Alterations of Gut Microbiome in Untreated Chronic Lymphocytic Leukemia (CLL); Future Therapeutic Potentials

Abstract

Introduction: Gut dysbiosis is an imbalance of the gut microbiome. The presence of dysbiosis can be a cause of systemic inflammation in the body or can be a contributing factor to it. Chronic systemic inflammation is a common feature of CLL, creating an environment in which CLL cells have a survival advantage. NF-κB and STAT3, master transcriptional regulators of pro-inflammatory markers, like IL-1 and IL-6, are reported to be involved in this process as are the Toll-like receptors (TLRs), key innate immunity receptors that are implicated in CLL pathophysiology. With increasing evidence for the role of dysbiosis in chronic inflammation, as well as the role of systemic inflammation in CLL, it seems relevant to prove the presence and the possible role of microbiome in the pathophysiology of CLL, to unravel the complex interaction between microbiome, nutrition and the host in patients with CLL. Our research investigate the hypothesis that dysbiosis i.e. the loss of "health-promoting" commensal gut microbes and/or the overgrowth of pathogenic bacteria distinguishes untreated patients with CLL versus aged-matched unaffected individuals. Methodology: Eight untreated CLL patients were with no history of gastrointestinal disorders, other malignancies and have not been on antibiotics for 4 weeks prior to samples collection. Two of them were not followed for logistical reasons. Six healthy volunteers matched for sex and age were also enrolled in the study. Stool samples from six patients and additional six matched healthy controls were collected and stored in a -40 freezer immediately until they were used for DNA isolation. Total genomic DNA was extracted using the Qiamp DNA stool mini kit and sequenced using Next Generation Sequencing and then analysis were done as per the manufacturer recommendations. Results: Our data indicates a reduced diversity and variability in bacterial phyla of gut microbiota in CLL patients as compare to healthy controls. Lower diversity with increase in certain bacterial types is a well-accepted sign of gut dysbiosis, which have been shown in many disorders such as; type-2 diabetes, obesity, and various autoimmune and neurological diseases. An increase in Proteobacteria numbers has been recognized as the signature of gut dysbiosis which we confirmed in our cohort of patients. Proteobacteria, Firmicutes and Bacteriodetes were also the most abundant bacterial phyla in CLL patients of our study which were reported previously in breast cancer patients. An elevated Firmicutes to Bacteroidetes ratio with altered gut microbiota in CLL patients compared with healthy subjects was also suggested in clinical studies involving obese individuals with insulin resistance. We have observed in CLL patients of this study relative increase in the numbers of Firmicutes and reduction in Bacteriodetes which is considered to be an inverted ratio as compared to healthy individuals which were also reported in ulcerative colitis, colonic and ileal crohn's disease as compared to healthy subjects. . Our finding of gut dysbiosis in this study is linked the association between CLL, inflammatory processes and dysbiosis. The microbiota may play a role in promoting malignancy through chronic inflammation, by disturbing the balance of cell proliferation, death and by initiating unwanted innate and adaptive immune responses. Conclusion: Restoring gut microbiota might open a new avenue for future researches as potential therapeutic intervention in CLL patients. Figure Disclosures No relevant conflicts of interest to declare.

Gut Microbiota in Untreated Diffuse Large B Cell Lymphoma Patients

“…Intestinal microecology plays an important role in the occurrence and development of many hematological malignancies (Christopher et al, 2019;Lee et al, 2019;Pianko et al, 2019). Gut microbiota may induce gene mutations (Arabski et al, 2005), possibly through chronic inflammation to disrupt the balance between cell proliferation and apoptosis (Kenza et al, 2018;Kawari et al, 2019), and may initiate unnecessary innate and adaptive immune responses (Calcinotto et al, 2018). Gene mutations and aberrant immune responses contribute to the occurrence and development of hematological malignancies.…”

The CLL comorbidity index in a population-based cohort: a tool for clinical care and research

“…18 Upper gastrointestinal disease, the third category in the CLL-CI, is associated with alterations in the intestinal microbiome. 19 Decreased intestinal microbial biodiversity may be more frequent in patients with CLL 20,21 and is associated with inferior response to immunotherapy in patients with certain cancers 22 and possibly also in CLL patients treated with chemotherapy. 23 We are currently investigating these hypotheses.…”

“… 19 Decreased intestinal microbial biodiversity may be more frequent in patients with CLL. 20,21 It is associated with inferior response to immunotherapy in patients with certain cancers 22 and possibly in patients with CLL who receive chemotherapy. 23 We are currently investigating these hypotheses.…”

Intestinal Microbes and Hematological Malignancies

“…In contrast to healthy donors, CLL patients had a diminished diversity and variability of intestinal flora, but enriched Proteobacteria , Scleroderma , and Bacteroides . In the clinical study of obese individuals with insulin resistance, the increased ratio of Firmicutes / Bacteroidetes in CLL patients was associated with insulin resistance [ 9 ].…”