A Root in Synapsis and the Other One in the Gut Microbiome-Brain Axis: Are the Two Poles of Ketogenic Diet Enough to Challenge Glioblastoma?

Abstract

Glioblastoma is the most frequent and aggressive brain cancer in adults. While precision medicine in oncology has produced remarkable progress in several malignancies, treatment of glioblastoma has still limited available options and a dismal prognosis. After first-line treatment with surgery followed by radiochemotherapy based on the 2005 STUPP trial, no significant therapeutic advancements have been registered. While waiting that genomic characterization moves from a prognostic/predictive value into therapeutic applications, practical and easy-to-use approaches are eagerly awaited. Medical reports on the role of the ketogenic diet in adult neurological disorders and in glioblastoma suggest that nutritional interventions may condition outcomes and be associated with standard therapies. The acceptable macronutrient distribution of daily calories in a regular diet are 45–65% of daily calories from carbohydrates, 20–35% from fats, and 10–35% from protein. Basically, the ketogenic diet follows an approach based on low carbohydrates/high fat intake. In carbohydrates starvation, body energy derives from fat storage which is used to produce ketones and act as glucose surrogates. The ketogenic diet has several effects: metabolic interference with glucose and insulin and IGF-1 pathways, influence on neurotransmission, reduction of oxidative stress and inflammation, direct effect on gene expression through epigenetic mechanisms. Apart from these central effects working at the synapsis level, recent evidence also suggests a role for microbiome and gut-brain axis induced by a ketogenic diet. This review focuses on rationales supporting the ketogenic diet and clinical studies will be reported, looking at future possible perspectives.

The connection between epigenetics and gut microbiota‐current perspective

“…On luminal epithelia, butyrate‐sensitive G protein‐coupled receptors (GPCRs) are expressed by butyrate 54 . Less body weight and increased fatty acid oxidation is observed with a modified promoter of DNA methylation by high‐fat‐diet‐induced resistin and expressed adiponectin in mice 55 …”

Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM)

“…These studies suggest that the ketogenic diet may have therapeutic potential in treating glioblastoma, and further research is warranted to determine its optimal use in this context. Thus, several clinical trials are ongoing to assess the use of a ketogenic diet as an adjuvant therapy for glioblastoma patients as shown in Table 1 [ 173 ].…”

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

“…Additionally, in GBM, EGFR has been found to be constitutively active because of point mutations in the extracellular domain, especially A289V, R108K, and T263P (Figure 4A) (26). Regardless of the molecular mechanism causing constitutive activation, EGFR strongly induces GBM tumor growth and participates in other cell processes, such as autophagy, aerobic glycolysis, and biosynthesis of fatty acids and pyrimidines (Figure 4B) (27).…”