Mediators of Host–Microbe Circadian Rhythms in Immunity and Metabolism

SIMPLE SUMMARY: Circadian rhythms serve as the body’s internal metronome, driving responses to environmental cues over a 24-h period. Essential to nearly all life forms, the core circadian clock gene network drives physiological outputs associated with metabolic and immune responses. Modern-day disruptions to host circadian rhythms, such as shift work and jet lag, result in aberrant metabolic responses and development of complex diseases, including obesity and Type 2 Diabetes. These complex diseases are also impacted by interactions between gut microbes and the host immune system, driving a chronic low-grade inflammatory response. Gut microbes exhibit circadian dynamics that are closely tied to host circadian networks and disrupting microbial rhythmicity contributes to metabolic diseases. The underlying mediators that drive communication between host metabolism, the immune system, gut microbes, and circadian networks remain unknown, particularly in humans. Here, we explore the current state of knowledge regarding the transkingdom control of circadian networks and discuss gaps and challenges to overcome to push the field forward from the preclinical to clinical setting. 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-h 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.