Rewinding the gut clock: from chronodisruption to targeted therapies

Circadian rhythms orchestrate daily oscillations in physiology and behaviour, enabling optimal alignment between internal biological processes and environmental cycles. A hierarchical system centred in the suprachiasmatic nucleus and supported by peripheral clocks across tissues ensures temporal alignment of metabolic, immune and GI functions. Within the GI tract, local clocks drive rhythmic programmes that regulate digestion, absorption, motility, hormone secretion, immune responses and interactions with the gut microbiota. Feeding-fasting cycles and microbial metabolites act as powerful zeitgebers for intestinal clocks, shaping rhythmic gene expression and intestinal metabolic oscillations. Chronodisruption-arising from misaligned light exposure, sleep disturbances or mistimed eating schedules-uncouples central and peripheral clocks. These disturbances, increasingly prevalent in shift workers, disrupt microbial rhythmicity and intestinal homeostasis. Chronodisruption contributes to metabolic disorders, including obesity, dyslipidaemia and type 2 diabetes, and increases the susceptibility to GI disorders such as IBD, IBS, GORD and colorectal cancer. Emerging therapeutic strategies aim to restore circadian alignment. Time-restricted feeding reinforces endogenous rhythmicity, improves metabolic health and restores GI rhythmic processes through entrainment of clock genes, nutrient-sensing pathways and microbial oscillations. Chronobiotics, including melatonin and phytochemicals, further offer non-invasive approaches to resynchronise disrupted clocks. Finally, chronotherapy and chronotype-tailored interventions further underscore the potential of personalised medicine based on circadian biology. Advances in research on rhythmic metabolites and interorgan metabolic coupling offer promising opportunities for understanding systemic circadian coordination. Overall, reinforcing circadian alignment holds potential for preventing and treating metabolic and GI diseases associated with modern lifestyle-induced chronodisruption.