Circadian rhythms and the gut microbiota: from the metabolic syndrome to cancer

Abstract

The metabolic syndrome is prevalent in developed nations and accounts for the largest burden of non-communicable diseases worldwide. The metabolic syndrome has direct effects on health and increases the risk of developing cancer. Lifestyle factors that are known to promote the metabolic syndrome generally cause pro-inflammatory alterations in microbiota communities in the intestine. Indeed, alterations to the structure and function of intestinal microbiota are sufficient to promote the metabolic syndrome, inflammation and cancer. Among the lifestyle factors that are associated with the metabolic syndrome, disruption of the circadian system, known as circadian dysrhythmia, is increasingly common. Disruption of the circadian system can alter microbiome communities and can perturb host metabolism, energy homeostasis and inflammatory pathways, which leads to the metabolic syndrome. This Perspective discusses the role of intestinal microbiota and microbial metabolites in mediating the effects of disruption of circadian rhythms on human health.

Fig. 1 |. The bidirectional bacteria–host relationship.

Host circadian rhythms influence intestinal microbiota structure and function, and microbial rhythms influence circadian rhythms in the digestive system; both systems being intact is key to maintaining host metabolic homeostasis. Modern lifestyle factors that lead to circadian rhythm disruption (for example, artificial light exposure at night, irregular sleep–wake cycles, eating late at night) interrupt this homeostasis by affecting the microbiota and the host circadian clock, shifting metabolism towards increased calorie extraction and decreased energy expenditure, providing an environment that promotes the metabolic syndrome (MetS), chronic inflammation and a number of malignancies.

Fig. 2 |. Microbiota signalling to the host circadian and metabolic systems occurs via both contact-dependent mechanisms and contact-independent mechanisms.

Pattern recognition receptors (PRRs) on intestinal epithelial cells and immune cells represent a contact-dependent signalling pathway where the activation of PRRs eventually leads to alterations in gene expression via nuclear receptors (such as nuclear factor, IL-3-regulated (NFIL3)), epigenetic alterations or other mechanisms (contact-dependent mechanism). Bacterial products (for example, metabolites) are responsible for contact-independent mechanisms; of these, bacterial fermentation of fibre and the production of short-chain fatty acids (SCFAs) regulate satiety and the function of metabolic organs (liver, pancreas and adipose tissue). FFARs, free fatty acid receptors; GLP1, glucagon-like peptide 1; MyD88, myeloid differentation primary response protein 88; NLRs, NOD-like receptors; PYY, peptide YY; TLRs,Toll-like receptors.