Evaluation of the Gut Microbiome in Chronic Lymphocytic Leukemia: Disease Insights and Potential Therapeutic Avenues

The gut microbiome is home to a community of microorganisms that play a crucial role in maintaining human health through the lifespan. The gut microbiome has been well-recognized as an enabling characteristic of cancer, with direction interactions between established cancer hallmarks. Recent studies have shed light on the complicated and intricate relationship between the gut microbiome and certain hematological malignancies; however, a more complete understanding of the role the gut microbiome plays in CLL is in high demand. CLL is a clonally derived B-cell malignancy whose pathogenesis is closely related to the activation critical survival pathways (e.g. BCR and TLR) where microbial antigens are known to be key stimulators driving CLL cell proliferation. Currently knowledge surrounding the role of the gut microbiome in CLL is limited. This work firstly sets out to establish that there is a role for the gut microbiome in CLL initiation and progression. With the use of two well-established murine models of CLL, we provide results implicating the gut microbiome as a potential factor in CLL, highlighting a unique and dysbiotic gut microbiome that forms as CLL disease develops. Additionally, we observed CLL penetration into the gastrointestinal (GI) tract, potentially suggesting a remodeling of the epithelial barrier resulting in increased intestinal permeability accompanies the dysbiotic microbiome observed during CLL progression. This work then shifted focus to examining how various modulations of the gut microbiome would impact the CLL disease course. Firstly, using a germ-free (GF) fecal microbiota transplant (FMT) model, an intriguing observation was made – colonization of leukemic-educated microbes seemingly provided a survival benefit over the colonization of healthy-educated microbes. Secondly, using a diet intervention model, we uncovered insight into a novel observation – diet intervention does contribute to earlier death primarily in mice consuming processed-like foods resembling a high-fat or fiber-poor diet. Collectively, this work confirms that the gut microbiome is influential in CLL disease initiation and progression, providing notable evidence to continue examining the causal relationships between the gut microbiome and CLL in order to fill in the necessary gaps addressed here.