AccScience Publishing / MI / Online First / DOI: 10.36922/MI026020009
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MINI-REVIEW

The sleep–microbiome–neurodegeneration triad: A new frontier in neuroimmunology

Gerardo Villalobos-Valdez1† ,  Karyme M. Alemán-Villa1† ,  David A. Armienta-Rojas1 ,  Alberto K. De la Herrán-Arita1*
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1 Department of Neuroscience, Faculty of Medicine, Autonomous University of Sinaloa, Culiacán, Sinaloa, Mexico
†These authors contributed equally to this work.
MI, 026020009 https://doi.org/10.36922/MI026020009
Received: 10 January 2026 | Revised: 10 February 2026 | Accepted: 26 February 2026 | Published online: 5 June 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

The pathogenesis of neurodegenerative diseases is increasingly recognized as a systemic failure of homeostatic axes rather than a localized central nervous system event. Central to this paradigm is the “sleep–microbiome–neurodegeneration triad,” a bidirectional framework where dietary inputs, gut microbial metabolites, and sleep architecture converge to regulate neuro–immune health. This mini review critically evaluates the evidence linking these domains, focusing on the mechanical and molecular bridges that facilitate their interaction. This mini review synthesizes data from recent (2015–December 2025) longitudinal clinical cohorts, metagenomic sequencing, and polysomnographic studies. We analyze the biochemical transition of dietary substrates, specifically the shift from fiber-derived short-chain fatty acids to ultra-processed food-induced endotoxemia, and relate these findings to neuroimaging evidence on glymphatic clearance efficiency. The evidence identifies a primary mechanistic “switch” in tryptophan metabolism. While fiber-rich diets promote microbial-led synthesis of serotonin and melatonin, the dysbiosis associated with Western diets upregulates the indoleamine 2,3-dioxygenase pathway. This reroutes tryptophan toward the kynurenine pathway, generating neurotoxic metabolites that correlate with sleep fragmentation. We further delineate how the resulting systemic inflammation primes microglial cells via toll-like receptor 4 signaling, concurrently disrupting slow-wave sleep. This disruption is shown to impair the aquaporin-4-dependent glymphatic system, leading to the reduced clearance of proteopathic aggregates, including β-amyloid and α-synuclein. This mini review proposes that the collapse of the sleep–microbiome–immune axis is a fundamental driver of proteinopathy. By characterizing these interactions, we identify modifiable metabolic checkpoints that offer novel targets for therapeutic intervention. Restoring this triad through precision nutrition and microbial modulation represents a vital strategy for stalling neurodegenerative progression.

Keywords
Glymphatic clearance
Gut-brain axis
Kynurenine pathway
Neuroinflammation
Slow-wave sleep
Proteostasis
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Cryan JF, O’Riordan KJ, Cowan CS, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99(4):1877-2013. doi: 10.1152/physrev.00018.2018

 

  1. Agirman G, Yu KB, Hsiao EY. Signaling inflammation across the gut-brain axis. Science. 2021;374(6571):1087-1092. doi: 10.1126/science.abi6087

 

  1. Camacho-Zamora A, Rábago-Monzón ÁR, Armienta- Rojas DA, et al. The gut–brain axis: Collective impact of psychosomatic conditions and gut microbiota on health and disease. J Clin Basic Psychosom. 2025;3(3):25-44. doi: 10.36922/JCBP025040008

 

  1. Camberos-Barraza J, Guadrón-Llanos AM, De la Herrán- Arita AK. The Gut Microbiome-Neuroglia Axis: Implications for Brain Health, Inflammation, and Disease. Neuroglia. 2024;5(3):254-273. doi: 10.3390/neuroglia5030018

 

  1. Silva YP, Bernardi A, Frozza RL. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol. 2020;11:25. doi: 10.3389/fendo.2020.00025

 

  1. Murphy EA, Velazquez KT, Herbert KM. Influence of high-fat diet on gut microbiota. Curr Opin Clin Nutr Metab Care. 2015;18(5):515-520. doi: 10.1097/MCO.0000000000000209

 

  1. Wang X, Sun G, Feng T, et al. Sodium oligomannate therapeutically remodels gut microbiota and inhibits neuroinflammation in Alzheimer’s disease. Cell Res. 2019;29(10):787-803. doi: 10.1038/s41422-019-0216-x

 

  1. Koh A, De Vadder F, Kovatcheva-Datchary P, et al. From dietary fiber to host physiology: Short-chain fatty acids as key bacterial metabolites. Cell. 2016;165(6):1332-1345. doi: 10.1016/j.cell.2016.05.041

 

  1. Liu P, Wang Y, Yang G, et al. The role of short-chain fatty acids in intestinal barrier function, inflammation, oxidative stress, and colonic carcinogenesis. Pharmacol Res. 2021;165:105420. doi: 10.1016/j.phrs.2021.105420

 

  1. Chassaing B, Vijay-Kumar M, Gewirtz AT. How diet can impact gut microbiota to promote intestinal inflammation and metabolic syndrome. Curr Opin Gastroenterol. 2017;33(6):417-421. doi: 10.1097/MOG.0000000000000401

