Novel gut microbiota and microbiota-metabolites signatures in gliomas and its predictive/prognosis functions

Abstract

AbstractGliomas are the most common malignant tumors in the central nervous system. Host genetic and environmental factors have been implicated as the causes and regulators of gliomas. Evidence shows that alterations of the gut microbiome play an important role in multiple diseases including central nervous system disorders. However, the influence of gut microbiome to the epigenesis of gliomas remains largely unknown. Here we profiled the gut microbiome and metabolome in fecal samples from healthy volunteers and the patients with gliomas through the 16S rRNA gene sequencing and LC-MS analyses. The fecal samples from primary glioma patients (n=51), recurrent glioma patients (n=11), patients who underwent TMZ radio-chemotherapy (n=16) and healthy volunteers (n=37) were collected. 56 discriminatory OTUs and 144 metabolites were observed in gliomas compared to those in healthy volunteers, and some species were correlated with clinical parameters, such as tumor grade, IDH-1 and MGMT status. Moreover, the gliomas group showed increased activity in pathways associated with ectoine biosynthesis, fatty acid elongation (saturated), and protocatechuate degradation. At the same time, we revealed 4 fatty-acid metabolites(palmitic acid, oleic acid, DL−beta−Hydroxypalmitic acid, 4−(Methylamino)−4−(3−pyridyl)butyric acid) as possibly interacting with glioma growth. Random forest modeling indicated that a model involving 8 genera and 10 metabolite biomarkers achieved a high accuracy in gliomas prediction (AUC=94.4%). We investigated interassociations between the microbial genera in glioblastoma multiforme (GBM) and progression-free survival (PFS) and overall survival (OS) by Spearman’s correlation analysis. Patients with high proportions of fecalFaecalibacteriumhad significantly better median PFS or OS than those with low proportions (mPFS 495 vs. 281 days, p=0.005; mOS 604 vs. 395 days, p=0.044). Moreover, animal experiments have verified the causal relationship between the structural changes of gut microbiome and glioma growth. Our current study comprehensively characterizes the perturbed interface of gut microbiome and metabolites in glioma patients, which may be used as diagnostic and prognostic biomarkers of gliomas.