Circadian rhythm and the gut microbiome: a synchrony to the metabolic response to diet

Abstract

The circadian clock and the gut microbiome function as integrated regulatory systems whose bidirectional interactions profoundly influence host metabolism and responses to dietary interventions. This narrative review critically synthesizes current evidence on the circadian-microbiome axis, with emphasis on its mechanistic basis, translational relevance to metabolic disease, and therapeutic opportunities for chrononutritional strategies. The central clock within the suprachiasmatic nucleus (SCN) synchronizes peripheral clocks throughout the body, including those in the gastrointestinal tract, while the gut microbiome exhibits diurnal oscillations in composition and function that are entrained primarily by host feeding rhythms. Reciprocally, microbial metabolites, particularly short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan derivatives, feedback to modulate circadian gene expression in multiple host tissues, establishing an integrated regulatory loop. Disruption of this synchrony through shift work, irregular eating patterns, or circadian gene mutations contributes to metabolic dysfunction including obesity, insulin resistance, and cardiovascular disease. We critically evaluate the mechanistic basis of circadian-microbiome interactions, highlighting key controversies including the relative contributions of light-driven host signals versus feeding-driven nutrient availability in entraining microbial rhythms, and the translational validity of animal models for human applications. By systematically comparing studies, identifying methodological limitations (particularly reliance on fecal microbiota as proxies and underutilization of metagenomic approaches), and delineating knowledge gaps requiring further investigation, this review provides a framework for future research. The circadian-microbiome axis represents a novel therapeutic target, with chrononutritional interventions such as time-restricted feeding offering promise for restoring metabolic homeostasis. We conclude by outlining priority questions and methodological recommendations to accelerate translation toward clinical applications.