 

  1. Gao K, Mu CL, Farzi A, Zhu WY. Tryptophan metabolism: A link between the gut microbiota and brain. Adv Nutr. 2020;11(3):709-723. doi: 10.1093/advances/nmz127

 

  1. Roth W, Zadeh K, Vekariya R, et al. Tryptophan metabolism and gut-brain homeostasis. Int J Mol Sci. 2021;22(6):2973. doi: 10.3390/ijms22062973

 

  1. O’Mahony SM, Clarke G, Borre YE, et al. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015;277:32-48. doi: 10.1016/j.bbr.2014.07.027

 

  1. Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. 2017;112:399-412. doi: 10.1016/j.neuropharm.2016.07.002

 

  1. Anderson G, Maes M. Interactions of tryptophan and its catabolites with melatonin and the alpha 7 nicotinic receptor in central nervous system and psychiatric disorders: role of the aryl hydrocarbon receptor and direct mitochondria regulation. Int J Tryptophan Res. 2017;10:1178646917691738. doi: 10.1177/1178646917691738

 

  1. Balmer ML, Schürch CM, Saito Y, et al. Microbiota-Derived compounds drive Steady-State granulopoiesis via MyD88/ TICAM signaling. J Immunol. 2014;193(10):5273-5283. doi: 10.4049/jimmunol.1400762

 

  1. Bayraktaroglu I, Ortí-Casañ N, Van Dam D, et al. Systemic inflammation as a central player in the initiation and development of Alzheimer’s disease. Immun Ageing. 2025;22(1):33. doi: 10.1186/s12979-025-00529-5

 

  1. Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014;10(4):217- 224. doi: 10.1038/nrneurol.2014.38

 

  1. Alemán-Villa KM, Armienta-Rojas DA, Camberos- Barraza J, et al. Neuroinflammation across the Spectrum of Neurodegenerative Diseases: Mechanisms and Therapeutic Frontiers. Neuroimmunomodulation. 2025;32(1):278-305. doi: 10.1159/000548021

 

  1. Szentirmai É, Millican NS, Massie AR, et al. Butyrate, a metabolite of intestinal bacteria, enhances sleep. Sci Rep. 2019;9(1):7035. doi: 10.1038/s41598-019-43502-1

 

  1. Rábago-Monzón ÁR, Osuna-Ramos JF, Armienta-Rojas DA, et al. Stress-Induced Sleep Dysregulation: The Roles of Astrocytes and Microglia in Neurodegenerative and Psychiatric Disorders. Biomedicines. 2025;13(5):1121. doi: 10.3390/biomedicines13051121

 

  1. Smith RP, Easson C, Lyle SM, et al. Gut microbiome diversity is associated with sleep physiology in humans. PLoS One. 2019;14(10):e0222394. doi: 10.1371/journal.pone.0222394

 

  1. Krueger J. The role of cytokines in sleep regulation. Curr Pharm Des. 2008;14(32):3408-3416. doi: 10.2174/138161208786549281

 

  1. Irwin MR. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol. 2019;19(11):702-715. doi: 10.1038/s41577-019-0190-z

 

  1. Hablitz LM, Nedergaard M. The glymphatic system: A novel component of fundamental neurobiology. J Neurosci. 2021;41(37):7698-7711. doi: 10.1523/JNEUROSCI.0619-21.2021

 

  1. Verghese JP, Terry A, de Natale ER, et al. Research evidence of the role of the glymphatic system and its potential pharmacological modulation in neurodegenerative diseases. J Clin Med. 2022;11(23):6964. doi: 10.3390/jcm11236964

 

  1. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111. doi: 10.1126/scitranslmed.3003748

 

  1. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377. doi: 10.1126/science.1241224

 

  1. la Herrán-Arita D, Alberto K. When sleep fails, brain clearance suffers: the role of glymphatic impairment in clinical neurology. Acta Neurol Belg. 2025:1-10. doi: 10.1007/s13760-025-02959-w

 

  1. Camberos-Barraza J, Camacho-Zamora A, Bátiz-Beltrán JC, et al. Sleep, Glial Function, and the Endocannabinoid System: Implications for Neuroinflammation and Sleep Disorders. Int J Mol Sci. 2024;25(6):3160. doi: 10.3390/ijms25063160

 

  1. Irwin MR, Vitiello MV. Implications of sleep disturbance and inflammation for Alzheimer’s disease risk. Lancet Neurol. 2018;17(4):296-306. doi: 10.1016/S1474-4422(18)30016-0

 

  1. Zinöcker MK, Lindseth IA. The Western Diet-Microbiome- Host Interaction and Its Role in Metabolic Disease. Nutrients. 2018;10(3):365. doi: 10.3390/nu10030365

 

  1. Barb JJ, Lee LJ, Ahmed A, et al. Associations between sleep and the gut microbiome in adults with colorectal cancer and their caregivers. Sci Rep. 2025;15(1):32624. doi: 10.1038/s41598-025-18402-2

