The circadian clock, metabolism, and inflammation-the holy trinity of inflammatory bowel diseases

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are characterized by relapsing-remitting immune activation and inflammation within the gastrointestinal tract. The immune system activity displays diurnal variation, which is regulated by the circadian clock. This is achieved by modulating the number of circulating lymphocytes, antibody production, cytokine production, host- pathogen interactions, and the activation of innate and adaptive immunity around the circadian cycle. Indeed, intestinal biopsies and peripheral blood cells obtained from patients with active IBD demonstrated reduced circadian clock gene expression. Key clock regulatory proteins, such as retinoic acid receptor-related orphan receptors, REV-ERBs, peroxisome proliferator-activated receptors (PPARs), PPARγ transcriptional co-activator 1α, adenosine monophosphate-activated protein kinase and Sirtuin 1, have a dual function as they regulate clock gene expression as well as the expression of certain pro- and anti-inflammatory factors through the NF-κB signaling pathway. All the aforementioned clock regulatory proteins are also key regulators of metabolism. Thus, these factors form a complex triangular network that regulates the circadian clock, inflammation, and metabolism. Emerging data support the notion that clock disruption is associated with inflammation and aberrant metabolic regulation and that regulators of the circadian clock may play a role in inflammatory and metabolic processes. In this review, we will focus on the interrelations among the circadian clock, metabolism, and inflammation in IBD.