversity and a shift in microbial community with a decreased proportion of Firmicutes and an elevated abundance of Proteobacteria at the phylum level. Besides, after the light/dark phase shift, the microflora was significantly enriched in biosynthesizing tryptophan, steroid hormone, secondary metabolites, lipids, and lipopolysaccharides. Mice that underwent FMT from the light/dark phase shift mice model exhibited higher visceral hypersensitivity and worse barrier function. Dysbiosis induced by light/dark phase shift can be transmitted to the mice pretreated with antibiotics by FMT not only at the aspect of microbiota composition but also at the level of bacterial function.ConclusionCircadian rhythm disturbance induced by the light/dark phase shift produces visceral hypersensitivity similar to the pathophysiology of IBS through modulating the gut microbiota, which may disrupt intestinal barrier function or induce a low-degree gut inflammation.

Homeostatic crosstalk among gut microbiome, hypothalamic and hepatic circadian clock oscillations, immunity and metabolism in response to different light–dark cycles: A multiomics study

“…Circadian rhythm disruption can also lead to the loss of rhythmicity in intestinal Lactobacillus and circulating tryptophan metabolites, contributing to inflammatory diseases and dysregulation of gut integrity 102 . Another study demonstrated that circadian rhythm disturbance induced by LD cycle shifts could trigger visceral hypersensitivity resembling the pathophysiology of irritable bowel syndrome, mediated by GM alterations such as Firmicutes and Proteobacteria, as well as their metabolites like tryptophan and steroid hormones 103 . It is well‐known that circadian rhythms control the GM and its key metabolic outputs, including tryptophan metabolites, which collectively contribute to the maintenance of host immunity 104 .…”

“…102 Another study demonstrated that circadian rhythm disturbance induced by LD cycle shifts could trigger visceral hypersensitivity resembling the pathophysiology of irritable bowel syndrome, mediated by GM alterations such as Firmicutes and Proteobacteria, as well as their metabolites like tryptophan and steroid hormones. 103 It is well-known that circadian rhythms control the GM and its key metabolic outputs, including tryptophan metabolites, which collectively contribute to the maintenance of host immunity. 104 Our work further expanded upon the understanding of the intricate relationship between circadian rhythms and the GMliver-brain axis in response to different LD cycles.…”

The protective role of microbiota in the prevention of MPTP/P-induced Parkinson's disease by resveratrol

“…48 Currently, as it is possible to provide full-spectrum microbiota, FMT is thought to be an effective microbial therapy for diseases and a valid technique to evaluate the contribution of microbiota in attenuating diseases. 49 For example, FMT was performed to confirm the relationship between the light/dark phase shift, gut microbiota, and visceral hypersensitivity, 50 or to investigate the ame-liorating effect of phloretin on colitis through regulating microbiota. 51 FMT was also used to explore the mechanism between gut microbial dysbiosis and the pathogenesis of PD.…”

A Narrative Review of the Carcinogenic Effect of Night Shift and the Potential Protective Role of Melatonin

“…Disruption in circadian rhythm also may increase progression of already existing cancer. Rats with sarcoma have increased tumor growth when kept in the alternative light/dark cycle compared to the constant cycle [23]. A study by Bollati et al where they examined peripheral blood from male shift workers showed night shift potentially has induced DNA methylation defect including changes in Alu repetitive elements methylation and gene-specific methylation of inflammatory genes such as IFN-γ and TNF-α [24].…”

“…With increasing evidence of night-shift workers and their cancer risk, it is imperative to conduct this type of experiment. Since there is evidence in animals that artificial lights at night can increase cancer risk [2,23], it might be imperative to conduct studies examining artificial light at night with cancer risk in night-shift workers and if implementing devices such as blue lightblocking glasses may be beneficial [67].…”