Unravelling the impact of early-life nutrition on microbiota-gut-brain axis signalling

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dc.check.date2029-12-31
dc.contributor.advisorCryan, John
dc.contributor.advisorCodagnone, Martin
dc.contributor.authorRatsika, Annaen
dc.contributor.funderScience Foundation Ireland
dc.date.accessioned2024-10-02T15:17:24Z
dc.date.available2024-10-02T15:17:24Z
dc.date.issued2024
dc.date.submitted2024
dc.description.abstractCurrent lifestyle habits such as aberrant diet are becoming disruptive to our health. Nutrition in early life is a key factor mediating immunity, neurodevelopment, and behavioural outcomes across the lifespan. Optimal nutrition in the first 1000 days of life, starting from preconception to early childhood, are essential for optimal growth, brain and immune system function. Growing lines of evidence suggest that gut microbiota play a role in immune system education, brain function and behaviour. Disruptions in the gut microbiota composition during critical periods of development perinatally might influence the developmental trajectory of the brain and the immune system, with implications for their function later in life. Although the effects of diet-induced microbiota alterations have been studied in the context of brain and immune system development, studies often overlook the interactions between these systems in critical time-windows of developmental opportunity. Given that external influences such as diet could be decisive for brain function there is a growing need for investigation of the effects of early-life nutrition on the microbiota-immune-brain axis during critical windows of development. In this thesis, I focused on the investigation of the influence of microbiota disruptions perinatally via 1. High-fat diet (HFD) during pregnancy and lactation, 2. C-section and 3. Early-life antibiotic administration on offspring brain and immune system development, and behaviour. Using a model of maternal HFD we disrupted the maternal microbiota, which led to increased potent neurotoxic metabolites in maternal circulation. The maternal-diet-induced microbiota disruption and associated metabolic signals had consequences for embryonic brain function and were associated with altered glutamate-related metabolites and genes in the fetal mouse brain and hyperactivity in adolescence specifically in the female offspring. Next, the impact of disruption of vertical microbiota transmission via C-section on the immune system education during weaning was investigated with outputs in the gut, the periphery and at the level of neuroimmune interactions in the juvenile brain. Our data shows that immune system priming in the gut and the periphery is aberrant in response to altered delivery mode, with implications for microglia activation in the male juvenile mouse brain. This highlights the timeframe around weaning as being a critical one for unmasking the enduring effects of early life microbiota disturbances. Lastly, the influence of postnatal early-life dietary intervention with human milk oligosaccharides (HMOs) and prebiotics was investigated on its ability to reverse the effects of antibiotic-induced microbiota depletion on brain transcriptome and behaviour in juvenile male mice. The combination of HMOs with prebiotics led to enhanced social recognition memory and learning and memory pathways in transcriptomic results in social brain areas, possibly via enriched abundance and function of the gut microbiota in male juvenile mice. Taken together, this work provides evidence that the diet and gut microbiota in critical windows of development regulate brain and immune system function. Moreover, we identified that dietary interventions targeting the gut microbiota in early life improve brain function and social behaviour, demonstrating that early-life gut microbiota is important for neurobehavioural outcomes.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationRatsika, A. 2024. Unravelling the impact of early-life nutrition on microbiota-gut-brain axis signalling. PhD Thesis, University College Cork.
dc.identifier.endpage240
dc.identifier.urihttps://hdl.handle.net/10468/16490
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2273/IE/Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine/
dc.rights© 2024, Anna Ratsika.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMicrobiota-gut-brain axis
dc.subjectNeurodevelopment
dc.titleUnravelling the impact of early-life nutrition on microbiota-gut-brain axis signalling
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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