Dottorato in FARMACOLOGIA E TOSSICOLOGIA

Titolo della tesi: Enteric glia: a heterogeneous population of peripheral neuroglia that link the “gut wellness to brain wellness”

The enteric nervous system (ENS) is an integrative neural network that provides local control over essential gastrointestinal (GI) functions, i.e. motility, secretion, nutrients absorption, and blood flow, along with other critically relevant processes, as immune and endocrine responses, host-microbes interaction, and epithelial barrier integrity. This vast repertoire of homeostatic functions is fulfilled through “brain-like” neural circuitry composed of neurons and glia. New data showed that bi-directional communication between enteric neurons and enteric glia influences the output of enteric neurocircuits in the ENS. This is beginning to transform the view of normal enteric circuits function, regulatory mechanisms implicate in gut health and disease, as well as of the gut-brain axis signaling. Enteric glia are a large and heterogeneous population of peripheral neuroglia that are associated with the cell bodies and processes of enteric neurons throughout the digestive tract. The antiquated concept of glia as supportive passive cells has been overtaken by unveiling enteric glia as one of the most dynamic components in the ENS. Enteric glia regulate all major GI functions via multiple bi-directional crosstalks with neurons and other cell types present in the intestinal wall. Furthermore, enteric glia are recently emerged as an active player in gut-brain signaling, suggesting that they might impact even on brain functions. Likewise, enteric glia display phenotypic changes that contribute to diverse disease processes including neuroinflammation, cancer, and infection, where glia acquire pro-inflammatory or pro-tumorigenic phenotypes. Alterations of the glial network occur in several GI pathologies and various extragastrointestinal diseases, whereby both losses and gains of glial functions contribute to altering ENS homeostasis and gut-brain signaling. The aim of the present thesis is to highlight the glial heterogeneity and plasticity that should be considered when investigating enteric glia involvement in controlling GI homeostasis and functions and, also, in the pathophysiology of intestinal diseases. Furthermore, to confirm the effect of enteric glia on central and peripheral neuroinflammatory events, I reported the effects of how reactive gliosis mitigation in the intestine improves neuropathological changes both in the ENS and central nervous system (CNS), as well as the mood dysfunction in a murine model of a high-fat diet (HFD)-induced leaky gut.