Unravelling the role of the gut microbiota in shaping neurodevelopment and myelination during critical windows of early-life

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dc.check.date2030-05-31
dc.contributor.advisorCryan, John
dc.contributor.advisorClarke, Gerard
dc.contributor.authorLynch, Caoimhe M. K.en
dc.date.accessioned2025-02-06T15:50:49Z
dc.date.available2025-02-06T15:50:49Z
dc.date.issued2024
dc.date.submitted2024
dc.description.abstractThere is a growing appreciation that the bidirectional communication between our gut microbes and brain, known as the microbiota-gut-brain axis, plays a crucial role in shaping neural development and function, particularly during critical windows of early life. Myelination, the process in which axons are wrapped in a lipid-rich membrane, is essential for efficient neural communication and cognitive function. Recently, research has begun to unravel the dynamic nature of myelin plasticity and its responsiveness to environmental factors, including the gut microbiota. Most of the research to date has employed proof-of-principle experiments using germ-free (GF) rodents to understand the impact of microbial signals on brain health and behaviour. However, recent investigations have begun to leverage simpler model organisms to interrogate microbiota-gut-brain interactions and improve the translational potential of findings across different model species. Deepening our understanding of how microbes regulate key neurodevelopmental processes during sensitive periods will enhance our knowledge of perturbed microbiota-gut-brain axis signalling in disorders linked to altered myelin plasticity. This thesis investigates the complex relationship between the microbiota-gut-brain axis and myelination, aiming to understand how disruptions or changes in this axis during key developmental periods affect myelin formation and related neurological outcomes. To this end, we adopted three models of perturbed microbiota-gut-brain axis signalling: (1) targeted ABX-induced microbiota depletion, (2) GF rodents and (3) GF zebrafish to characterise the mechanisms underlying microbial regulation and the neuroactive potential of microbial metabolites during early life. We demonstrate that targeted microbiota disruption during critical windows of early life has enduring effects on the structure and function of the gut microbiota. These changes were associated with sex- and time-dependent shifts in circulating immune cells, myelin-related gene expression in the prefrontal cortex, and microglial morphology in the basolateral amygdala. Moreover, females treated with antibiotics before weaning exhibited altered anxiety-like behaviours later in life, suggesting that alterations in key neuromodulators may mediate these effects. To further explore the significance of early-life priming for myelin formation, we adopted a cross-species approach using GF mice and zebrafish. We found that the microbiota is essential for neuronal activity and myelination in a sex- and time-dependent manner. Multi-omics analysis revealed that changes in myelin-related transcriptomic profiles were linked to functional shifts in metabolites related to neurotransmission and cellular metabolism. Disruption of myelin and activity-related pathways occurred alongside the maturation of the prefrontal cortex, resulting in subtle variations in myelin growth during development. Similarly, GF zebrafish exhibited changes in myelin, microglia, and activity-related gene expression. Additionally, our findings show that the microbiota influences microglia maturation across species, including the dynamic regulation of microglia-oligodendrocyte contacts in the spinal cord and microglia infiltration in the brain. Lastly, we demonstrate the neuroactive potential of microbial metabolites on glial and myelin-related gene expression. Moreover, behavioural assessments show that the microbiota did not significantly alter anxiety-like behaviour at 5 days post fertilisation (dpf), though microbially derived metabolites produced subtle effects. Additionally, we show for the first time that the microbiota influences the startle response, where GF larvae exhibit hyperactivity, suggesting impaired habituation to stimuli, which can only be rescued by specific microbial metabolites. Overall, this thesis offers compelling evidence regarding the potential mechanisms by which microbes regulate myelination across species. These findings expand on existing research and enhance the translational potential of microbial regulation on myelination and related behaviours. This work also identifies new possibilities for therapeutic interventions that target the microbiota-gut-brain axis to promote healthy myelination and address disorders linked to myelin disruption.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLynch, C. M. K. 2024. Unravelling the role of the gut microbiota in shaping neurodevelopment and myelination during critical windows of early-life. PhD Thesis, University College Cork.
dc.identifier.endpage332
dc.identifier.urihttps://hdl.handle.net/10468/17003
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2024, Caoimhe Lynch.
dc.rights.urihttps://creativecommons.org/publicdomain/zero/1.0/
dc.subjectMicrobiota-gut-brain axis
dc.subjectMyelination
dc.subjectNeurodevelopment
dc.subjectDevelopment
dc.subjectNeuronal activity
dc.subjectMicroglia
dc.subjectZebrafish
dc.subjectGerm-free
dc.subjectCritical windows
dc.titleUnravelling the role of the gut microbiota in shaping neurodevelopment and myelination during critical windows of early-life
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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