Enduring neurobehavioural effects induced by early-life microbiota-gut-brain axis alterations

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dc.contributor.advisor Cryan, John F. en
dc.contributor.advisor Dinan, Timothy G. en
dc.contributor.author Hecke Morais, Livia
dc.date.accessioned 2019-01-21T16:48:22Z
dc.date.issued 2018
dc.date.submitted 2018
dc.identifier.citation Hecke Morais, L. 2018. Enduring neurobehavioural effects induced by early-life microbiota-gut-brain axis alterations. PhD Thesis, University College Cork. en
dc.identifier.endpage 298 en
dc.identifier.uri http://hdl.handle.net/10468/7335
dc.description.abstract There is a growing appreciation of the importance of the bidirectional communication between our gut and brain on regulating the function and development of multiple physiological systems, including the central nervous system. Recently, the gut microbiota was demonstrated to interact with the gut-brain axis to regulate behaviour which has driven a paradigm shift in our understanding of neuropsychiatric disorders. An individual’s microbiota starts to develop mainly upon birth and continues to change throughout life. This initial colonization has a significant impact on development and maturation of the immune system. Conversely, disruptions of early-life microbiota have been implicated to long-lasting effects on stress, social behaviour and anxiety. Understanding the importance of early-life for shaping the gut-brain axis will further contribute to better strategies for disease prevention and treatment. This thesis investigated the impact of the gut-brain axis disruptions in early-life and the neurobehavioural consequences in two different scenarios: birth by C-section and maternal immune activation with polyinosinic-polycytidylic acid during pregnancy. To this end, here we developed a mouse model of C-section in NIH Swiss mice and demonstrated for the first time that the mode of delivery at birth can alter the stress-response, social behaviour, anxiety-like behaviour and cognition across the lifespan. These neurobehavioural deficits were associated with marked changes in the gut microbiota composition and diversity in early-life and adolescence with special decrease in Bifidobacterium spp. Further, we demonstrated that some deficits in social behaviour and cognition induced by the mode of delivery are reversed by targeting the gut microbiota in early-life through prebiotic, probiotic treatment, microbial transfer, and by pharmacological treatment with oxytocin. Complementary to the findings in mice some aspects of stress-related behavioural and physiological changes were also observed in a cohort of young-adults individuals. To further interrogate the importance of early-life for priming the gut-brain axis function in a different animal model, we investigated whether maternal immune activation with polyinosinic-polycytidylic acid (poly I:C) at gestational day 12.5 could behavioural, physiological and molecular aspects relevant to neurodevelopmental disorders in offspring of an outbred (NIH Swiss) and an inbred (C57BL6/J) strain. By looking at these two different strains we were able investigate whether gene and environment can interact in the susceptibility to develop gut-brain axis phenotype. We demonstrated that these strains differ in anxiety and depression-like behaviours with the effects being more pronounced in NIH Swiss mice. These strain-specific behavioural effects in the NIH Swiss mice were associated with marked changes in important components of gut-brain axis communication: stress and gut permeability. Taken together, these data suggest that gut-brain axis alterations in early-life may underpin altered programming of the developing brain and behaviours. Moreover, genetic background is a critical factor in susceptibility to the gut-brain axis alterations in certain conditions. Further efforts into understanding the factors that contribute to the major role for the gut-brain axis on programing brain health in early life may allow the development of new treatment strategies. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2018, Livia Hecke Morais. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Caesarean-section en
dc.subject Maternal immune activation en
dc.subject Oxytocin en
dc.subject Microbiota en
dc.title Enduring neurobehavioural effects induced by early-life microbiota-gut-brain axis alterations en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD en
dc.internal.availability Full text not available en
dc.description.version Accepted Version
dc.contributor.funder Science Foundation Ireland en
dc.contributor.funder APC Microbiome Institute, College of Medicine and Health, University College Cork en
dc.contributor.funder Coordenação de Aperfeiçoamento de Pessoal de Nível Superior en
dc.description.status Not peer reviewed en
dc.internal.school Anatomy and Neuroscience en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat Apply the embargo to both hard bound copy and e-thesis (If you have submitted an e-thesis and a hard bound thesis and want to embargo both) en
ucc.workflow.supervisor j.cryan@ucc.ie
dc.internal.conferring Spring 2019 en
dc.internal.ricu APC Microbiome Institute en
dc.relation.project Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Science Without Borders) en


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© 2018, Livia Hecke Morais. Except where otherwise noted, this item's license is described as © 2018, Livia Hecke Morais.
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