Gut microbiome profiling in Eµ-TCL1 mice reveals intestinal changes and a dysbiotic signature specific to chronic lymphocytic leukemia

The gut microbiome’s role in the pathogenesis of hematological malignancies is actively being explored; yet studies in chronic lymphocytic leukemia (CLL) are limited. Using the Eµ-TCL1 murine model of CLL, we identify a unique and dysbiotic disease-associated gut microbiome that develops in mice over time. Leukemic mice show an increase in abundance of pathogenic bacteria, specifically members of the Proteobacteria phylum. We found that this dysbiotic microenvironment is associated with CLL involvement within the intestinal tract and high levels of markers indicative of altered tight junction permeability (e.g., CLDN2, sCD14, zonulin). Moreover, utilizing the syngeneic model of CLL in tandem with a microflora antibiotic-ablation approach, we found that leukemic mice receiving microflora-ablating antibiotics show marked changes to the gut microbiome and a delayed disease onset compared to mice receiving antibiotics-free water. Immunophenotyping of murine spleens showed that this delay in disease was accompanied by more tumor-reactive CD8+ T cells that co-expressed fewer inhibitory receptors (e.g., PD-1, LAG3, TIM3). These findings confirm a dysbiotic gut microbiome develops during CLL disease and demonstrate unique intestinal involvement and potential immune dysregulation occurring during CLL progression that may be influencing the overall microbial signature.