Sleep and the gastrointestinal (GI) tract interact in a complex and reciprocal relationship, although the molecular and physiological pathways underlying this interaction remain only partially defined. Communication between the central (CNS) and enteric nervous systems (ENS) spans neural, immune, endocrine, and metabolic pathways, including vagal nerve signaling, the hypothalamic-pituitary-adrenal (HPA) axis, gut-resident microbiota, and circulating microbial metabolites, such as bile acids with neuroinflammatory or neurotransmitter activity. In this narrative review, we synthesize evidence from animal models, observational cohorts, and intervention trials to map this bidirectional axis, focusing on several underexamined modulatory mechanisms including the interaction between the gut microbiome and the glymphatic system, the brain's perivascular waste-clearance network, which is implicated in the removal of amyloid-β (Aβ) and tau in Alzheimer's disease; neuroendocrine regulation and sex-related differences in gut microbiome composition and sleep patterns, which may help explain the divergent neurodegenerative disease risks between men and women; and age-related parallel trajectories of microbiome senescence and sleep fragmentation in older adults. We discuss melatonin, cortisol, estrogen, and ghrelin as endocrine mediators linking circadian biology to gut physiology, and we consider how environmental and lifestyle factors further perturb this system. These mechanisms form an integrative framework of the gut-brain-sleep axis and highlight priority directions for mechanistic and translational research, including significant nodes in this pathway where targeted interventions may help cognitive resilience and slow the neurodegenerative disease progression. More research clarifying these mechanisms may help identify the most promising targets, potentially leading to personalized, precision-medicine-based therapeutic strategies.
