The Gastro-Circadian Metabolic Axis: A Comprehensive Framework for Chronotherapy in Gastroenterology.

Circadian rhythms exert fundamental control over gastrointestinal and metabolic physiology, governing 24-hour patterns of motility, secretion, nutrient absorption, microbial activity, immune regulation, and hepatic metabolism. Accumulating evidence indicates that the gastrointestinal tract is not an isolated system but is tightly integrated with systemic metabolic and neuroendocrine networks, forming a coordinated gastro-circadian metabolic axis (GCMA). This axis links molecular clocks in the gut, liver, adipose tissue, and skeletal muscle with rhythmic inputs from the gut microbiome, feeding-fasting cycles, autonomic signaling, and enteroendocrine mediators. Disruption of circadian alignment, through shift work, sleep deprivation, irregular meal timing, or nocturnal light exposure, leads to desynchronization between central and peripheral clocks, promoting inflammation, impaired epithelial barrier function, dysbiosis, altered bile acid signaling, insulin resistance, and disturbed energy homeostasis. These mechanisms contribute to a wide spectrum of gastrointestinal disorders, including gastroesophageal reflux disease, functional dyspepsia, irritable bowel syndrome, metabolic dysfunction-associated steatotic liver disease, inflammatory bowel disease, and potentially gastrointestinal malignancies. This review synthesizes molecular, translational, and clinical evidence to position the GCMA as a unifying framework for understanding circadian influences on digestive and metabolic disease. Importantly, it highlights emerging therapeutic opportunities in chronotherapy, including time-optimized pharmacotherapy, chrononutrition, and microbiota-targeted interventions. While current translation is limited by interindividual chronotype variability and heterogeneous clinical evidence, advances in wearable circadian monitoring, multi-omics profiling, and computational modeling offer promising avenues for precision implementation. Integrating GCMA principles into clinical practice may improve disease outcomes and establish circadian alignment as a cornerstone of preventive and therapeutic gastroenterology.