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

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Hecke Morais, Livia
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University College Cork
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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.
Caesarean-section , Maternal immune activation , Oxytocin , Microbiota
Hecke Morais, L. 2018. Enduring neurobehavioural effects induced by early-life microbiota-gut-brain axis alterations. PhD Thesis, University College Cork.
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