Mediators of Host-Microbe Circadian Rhythms in Immunity and Metabolism

Abstract

Circadian rhythms are essential for nearly all life forms, mediated by a core molecular gene network that drives downstream molecular processes involved in immune function and metabolic regulation. These biological rhythms serve as the body's metronome in response to the 24-hour light:dark cycle and other timed stimuli. Disrupted circadian rhythms due to drastic lifestyle and environmental shifts appear to contribute to the pathogenesis of metabolic diseases, although the mechanisms remain elusive. Gut microbiota membership and function are also key mediators of metabolism and are highly sensitive to environmental perturbations. Recent evidence suggests rhythmicity of gut microbes is essential for host metabolic health. The key molecular mediators that transmit rhythmic signals between microbes and host metabolic networks remain unclear, but studies suggest the host immune system may serve as a conduit between these two systems, providing homeostatic signals to maintain overall metabolic health. Despite this knowledge, the precise mechanism and communication modalities that drive these rhythms remain unclear, especially in humans. Here, we review the current literature examining circadian dynamics of gut microbes, the immune system, and metabolism in the context of metabolic dysregulation and provide insights into gaps and challenges that remain.

Keywords: Keywords: circadian rhythms; gut microbiota; immune function; metabolism; microbial metabolites.

Figure 1

Circadian networks set the metronome of life. The highly conserved molecular circadian gene network is made up of a core negative feedback loop of transcription factors that respond to environmental Zeitgebers over a ~24 h period. The feedback loop consists of two primary activators (CLOCK and BMAL1), that dimerize and bind to E-Box promoter regions which induces transcription of clock-controlled genes (CCGs), including repressors Period 1-3 (PER) and Cryptochrome 1/2 (CRY). These proteins heterodimerize to prevent further transcription induction by CLOCK:BMAL1. Stabilizing loop components contribute to molecular clock regulation, including retinoic acid-related orphan nuclear receptors REV-ERBα and RORα, which induce vs. repress Bmal1 transcription via RORE promoter binding. The accessory loop is made up of the activator albumin-D-box binding protein (DBP) and repressor nuclear factor interleukin 3 (Nfil3), which influence Per gene expression via D-box promoter binding. These loops drive and maintain rhythmic expression of the underlying circadian clock network and each contributes to overlapping and mutually exclusive sets of CCGs that drive rhythmic physiological responses.

Figure 2

Mediators of circadian orchestration between environment, gut microbes, and the immune system that contribute to metabolic dysregulation. Environmental stimuli and host behavioral outputs contribute to intestinal eubiosis vs. dysbiosis. For instance, low-fat, high fiber diets contribute to eubiosis characterized by increased microbial diversity exhibiting diurnal oscillations in membership and function (e.g., SCFA production). Diurnal stimulation and release of AMPs mediated by TLR stimulation on both epithelial and immune cells, such as antigen presenting cells (APCs) and innate lymphoid cells (ILCs), coupled with normal cytokine production aid in maintaining the mucosal layer and epithelial barrier, preventing overexposure to LPS and other microbially-derived products. High fat diet (HFD) or other circadian disruptions lead to intestinal dysbiosis, characterized by decreased microbial diversity and a loss of microbial oscillators with decreased functional outputs, such as SCFAs. A HFD shifts bile acid profiles and elevates LPS-producing bacteria resulting in a thinner mucosal layer, epithelial barrier dysfunction and increased stimulation of APCs and ILCs leading to heightened production of pro-inflammatory cytokines, contributing to metabolic dysregulation and disease.