Microbiota-gut-immune-brain communication across the lifespan

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Cruz-Pereira, Joana S.
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University College Cork
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While the exploration of the gut microbiome in health and disease evolves, the implications of the microorganisms that inhabit the gut for host brain health also multiply. As we grow up and grow old, the gut microbiota along with the host physiological systems, undergoes significant remodelling. The influences of the gut microbiome on host physiology are relevant across the lifespan, with continuous communication between the gut microbiome and the central nervous system (CNS) representing an important aspect of this host-microbe dialogue. A growing body of research into dissecting the involvement of the gut microbiota in the behaviour and functioning of the CNS raises the need to understand how these integrated systems communicate throughout the lifespan of the host, and how it is phenotypically reflected. Understanding the gut-brain axis across the lifespan is imperative, as these insights can be used to further support healthy brain aging, along with the development of better biomarkers towards the development of personalized therapeutic strategies. In this thesis, we aimed to investigate the influence of the gut microbiome in immune and behavioural features throughout the lifespan of the host: in early-life and aging. To this end, we assessed the effect of microbiota depletion in aged mice and demonstrated for the first time that the gut microbiome is associated with social behaviour and restricts the accumulation of T-helper cells in the choroid plexus in aged mice. This was accompanied by modulation of caecal metabolite levels, and in particular, some metabolites previously associated with age-dependent processes, namely argininosuccinic acid and N-formylmethionine. To further examine the involvement of the gut microbiome in aging, we explored whether supplementation with the prebiotic FOS-Inulin could alter behavioural and physiological aspects along the gut-brain axis in stressed aged mice. We demonstrated that FOS-Inulin supplementation can ameliorate the disrupted social behavioural responses that arise following a stress exposure, including the alterations in social interaction with a non-aggressive mouse and social novelty, while promoting the remodelling of caecal and prefrontal cortex metabolite levels. More specifically, dietary supplementation with FOS-Inulin promotes the amelioration of the levels of 4-Hydroxybenzaldehyde and spermine in the prefrontal cortex of stressed aged mice. Additionally, we evaluated if FOS-Inulin supplementation could alter adult social, depressive- and anxiety-like behavioural and immune markers in offspring exposed to early life microbial disruption. In our study, we observed altered intestinal immune markers and subtle behavioural changes following this intervention. Taken together, these results provide novel insights on time sensitive critical windows for the gut microbiome, and its impact in behaviour and immunity outcomes in the host. While further investigation into the mechanisms underlying these effects is crucial, these findings highlight the involvement of gut microbial signalling on host behaviour and immunity. This research paves the way for the future development of therapeutic options that target the gut microbiome to modify these age-dependent behavioural and metabolite alterations.
Gut microbiome , Aging , Metabolites , Behaviour , Lifespan , Neuroimmunology
Cruz-Pereira, J. S. 2022. Microbiota-gut-immune-brain communication across the lifespan. PhD Thesis, University College Cork.