A gut perspective on neurodevelopmental and neurodegenerative brain disorders

Abstract

Neurodevelopmental and neurodegenerative disorders are increasingly recognized as systemic conditions that extend beyond the central nervous system (CNS). A growing body of evidence highlights the microbiota-gut-brain axis as a key integrative network linking the CNS with the gastrointestinal tract through neural, immune, endocrine, and metabolic pathways.

This thesis aimed to investigate the interplay between the gut, the enteric nervous system (ENS), and the brain in the context of neurological disorders, with a particular focus on enteric glial cells, gut microbiota, and peripheral manifestations of disease. Using a combination of literature review and experimental approaches in rodent models, both neurodevelopmental and neurodegenerative conditions were examined.

In a mouse model of neurodevelopmental disorders, alterations in gut motility, ENS composition, and microbiota were identified in the absence of overt peripheral inflammation. Notably, fecal microbiota transplantation improved cognitive deficits in mutant mice, highlighting a functional role of the microbiome in modulating brain-related outcomes. In contrast, neurodegenerative models of Alzheimer’s disease revealed gastrointestinal dysfunction characterized by intestinal inflammation, amyloid-β accumulation within enteric neurons, and altered gut motility. In the TgF344-AD rat model, systemic low-grade inflammation was observed in peripheral organs, further supporting the concept of Alzheimer’s disease as a whole-body disorder.

Overall, this work provides insight into bidirectional interactions within the microbiota-gut-brain axis and underscores its relevance in both neurodevelopmental and neurodegenerative disorders. Targeting this axis may offer novel opportunities for therapeutic intervention and improved management of CNS diseases.