Dottoressa di ricerca

ciclo: XXXIV

supervisore: Prof.ssa Cristina Limatola

Titolo della tesi: The role of Short Chain Fatty Acids in the modulation of brain tumor microenvironment

Glioblastoma is one of the most frequent and lethal cancers in the Central Nervous System (CNS) in adults (Louis et al., 2007; Ostrom et al., 2014). Over the past decade, several evidences suggested that the intestinal microbiota, the complex community of microorganisms that populate the intestine, has a functional role in influencing the tumor microenvironment of their host. Short Chain Fatty Acids (SCFAs), the main metabolites produced in the colon by gut microbial metabolism (Natarajan et al., 2016; Silva et al., 2020), are speculated to play a key role in neuro-immunology regulation (Silva et al., 2020; Mossad and Erny, 2020). By performing metagenomic and metabolomic analyses of feces derived from mice housed in different environmental conditions, standard environment (SE) and enriched environment (EE), we have recently identified environment-specific microbial community and metabolic profiles, and in particular an increase in the level of formate and acetate in EE mice (Marrocco, Delli Carpini et al., under second revision). Considering also the beneficial impact of EE on glioma growth (Garofalo et al., 2015), in this PhD thesis we investigated the involvement of SCFAs in mediating microbiota-gut-brain interaction with a putative role in contrasting glioma progression. Our data showed that: (i) SCFAs had a direct effect on glioma proliferation in vitro, inhibiting cell growth both in murine glioma and human glioblastoma cell lines, and also in primary human glioblastoma cells; and (ii) SCFAs reduced microglia phagocytic activity driven by glioma-conditioned medium (GCM). In vivo, oral SCFAs administration to glioma-bearing mice: (i) increased the frequency of microglia cells in the tumoral hemisphere, correlated with a reduction in the expression of ARG1, which is a typical pro-tumoral anti-inflammatory marker; (ii) reduced the frequency of infiltrating monocytes/macrophages in the tumoral hemisphere; and (iii) decreased the frequency of Treg lymphocytes both in brain tumor hemisphere and at a systemic level, suggesting a role in modifying the glioma tumor landscape towards a less permissive phenotype to tumor progression. We didn’t find a reduction in glioma growth in SCFAs-treated mice compared to controls at twenty-one days after tumor injection. Nevertheless, we found a significant extension of mice survival performing a Kaplan-Meier curve analysis, suggesting that SCFAs can concur to the beneficial effects driven by EE microbiota on glioma.

Produzione scientifica

11573/1638245 - 2022 - Short-chain fatty acids promote the effect of environmental signals on the gut microbiome and metabolome in mice
Marrocco, Francesco; Delli Carpini, Mary; Garofalo, Stefano; Giampaoli, Ottavia; De Felice, Eleonora; Di Castro, Maria Amalia; Maggi, Laura; Scavizzi, Ferdinando; Raspa, Marcello; Marini, Federico; Tomassini, Alberta; Nicolosi, Roberta; Cason, Carolina; Trettel, Flavia; Miccheli, Alfredo; Iebba, Valerio; D’Alessandro, Giuseppina; Limatola, Cristina - 01a Articolo in rivista
rivista: COMMUNICATIONS BIOLOGY ([London]: Springer Nature) pp. 1-13 - issn: 2399-3642 - wos: WOS:000803887600003 (18) - scopus: 2-s2.0-85130993774 (20)

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