Gut microbiome study on Primary central nervous system lymphoma (PCNSL) demonstrates that chemotherapy response modulation is driven by specific microorganisms through the gut-brain axis.

Gut microbiota has gained attention as a potential modulator of occurrence, progression, and response to cancer therapy, with host immune regulation as one potential mechanism. Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma whose treatment relies on a high-dose methotrexate (HD-MTX) 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 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 was subsequently used as a validation cohort. Unsupervised clustering on microbial data revealed two microbial communities associated with significantly distinct PFS, OS and Parabacteroides Distasonis content in PCNSL patients. Further stratifying patients according to this bacterium content showed an association with plasma presence of the betaine;valine metabolite along with CD8 T cell infiltration to the CSF, suggesting a link between host immune cell regulation and gut microbiome composition. Stratifying patients by betaine;valine content in the validation cohort led to the same clinical associations.Our findings suggest that gut microbiome communities modulate response to standard treatment and clinical outcomes in PCNSL patients. Moreover, the identification of Parabacteroides Distasonis could potentially provide a basis for patient stratification and guide personalized therapeutic strategies.