Gut microbiome modulates the outcome in primary central nervous system lymphoma patients undergoing chemotherapy: An...

Primary central nervous system lymphoma (PCNSL) treatment relies on a high-dose methotrexate-based chemotherapy (HD-MTX-based CT) regimen; however, whether there is a specific microbiota composition association with treatment response and clinical outcomes remains incompletely understood.

We conducted a prospective study of PCNSL patients, included in the clinical trial NCT02313389 and the ancillary study NCT04253496 from 2020 to 2023, where patients were treated with first-line HD-MTX-based polychemotherapy without a consolidation treatment. Stool (n = 52), cerebrospinal fluid (CSF, n = 52), and plasma samples (n = 35) were collected before and/or after therapy initiation to perform metagenomic, flow cytometry, and metabolomic analyses. Plasma metabolomic data of 90 patients also included in the BLOCAGE clinical trial was subsequently used as a validation cohort.

Unsupervised clustering of microbial data identified two distinct gut microbial communities, differing in Parabacteroides distasonis abundance, which correlated with progression-free survival and overall survival in both uni- and multivariate analyses. Higher P. distasonis levels were linked to increased plasma betaine-valine metabolites and enhanced CD8 T cell infiltration in the CSF, suggesting a connection between gut microbiota and immune regulation. Stratifying the validation cohort by betaine-valine content confirmed these clinical associations.

Our findings suggest that gut microbiome communities modulate clinical outcomes in PCNSL patients undergoing standard treatment. Moreover, after future validation in external cohorts, the quantification of Parabacteroides distasonis could potentially provide a basis for patient stratification and guide personalized therapeutic strategies in the near future.