Circadian Host-Microbiome Interactions in Immunity

Abstract

The gut microbiome plays a critical role in regulating host immunity and can no longer be regarded as a bystander in human health and disease. In recent years, circadian (24 h) oscillations have been identified in the composition of the microbiota, its biophysical localization within the intestinal tract and its metabolic outputs. The gut microbiome and its key metabolic outputs, such as short chain fatty acids and tryptophan metabolites contribute to maintenance of intestinal immunity by promoting barrier function, regulating the host mucosal immune system and maintaining the function of gut-associated immune cell populations. Loss of rhythmic host-microbiome interactions disrupts host immunity and increases risk of inflammation and metabolic complications. Here we review factors that drive circadian variation in the microbiome, including meal timing, dietary composition and host circadian clocks. We also consider how host-microbiome interactions impact the core molecular clock and its rhythmic outputs in addition to the potential impact of this relationship on circadian control of immunity.

Keywords: circadian; diurnal; immunity; microbiome; short chain fatty acids.

Figure 1

Metabolic outputs from the microbiome influence immunity. Bacteria within the gut breakdown substances derived from the diet. Emerging evidence demonstrates that production of a number of these metabolites is rhythmic, a consequence of feeding rhythms and rhythmic function of the microbiome. Many of these microbial metabolites (e.g. short chain fatty acids, tryptophan metabolites and bile acids) play a key role in immunity, contributing to: intestinal epithelial cell (IEC) function; maintenance of leukocyte populations such as regulatory T cells and macrophages and intestinal tolerance.

Figure 2

Interaction between the aryl hydrocarbon receptor (AhR) and the molecular clock. (A) In normal circadian clock function, CLOCK and BMAL heterodimerise and bind the E-box promotor, to transcribe Per1. (B) AhR shares sequence homology with CLOCK. Ligand-bound AhR heterodimerises with aryl hydrocarbon receptor nuclear translocator (ARNT) in the nucleus leading to transcription of enzyme superfamilies. (C) Ligand-bound AhR can also heterodimerise to BMAL1, which disrupts normal binding of CLOCK/BMAL to the Per1 promoter, leading to circadian disruption.

Figure 3

The rhythmic microbiome. In homeostasis, the microbiome is rhythmic in its composition, abundance and biogeographic distance from the intestinal mucosa, with its abundance peaking in the murine dark, active phase. Possible entraining factors include light:dark cycles, timing and composition of food intake and host molecular clock function. Functioning oscillations in the microbiome drive homeostasis in both immunity and metabolism, both locally in the intestine and further afield in organs such as the liver. In disease, disruption to entrainment via jet lag, high fat diet, illness and treatments such as antibiotics lead to perturbations in microbiome rhythmicity and subsequent impairment of local and systemic immune-metabolic homeostasis.

Figure 4

The role of the ILC3 clock in regulating the rhythmic microbiome and barrier function. Clocks within ILC3s are synchronized by the SCN and local microbiome-derived cues. Genetic manipulation of core clock genes within ILC3s demonstrates the importance of this intrinsic clock for regulating crosstalk between the host and the microbiome. Loss of the ILC3 clock results in decreased gene expression of anti-microbial peptides, reduced mucus production, disrupted oscillations in components of the microbiota and cytokines and impaired responses to harmful bacteria.

Figure 5

The microbiota influences metabolic programmes within the gut. Signals derived from gram-negative flagellated bacteria resident within a healthy microbiome activate toll-like receptors on lamina propria CD11c⁺ dendritic cells and induce IL23 secretion. In response to increased IL23 levels, ILC3s signal to intestinal epithelial cells via IL22, which activates a STAT3 signaling pathway to repress rev-erbα expression, with subsequent de-repression of nfil3 transcription. Increased nfil3 expression drives circadian lipid homeostasis and development of ILCs and T_h17 cells, promoting intestinal homeostasis. DC, dendritic cell. ILC, innate lymphoid cell, STAT, signal transducer and activator of transcription.