Circadian Rhythms and Melatonin Metabolism in Patients With Disorders of Gut-Brain Interactions

Abstract

Circadian rhythms are cyclic patterns of physiological, behavioural and molecular events that occur over a 24-h period. They are controlled by the suprachiasmatic nucleus (SCN), the brain's master pacemaker which governs peripheral clocks and melatonin release. While circadian systems are endogenous, there are external factors that synchronise the SCN to the ambient environment including light/dark cycles, fasting/fed state, temperature and physical activity. Circadian rhythms also provide internal temporal organisation which ensures that any internal changes that take place are centrally coordinated. Melatonin synchronises peripheral clocks to the external time and circadian rhythms are regulated by gene expression to control physiological function. Synchronisation of the circadian system with the external environment is vital for the health and survival of an organism and as circadian rhythms play a pivotal role in regulating GI physiology, disruption may lead to gastrointestinal (GI) dysfunction. Disorders of gut-brain interactions (DGBIs), also known as functional gastrointestinal disorders (FGIDs), are a group of diseases where patients experience reoccurring gastrointestinal symptoms which cannot be explained by obvious structural abnormalities and include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Food timing impacts on the production of melatonin and given the correlation between food intake and symptom onset reported by patients with DGBIs, chronodisruption may be a feature of these conditions. Recent advances in immunology implicate circadian rhythms in the regulation of immune responses, and DGBI patients report fatigue and disordered sleep, suggesting circadian disruption. Further, melatonin treatment has been demonstrated to improve symptom burden in IBS patients, however, the mechanisms underlying this efficacy are unclear. Given the influence of circadian rhythms on gastrointestinal physiology and the immune system, modulation of these rhythms may be a potential therapeutic option for reducing symptom burden in these patients.

Keywords: circadian rhythm; disorders of gut brain interaction; functional dyspepsia; functional gastrointestinal disorder; irritable bowel syndrome; melatonin.

FIGURE 1

Circadian gene transcription and translational feedback loop. CLOCK and BMAL1 genes heterodimerise and bind to the E-box element on PER, CRY, ROR, and REV-ERBA genes which activates transcription. CRY and PER gene products inhibit CLOCK and BMAL1 gene expression. REV-ERB inhibits the RORE element on BMAL1 genes and ROR activates it to increase BMAL1 gene expression. Adapted from Wang et al. (2014) International Journal of Molecular Sciences. Image created using Biorender.com.

FIGURE 2

The role of melatonin in the intestinal immune system. Melatonin is produced from the pineal gland, and it influences circadian rhythms and immune function. It is also secreted in the gut from enterochromaffin and immune cells where it regulates GIT motility, immunity and the microbiota. Adapted from Ma et al. (2020) Medicinal Research Reviews. Image created using Biorender.com.