Gut microbiota circadian rhythms: a key regulator of immunometabolic homeostasis

Abstract

Emerging studies have revealed that disruptions in circadian crosstalk between the gut microbiota and the host play an essential role in the pathogenesis of metabolic disorders. Under physiological conditions, host circadian clocks regulate microbial diurnal oscillations through rhythmic behaviors, including feeding patterns and sleep-wake cycles. This temporal regulation manifests as robust 24-hour oscillations in microbial community composition, spatial organization, and metabolic activity. These rhythmic microbial signals and their metabolic outputs are subsequently translated into host immune modulation, establishing a bidirectional temporal dialogue between the host and microbiota. Modern lifestyle disruptions, including erratic eating patterns and shift work, desynchronize this temporal dialogue, leading to the loss of microbial rhythms, impaired intestinal barrier function, maladaptive immune responses, chronic inflammation, and systemic metabolic dysregulation. This review delineates the mechanisms through which host-microbiota circadian crosstalk governs immunometabolic homeostasis, provides a mechanistic framework for understanding immunometabolic diseases, and highlights therapeutic strategies that target microbial rhythms to reset host immunity and metabolism.

1. Introduction

The Earth's rotation over 24 hours establishes a daily cycle of light and darkness, acting as a universal clock that has driven the development of circadian rhythms in almost all living organisms [1]. These molecular oscillators, which are centered on transcriptional-translational feedback loops that involve "Bmal1/Clock" and "Per/Cry" genes, enable organisms to anticipate and adapt to daily environmental fluctuations, optimizing physiological processes such as metabolism, immune function, and behavior [2,3]. Circadian rhythms are characterized by three fundamental properties: (1) sustained oscillations with extreme precision under constant environmental conditions; (2) temperature compensation, as evidenced by period stability despite environmental temperature variations; (3) synchronization of the endogenous pacemaker to the environmental light-dark cycle [4]. Remarkably, these properties are conserved even in isolated mammalian cells, underscoring their evolutionary optimization under natural selection [4–6].

In humans, circadian regulation extends beyond sleep-wake cycles to orchestrate systemic metabolism, immune function, and neurobehavioral processes. Accumulating evidence implicates that the gut microbiota, a complex ecosystem comprising approximately 100 trillion microbes encoding 150-fold more genetic material than the human genome, serves as a critical mediator of host circadian physiology [7,8]. The microbiota, referred to as the "forgotten organ", demonstrates circadian fluctuations in its composition, the production of metabolites and spatial organization, synchronizing with host rhythms to regulate energy harvest, immune homeostasis, and metabolic gene expression [9]. For instance, microbial-derived butyrate and propionate oscillate rhythmically under normal conditions, directly modulating hepatic gluconeogenesis and adipose tissue lipolysis while synchronizing circadian oscillators in the liver and adipocytes, thereby linking microbial rhythms to host metabolic outputs.

For the gut microbial diurnal rhythm, a recent investigation demonstrated circadian transcriptional oscillations of molecular clock genes in Escherichia coli, namely, radA, a kaiC homologue [10], indicating that the gut microbiota may have endogenous rhythms. However, the prevailing consensus among current studies suggests that the gut microbial diurnal rhythm might be modulated by particular environmental stimuli within the gut, including dietary patterns, behaviors, and the expression of host clock genes [11]. This bidirectional temporal dialogue between the host and microbiota results in crosstalk, wherein host clocks regulate microbial oscillation through host rhythmic behaviors such as feeding rhythms, whereas microbial oscillations reciprocally entrain and modulate the host immune system. Modern lifestyle challenges, including pervasive shift work, chronic jet lag, and Western-style dietary patterns, disrupt this delicate temporal dialogue and lead to the development of immunometabolic diseases. A comprehensive understanding of the mechanisms underlying circadian host-microbiota crosstalk in immunometabolism remains to be elucidated. This review therefore aims to synthesize current evidence on the specific mechanisms underlying the circadian crosstalk between the host and microbiota, and how this dialogue regulates host immunometabolism. We further discuss the emerging therapeutic strategies targeting the microbiota to restore circadian alignment and improve metabolic health.