Bidirectional interactions between circadian rhythms and the gut microbiome.

Circadian rhythms are endogenous, near-24-h cycles that synchronize physiological and behavioral functions with environmental cues such as light/dark cycles and food intake. While the central pacemaker in the suprachiasmatic nucleus orchestrates these rhythms, peripheral clocks distributed across organs, including the gastrointestinal tract, exhibit autonomous oscillations that are crucial for local homeostasis. Concurrently, the gut microbiota undergoes diurnal fluctuations in composition and metabolic activity that are tightly coupled to host circadian mechanisms. Recent discoveries reveal a bidirectional relationship: host clocks influence microbial dynamics through feeding behavior, immune signaling, and epithelial renewal, whereas microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids modulate circadian gene expression in peripheral tissues. Disruptions in circadian alignment, whether due to genetic mutations, lifestyle factors like shift work and irregular eating, or environmental perturbations, lead to microbial dysbiosis, metabolic dysfunction, inflammation, and heightened disease susceptibility. Conversely, altered microbiota rhythms can feed back into host systems, impairing metabolic control, immune responses, and neuroendocrine signaling. This reciprocal regulation extends to disease contexts, where circadian-microbiota misalignment contributes to obesity, type 2 diabetes, inflammatory bowel disease, and even neuropsychiatric disorders. This review synthesizes current insights into the molecular and physiological cross-talk between host circadian clocks and the gut microbiota. We discuss how temporal dynamics at the cellular, systemic, and microbial levels are integrated and how their disruption underlies pathogenesis. We further explore the potential of chronobiotics and chrononutrition, including time-restricted feeding (TRF) and bioactive dietary compounds, as emerging strategies to restore circadian-microbial synchrony and improve metabolic health. Understanding this intricate dialogue between host and microbiome may pave the way for personalized, time-based interventions to enhance healthspan and prevent disease occurrence or progression. KEY POINTS: • Circadian rhythms and microbiota form a bidirectional regulatory feedback loop. • Disruption of circadian-microbial synchrony drives metabolic and inflammatory disease. • Chrononutrition offers novel strategies to restore health via circadian-microbiota alignment.