Sleep and the Gut-Brain Axis: Bidirectional, Converging Mechanisms Linking Brain Health, Neuroinflammation, and Neurodegeneration.
5 affiliations
- 1College of Medicine, Oklahoma University Health Center, Oklahoma City, OK 73104, USA.
- 2Behavioral Neurology-Neurology Department, Oklahoma University Health Center, Oklahoma City, OK 73104, USA.
- 3Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
- 4Department of Biochemistry & Physiology, Oklahoma University Health Center, Oklahoma City, OK 73104, USA.
- 5Neuroscience Program, Oklahoma University Health Center, Oklahoma City, OK 73104, USA.
Abstract
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.
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BibTeX
@article{bowler2026sleep,
title = {{Sleep and the Gut-Brain Axis: Bidirectional, Converging Mechanisms Linking Brain Health, Neuroinflammation, and Neurodegeneration.}},
author = {Bryce Bowler and Abdul Rehman Nasir and Aldona Szewczyk and Sarah Ocanas and Archana Unnikrishnan and Claire Delpirou Nouh},
journal = {Pathophysiology : the official journal of the International Society for Pathophysiology},
year = {2026},
month = sep,
doi = {10.3390/pathophysiology33040074},
url = {https://europepmc.org/article/MED/42924825},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sleep and the Gut-Brain Axis: Bidirectional, Converging Mechanisms Linking Brain Health, Neuroinflammation, and Neurodegeneration.
AU - Bryce Bowler
AU - Abdul Rehman Nasir
AU - Aldona Szewczyk
AU - Sarah Ocanas
AU - Archana Unnikrishnan
AU - Claire Delpirou Nouh
PY - 2026
DA - 2026/09/30
JO - Pathophysiology : the official journal of the International Society for Pathophysiology
DO - 10.3390/pathophysiology33040074
UR - https://europepmc.org/article/MED/42924825
AB - 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.
SN - 0928-4680
SN - 1873-149X
ER -