BMAL1 Regulates the Daily Timing of Colitis

Abstract

Many physiological functions exhibit circadian rhythms: oscillations in biological processes that occur in a 24-hour period. These daily rhythms are maintained through a highly conserved molecular pacemaker known as the circadian clock. Circadian disruption has been proposed to cause increased risk of Inflammatory Bowel Disease (IBD) but the underlying mechanisms remain unclear. Patients with IBD experience chronic inflammation and impaired regeneration of intestinal epithelial cells. Previous animal-based studies have revealed that colitis models of IBD are more severe in mice without a circadian clock but the timing of colitis, and whether its inflammatory and regenerative processes have daily rhythms, remains poorly characterized. We tested circadian disruption using Bmal1-/- mutant mice that have a non-functional circadian clock and thus no circadian rhythms. Dextran Sulfate Sodium (DSS) was used to induce colitis. The disease activity of colitis was found to exhibit time-dependent variation in Bmal1+/+ control mice but is constant and elevated in Bmal1-/- mutants, who exhibit poor recovery. Histological analyses indicate worsened colitis severity in Bmal1-/- mutant colon, and colon infiltration of immune system cells shows a daily rhythm that is lost in the Bmal1-/- mutant. Similarly, epithelial proliferation in the colon has a daily rhythm in Bmal1+/+ controls but not in Bmal1-/- mutants. Our results support a critical role of a functional circadian clock in the colon which drives 24-hour rhythms in inflammation and healing, and whose disruption impairs colitis recovery. This indicates that weakening circadian rhythms not only worsens colitis, but delays healing and should be taken into account in the management of IBD. Recognition of this is important in the management of IBD patients required to do shift work.

Targeting the intestinal circadian clock by meal timing ameliorates gastrointestinal inflammation

“…This is in accordance with previous literature which showed that environmental circadian disruption in form of shift work as well as system-wide genetic clock dysfunction, e.g. in Per1/2 -/- , Rev- erbα -/- and Bmal1 -/- mice promotes the severity of DSS-induced colitis 47–49 . Similarly, recent literature indicated disruption of diurnal intestinal rhythmicity contributes to the DSS-induced colitis 50 .…”

Relationship between the Biological Clock and Inflammatory Bowel Disease

“…Bmal1 −/− mice showed a consistently high inflammation rate, whereas inflammatory activity in Bmal1 +/+ mice varied throughout the day. This suggests that clock-deprived animals are more susceptible to colitis damage and that disease activity varies throughout the day in mice with functioning clock rhythms [ 64 ]. DSS mice under jet lag had increased colitis damage compared to mice treated with DSS alone [ 69 ].…”

“…No changes in goblet cells or crypt abscess scores were found in Bmal1 -deficient colitis mice [ 68 ]. Nevertheless, Bmal1 −/− mutants showed significant morphological abnormalities and increased immune cell infiltration compared to wild-type colitis mice [ 64 ]. In addition to alterations in intestinal barrier cells, DSS-injured mice lacking the circadian transcription factor RORα showed a twofold increase in bacterial 16S rDNA in the mesenteric lymph node after 14 days, indicating increased intestinal barrier permeability [ 65 ].…”

Circadian clock-related genome-wide Mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

“…ARNTL participates in metabolic homeostasis including lipid, glucose, and cholesterol (42). ARNTL is essential for treating colitis, as demonstrated by a prior study that found the ARNTL-knockout mice model caused more severe colitis (43). Additionally, ARNTL is crucial for osteoarthritis chondrocyte growth and cartilage tissue integrity (44)(45)(46).…”