Glioma and temozolomide induced alterations in gut microbiome

Anthony Patrizz,Nuruddin Husein,Louise D Mccullough,Octavio Arevalo,Nitin Tandon,Yoshihiro Otani,Soheil Zorofchian,Takeshi Takayasu,Gabriella Hines,Jude Savarraj,Bhanu P Ganesh,Balveen Kaur,Antonio Dono,H Alex Choi,Yoshua Esquenazi,Leomar Y Ballester

doi:10.1038/s41598-020-77919-w

Abstract

The gut microbiome is fundamental in neurogenesis processes. Alterations in microbial constituents promote inflammation and immunosuppression. Recently, in immune-oncology, specific microbial taxa have been described to enhance the effects of therapeutic modalities. However, the effects of microbial dysbiosis on glioma are still unknown. The aim of this study was to explore the effects of glioma development and Temozolomide (TMZ) on fecal microbiome in mice and humans. C57BL/6 mice were implanted with GL261/Sham and given TMZ/Saline. Fecal samples were collected longitudinally and analyzed by 16S rRNA sequencing. Fecal samples were collected from healthy controls as well as glioma patients at diagnosis, before and after chemoradiation. Compared to healthy controls, mice and glioma patients demonstrated significant differences in beta diversity, Firmicutes/Bacteroides (F/B) ratio, and increase of Verrucomicrobia phylum and Akkermansia genus. These changes were not observed following TMZ in mice. TMZ treatment in the non-tumor bearing mouse-model diminished the F/B ratio, increase Muribaculaceae family and decrease Ruminococcaceae family. Nevertheless, there were no changes in Verrucomicrobia/Akkermansia. Glioma development leads to gut dysbiosis in a mouse-model, which was not observed in the setting of TMZ. These findings seem translational to humans and warrant further study.

Highlights

The gut microbiome is fundamental in neurogenesis processes
We performed a comparison of samples before tumor implantation (1st sample-baseline) vs. sacrifice (4th sample) to evaluate if glioma growth changes the gut microbiome (GM)
After our mice experiments demonstrating the effects of glioma development and TMZ in the GM of mice, we evaluated if this effects were observed in glioma patients compared to healthy controls

Summary

Introduction

The gut microbiome is fundamental in neurogenesis processes. Alterations in microbial constituents promote inflammation and immunosuppression. The aim of this study was to explore the effects of glioma development and Temozolomide (TMZ) on fecal microbiome in mice and humans. Mice and glioma patients demonstrated significant differences in beta diversity, Firmicutes/Bacteroides (F/B) ratio, and increase of Verrucomicrobia phylum and Akkermansia genus. These changes were not observed following TMZ in mice. Glioma development leads to gut dysbiosis in a mouse-model, which was not observed in the setting of TMZ. These findings seem translational to humans and warrant further study. The goals of this study were (1) to explore the GM changes following glioma growth and after oral TMZ in a glioma mouse-model and (2) to identify glioma induced GM changes and the effects of TMZ in a prospective glioma patient cohort

Objectives

Methods

Results

Discussion

Conclusion