Disrupted Circadian Rest-Activity Cycles in Inflammatory Bowel Disease Are Associated With Aggressive Disease Phenotype, Subclinical Inflammation, and Dysbiosis

Abstract

Patients with inflammatory bowel disease (IBD)—Crohn's disease (CD), and ulcerative colitis (UC), have poor sleep quality. Sleep and multiple immunologic and gastrointestinal processes in the body are orchestrated by the circadian clock, and we recently reported that a later category or chronotype of the circadian clock was associated with worse IBD specific outcomes. The goal of this study was to determine if circadian misalignment by rest-activity cycles is associated with markers of aggressive disease, subclinical inflammation, and dysbiosis in IBD. A total of 42 patients with inactive but biopsy-proven CD or UC and 10 healthy controls participated in this prospective cohort study. Subjects were defined as having an aggressive IBD disease history (steroid dependence, use of biologic or immunomodulator, and/or surgery) or non-aggressive history. All participants did two weeks of wrist actigraphy, followed by measurement of intestinal permeability and stool microbiota. Wrist actigraphy was used to calculate circadian markers of rest-activity– interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA). Aggressive IBD history was associated with decrease rest-activity stability (IS) and increased fragmentation compared to non-aggressive IBD and health controls at 0.39 ±.15 vs. 0.51 ± 0.10 vs. 0.55 ± 0.09 (P < 0.05) and 0.83 ± 0.20 vs. 0.72 ± 0.14 (P < 0.05) but not HC at 0.72 ± 0.14 (P = 0.08); respectively. There was not a significant difference in RA by IBD disease history. Increased intestinal permeability and increased TNF-α levels correlated with an increased rest activity fragmentation (IV) at R = 0.35, P < 0.05 and R = 0.37, P < 0.05, respectively; and decreased rest-activity amplitude (RA) was associated with increased stool calprotectin at R = 0.40, P < 0.05. Analysis of intestinal microbiota showed a significant decrease in commensal butyrate producing taxa and increased pro-inflammatory bacteria with disrupted rest-activity cycles. In this study, different components of circadian misalignment by rest-activity cycles were associated with a more aggressive IBD disease history, increased intestinal permeability, stool calprotectin, increased pro-inflammatory cytokines, and dysbiosis. Wrist activity allows for an easy non-invasive assessment of circadian activity which may be an important biomarker of inflammation in IB.

Bilateral Uveitis in Silent Ulcerative Colitis: Case Report

“…Mucosal immune dysregulation has an important role in the alteration of the stomach's microbiota, as well as the disruption of the intestinal barrier function, which could drive the immune system to trigger a reaction to inflammatory processes. 12…”

“…11 Mucosal immune dysregulation has an important role in the alteration of the stomach's microbiota, as well as the disruption of the intestinal barrier function, which could drive the immune system to trigger a reaction to inflammatory processes. 12 As a result, there are unmet requirements to determine additional environmental factors which impact the subclinical inflammatory process of IBD. There are some coincidental examination findings which were incidentally identified in the period of or just before the asymptomatic IBD diagnosis and can facilitate early diagnosis, including extraintestinal manifestations of IBD, like inflammatory back pain, 13 chronic unexplained anemia, erythema nodosum, and venous thromboembolism, 14 which are also correlated to previously unrecognized IBD.…”

BMAL1/FOXA2-induced rhythmic fluctuations in IL-6 contribute to nocturnal asthma attacks

“…The dysregulation of the clock leads to dysregulated inflammation. Since inflammation can directly affect circadian rhythmicity, this constitutes a vicious cycle (44). We hope to use IL-6 as an example to provide research ideas for the study of circadian clock genes that regulate changes in airway inflammation.…”

Circadian immunity from bench to bedside: a practical guide

“…They also help to explain growing epidemiological evidence linking low circadian system robustness (usually judged by actigraphy or sleep fragmentation) to hospitalizations for a variety of ailments (92). For example, in inflammatory bowel disease circadian misalignment correlates with a more aggressive course of disease, increased intestinal permeability, elevated blood TNF-α, and elevated stool calprotectin levels, which are considered indicative of neutrophil migration and inflammation of the intestine (93). Conversely, clock gene expression is significantly reduced in patients with active ulcerative colitis compared with that in healthy controls and those in remission, suggesting that feedback regulation of intestinal circadian clocks might contribute to pathogenesis (94).…”