Abstract
BackgroundPhysiological circadian rhythms (CRs) are complex processes with 24-hour oscillations that regulate diverse biological functions. Chronic weekly light/dark (LD) shifting (CR disruption; CRD) in mice results in colonic hyperpermeability. However, the mechanisms behind this phenomenon are incompletely understood. One potential innovative in vitro method to study colonic CRs are colon organoids. The goals of this study were to utilize circadian clock gene Per2 luciferase reporter (Per2::Luc) mice to measure the effects of chronic LD shifting on colonic tissue circadian rhythmicity ex vivo and to determine if organoids made from shifted mice colons recapitulate the in vivo phenotype.MethodsNon-shifted (NS) and shifted (S) BL6 Per2::Luc mice were compared after a 22-week experiment. NS mice had a standard 12h light/12h dark LD cycle throughout. S mice alternated 12h LD patterns weekly, with light from 6am-6pm one week followed by shifting light to 6pm-6am the next week for 22 weeks. Mice were tested for intestinal permeability while colon tissue and organoids were examined for CRs of bioluminescence and proteins of barrier function and cell fate.ResultsThere was no absolute difference in NS vs. S 24h circadian period or phase. However, chronic LD shifting caused Per2::Luc S mice colon tissue to exhibit significantly greater variability in both the period and phase of Per2::Luc rhythms than NS mice colon tissue and organoids. Chronic LD shifting also resulted in increased colonic permeability of the Per2::Luc mice as well as decreased protein markers of intestinal permeability in colonic tissue and organoids from shifted Per2:Luc mice.ConclusionsOur studies support a model in which chronic central circadian disruption by LD shifting alters the circadian phenotype of the colon tissue and results in colon leakiness and loss of colonic barrier function. These CRD-related changes are stably expressed in colon stem cell derived organoids from CRD mice.
Highlights
Physiological circadian rhythms are complex biological processes with 24-hour oscillations that regulate diverse bodily functions, including metabolism, regeneration, immunology, endocrinology, and behavior
Our studies support a model in which chronic central circadian disruption by LD shifting alters the circadian phenotype of the colon tissue and results in colon leakiness and loss of colonic barrier function
Disruption of normal circadian rhythm has been associated with many gastrointestinal (GI) pathologies including exacerbated irritable bowel disease (IBS), increased risk of colorectal cancer [9, 10], and GI complaints associated with jet lag [11]
Summary
Physiological circadian rhythms are complex biological processes with 24-hour oscillations that regulate diverse bodily functions, including metabolism, regeneration, immunology, endocrinology, and behavior. These rhythms are entrained to environmental cues like light/ dark (LD) cycles [1, 2] and are orchestrated by the central circadian clock as well as peripheral circadian machinery present in all human tissues [3,4,5]. Chronic environmental circadian disruption of mice through LD shifting for 22 weeks induces colonic hyperpermeability, or gut leakiness [14]. Physiological circadian rhythms (CRs) are complex processes with 24-hour oscillations that regulate diverse biological functions. The goals of this study were to utilize circadian clock gene Per luciferase reporter (Per2::Luc) mice to measure the effects of chronic LD shifting on colonic tissue circadian rhythmicity ex vivo and to determine if organoids made from shifted mice colons recapitulate the in vivo phenotype
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