Mateu, Baptiste (2026) The role of microbiota in gut-brain axis modulation: a mechanistic approach for neurological disease. [Tesi di dottorato]

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Abstract

The gut microbiota has emerged as a key integrative regulator of host physiology, coordinating processes that extend to central nervous system functions. This thesis aims to elucidate the role of gut microbiota within the gut-brain axis by employing mechanistic approaches, moving beyond descriptive and correlative association-based analyses. Two main methodological approaches using animal models were adopted to identify a potential causal role of the gut microbiota in neurological disorders with behavioural outcomes. The first approach is based on the transplantation of microbial communities derived from postbiotic-treated epileptic rat donors to assess phenotype modulation in recipient epileptic rats. The second approach, developed in a mouse model of early-life antibiotic-induced gut microbiota perturbation, seeks to further elucidate the interaction between the gut microbiota and the developing brain. It aims to determine whether early-life perturbations of the intestinal microbiota can induce epigenetic modifications at both peripheral sites and in the central nervous system, thereby influencing cellular reprogramming and negatively impacting gut and brain developmental trajectories. In the epilepsy rat model, FMT from butyrate-treated epileptic rats reshaped gut microbiota and its associated metabolic pathways in recipient epileptic rats, while reducing the seizure phenotype, supporting the idea that gut-derived signals can influence neuronal excitability. On the other hand, transient perturbation of the gut microbiota at a juvenile age, a critical neurodevelopmental window, resulted in robust transcriptional and DNA methylation remodelling in the colon mucosa, as well as more subtle gene expression and epigenetic changes in the striatum. Anxiety-like behaviour was observed as a downstream phenotypic effect of these alterations, possibly together supporting the microbiota-dependent reprogramming of gene expression and epigenetic signatures as underpinning behavioural outcomes through modulation of the gut-brain axis. Through these studies, the gut microbiota emerges as a critical component able to impact brain functions from the periphery through both signalling mechanisms and epigenetic programming. This work provides mechanistic insight into the microbiota-gut-brain axis and suggests that targeted strategies aimed at modulating microbiota structure and function may be relevant for ameliorating compromised gut-brain crosstalk in neurological diseases.

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