Titolo della tesi: Exploring the role of gut microbiota and ketogenic diet on glioma growth and tumor microenvironment
Glioblastoma (GBM) is the most prevalent malignant brain tumor with few therapeutic options.
Recently, several studies have demonstrated a close association between gut microbiota and
the development of GBM, highlighting the importance of gut-derived metabolites in mediating
neuronal and glial cell cross-talk in physiological and pathological conditions. Gut dysbiosis
may affect cerebral tumor growth and progression, but the specific metabolites involved in this
modulation have not been identified yet. Many factors can influence microbiota composition,
including infection, antibiotic (ABX) medications, diet, environmental stressors, host genetics,
and aging. Since the current treatments for glioblastoma show no significant improvement in
the survival rate, novel coadjuvant therapies have been recently explored in conjunction with
standard radio-chemotherapy approaches. The use of a ketogenic diet (KD) in glioma is
currently tested as an adjuvant treatment in standard chemotherapy regimens. The metabolic
shift induced by the KD leads to the generation of ketone bodies that can influence glioma cells
and the surrounding microenvironment but the mechanisms have not yet been fully elucidated.
We investigated, the role of dysbiosis induced by the administration of non-absorbable
antibiotics on mouse metabolome and tumor microenvironment and how the ketogenic diet is
counteracting glioma progression. We report that antibiotics treatment induced alteration of the
gut and brain metabolome profiles, modeling of tumor microenvironment toward a pro
angiogenic phenotype in which microglia and glioma cells are actively involved, increased
glioma stemness, trans-differentiation of glioma cells into endothelial precursor cells, thus
increasing vasculogenesis. We propose glycine as a metabolite that, in ABX-induced
dysbiosis, shapes the brain microenvironment and contributes to glioma growth and
progression. On the other hand, we investigated the potential involvement of glial cells as
mediators of the KD-induced effects on tumor growth and survival rate in glioma-bearing mice.
Specifically, we describe that exposing glioma-bearing mice to a KD or to β-hydroxybutyrate
(β-HB), one of the main KD metabolic products, reduced glioma growth in vivo, induced a
pro-inflammatory phenotype in astrocytes, and increased functional glutamate transporters.
Moreover, we described increased intracellular basal Ca2+ levels in GL261 glioma cells treated
with β-HB or co-cultured with astrocytes. All these data suggest that pro-inflammatory
astrocytes triggered by β-HB can be beneficial in counteracting glioma proliferation and
neuronal excitotoxicity, thus proving a beneficial effect on brain parenchyma.