The impact of an animal protein-based diet on a murine glioma model

Glioblastoma (GB) is the most aggressive primary brain tumor, with limited therapeutic options and poor prognosis. Recent research highlighted the gut-brain axis (GBA) role in influencing central nervous system pathophysiology, including tumor progression. One possible mechanism embroils the production of hydrogen sulfide (H2S), a gaseous signaling molecule mainly produced by gut microbiota through the metabolism of dietary proteins. In this study, we explored how gut-derived H2S affects glioblastoma growth via both direct (blood circulation) and indirect (vagus nerve-mediated) mechanisms. Using a glioma-bearing model of GB, we administered a standard animal-protein (AP) diet or a control diet for two weeks prior to tumor inoculation and for the next three weeks. To block bacterial H2S production in the gut, mice received aminooxyacetic acid (AOAA), an inhibitor of cystathionine β-synthase (CBS), ad libitum in drinking water. Contextually, we investigated the vagal pathway by pharmacologically blocking TRPV1 channels with capsazepine (CPZ), which are known to be activated by H2S and TRPV1 inhibition was validated through a tail-flick test assessing behavioral sensitivity to thermal stimuli. At the end of the experiment, fecal samples were collected to assess gut-microbiota modification. Our findings reveal that an AP diet reduce tumor growth, likely through shifts in H2S production and AOAA treatment reversed its antitumor effect and modify tumor microenvironment, suggesting a protective role of gut-derived H2S. Similarly, CPZ treatment promoted tumor growth, implicating vagal afferent signaling via TRPV1 in mediating H2S effects on the brain. These results suggest a dual role of the H2S (metabolic and neurogenic) in a GB progression, offering novel therapeutic strategies that target microbial and vagal pathways.