 

  1. Fraga CG, Croft KD, Kennedy DO, et al. The effects of polyphenols and other bioactives on human health. Food Funct. 2019;10(2):514-528. doi: 10.1039/C8FO01997E

 

  1. Vauzour D. Polyphenols and brain health. OCL. 2017;24(2):A202. doi: 10.1051/ocl/2017008

 

  1. Schwarcz R, Stone TW. The kynurenine pathway and the brain: Challenges, controversies and promises. Neuropharmacology. 2017;112:237-247. doi: 10.1016/j.neuropharm.2016.08.003

 

  1. Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut. 2021;70(6):1174-1182. doi: 10.1136/gutjnl-2020-323071

 

  1. Brandl S, Reindl M. Blood–Brain barrier breakdown in neuroinflammation: current in vitro models. Int J Mol Sci. 2023;24(16):12699. doi: 10.3390/ijms241612699

 

  1. Cunningham C, Hennessy E. Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research. Alzheimers Res Ther. 2015;7(1):33. doi: 10.1186/s13195-015-0117-2

 

  1. Aragón-Arreola JF, Moreno-Villegas CA, Armienta-Rojas DA, De la Herrán-Arita AK. An insight of sleep disorders in Africa. eNeurologicalSci. 2016;3:37-40. doi: 10.1016/j.ensci.2016.02.006

 

  1. Camacho-Zamora A, Camberos-Barraza J, Rábago- Monzón ÁR, et al. Psychosomatic influences on insomnia: Mechanisms, diagnosis, and treatment strategies. J Clin Basic Psychosom. 2024;3(1):32. doi: 10.36922/jcbp.4588

 

  1. Osuna-Ramos JF, Camberos-Barraza J, Torres-Mondragon LE, et al. Interplay between the Glymphatic System and the Endocannabinoid System: Implications for Brain Health and Disease. Int J Mol Sci. 2023;24(24):17458. doi: 10.3390/ijms242417458

 

  1. Shokri-Kojori E, Wang GJ, Wiers CE, et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci USA. 2018;115(17):4483- 4488. doi: 10.1073/pnas.1721694115

 

  1. Alemán-Villa KM, Sosa-Arámbula HJ, Armienta-Rojas DA, et al. The role of melatonin timing on short-term memory retention during sleep restriction. Psychopharmacology. 2025:1-10. doi: 10.1007/s00213-025-06887-8

 

  1. Ding Z, Fan X, Zhang Y, et al. The glymphatic system: a new perspective on brain diseases. Front Aging Neurosci. 2023;15:1179988. doi: 10.3389/fnagi.2023.1179988

 

  1. Wu H, Liu B, Liu WV, et al. Glymphatic system dysfunction correlated with gut dysbiosis and cognitive impairment in schizophrenia. Schizophrenia. 2025;11(1):113. doi: 10.1038/s41537-025-00661-7

 

  1. Rothhammer V, Borucki DM, Tjon EC, et al. Microglial control of astrocytes in response to microbial metabolites. Nature. 2018;557(7707):724-728. doi: 10.1038/s41586-018-0119-x

 

  1. Cattaneo A, Cattane N, Galluzzi S, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60-68. doi: 10.1016/j.neurobiolaging.2016.08.019

 

  1. Ju YE, McLeland JS, Toedebusch CD, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013;70(5):587- 593. doi: 10.1001/jamaneurol.2013.2334

 

  1. Madhu MT, Balaji O, Kandi V, et al. Role of the glymphatic System in Alzheimer’s Disease and Treatment Approaches: A Narrative review. Cureus. 2024;16(6):e63448. doi: 10.7759/cureus.63448

 

  1. Camberos-Barraza J, Alemán-Villa KM, Alberto K. The mind awake at night: Glymphatic dysfunction as a mechanistic bridge linking multifactorial sleep disturbances to neurodegeneration. J Clin Basic Psychosom. 2025:025390076. doi: 10.36922/JCBP025390076

 

  1. Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211. doi: 10.1016/S0197-4580(02)00065-9

 

  1. Sampson TR, Debelius JW, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167(6):1469-1480. doi: 10.1016/j.cell.2016.11.018

 

  1. Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behavior disorder: A multicenter study. Brain. 2019;142(3):744-759. doi: 10.1093/brain/awz030

 

  1. Bourassa MW, Alim I, Bultman SJ, et al. Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health? Neurosci Lett. 2016;625:56-63. doi: 10.1016/j.neulet.2016.02.009

 

  1. Thaiss CA, Levy M, Korem T, et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell. 2016;167(6):1495-1510. doi: 10.1016/j.cell.2016.11.003

 

  1. Ito H, Tomura Y, Kitagawa Y, et al. Effects of probiotics on sleep parameters: A systematic review and meta-analysis. Clin Nutr ESPEN. 2024;63:623-630. doi: 10.1016/j.clnesp.2024.07.006

 

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Microbes & Immunity, Electronic ISSN: 3029-2883 Print ISSN: 3041-0886, Published by AccScience Publishing
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