Investigations on the role of the gut microbiota in hippocampal neuroplasticity and behaviour throughout the lifespan

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Guzzetta, Katherine E.
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University College Cork
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Trillions of microorganisms inhabit the gastrointestinal tract, and while their importance in host digestion is well established, these microbes have recently been shown to harness the ability to influence neuroplasticity within the hippocampus of the brain, as well as hippocampus-dependent behavioural processes. The hippocampus is one of the few brain regions in which new neurons are born throughout life, an ability that is critical for specific cognitive and emotional processes, making it imperative to understand the biological controls of hippocampal neurogenesis. Hippocampal neuroplasticity is shaped by factors such as aging, diet, and psychological stress. However, the underlying mechanisms by which these factors influence neuroplasticity in the hippocampus are not fully known. In parallel, the gut microbiome is highly sensitive to diet and stressful life events, however it is unknown whether the gut microbiota is an active mediator in the impact of these factors on hippocampal neurogenesis. Furthermore, the gut microbiota is initially seeded at birth and undergoes compositional and functional changes as its host ages, though whether it is a contributor to the processes of brain aging, including the declining cognition and hippocampal plasticity observed in aging, has previously not been demonstrated. Herein, this thesis explores the relationships between the gut microbiome and host hippocampal neuroplasticity and related behaviours throughout the lifespan, including in early life following caesarean section birth, early life stress, and/or microbiota-targeted dietary interventions, and in aging using preclinical rodent models. This thesis demonstrates for the first time that transferring the gut microbiota from young to aged mice is sufficient to restore aging-related deficits in hippocampus-dependent spatial memory and learning, as well as some components of the hippocampal metabolome and transcriptome. Interestingly, there was no effect on age-associated decline in hippocampal neurogenesis. However, this thesis also realised that transferring a consortium of bacteria identified as highly abundant in elderly patients with mild cognitive decline could not induce cognitive deficits in young rat recipients, suggesting a limit to the potential of the aging-related gut microbiota to impact host cognition. Furthermore, this thesis demonstrated that early life stress induced changes in the gut microbiome composition and predicted functional ability within the gut-brain axis, as well as the expression of genes related to hippocampal neuroplasticity. Some of these early life stress-induced alterations were ameliorated with the microbiota-targeted dietary supplementation of fish oil or various polyphenols, highlighting the importance of diet within the microbiota-gut-brain axis. Finally, it was demonstrated that the mode of birth, which has a strong influence on the early life gut microbiome, can lead to critical changes in dorsal hippocampal neurogenesis, effects which were sex-dependent and exacerbated by early life antibiotic exposure. Taken together, the findings within this thesis highlight the importance of the gut microbiota in shaping hippocampal neuroplasticity and related behaviours of its host. Moreover, these effects are complex, but reveal potential opportunities for novel microbiota-targeted therapeutics throughout the lifespan.
Gut microbiome , Gut microbiota , Nurogenesis , Hippocampal neurogenesis , Neuroplasticity , Ageing , Microbiota-gut-brain axis , Caesarean section
Guzzetta, K. E. 2022. Investigations on the role of the gut microbiota in hippocampal neuroplasticity and behaviour throughout the lifespan. PhD Thesis, University College Cork.
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