Bacteriophage-mediated microbiota modification to prevent colorectal cancer development

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PROJECT SUMMARY Colorectal cancer remains as the second most lethal cancer and the third most prevalent malignant tumor worldwide. An intestinal colonization with Klebsiella pneumoniae carrying a pathogenic polyketide synthase (pks) island was shown by Dr. Jobin laboratory to singly induce intestinal inflammation and influence colorectal cancer in a pre-clinical model. Restoration of the normal balance of the gut flora and reduction or control of K. pneumoniae concentration may curtail colorectal cancer cell growth and improve outcomes in the host. Unfortunately, the current strategy to eliminate infectious microorganisms rely almost exclusively on antibiotic strategy, which significantly disrupt microbiota balance and often cause adverse effects. One innovative approach to bring precision in the intervention and restore the microbiome balance of the gut flora is the use of bacteriophages (i.e., phages). Phages are natural entities capable of lysing specific pathogens without disturbing the host’s normal flora while averting the collateral damage of antimicrobial usage. Our preliminary data indicate that isolated phages can specifically eradicate pks-positive K. pneumoniae in vitro without infecting commensal bacteria such as other K. pneumoniae and Escherichia coli strains. Additionally, the presence of phages in the murine gut was maintained over time and did not trigger any inflammation. Still, it is unclear how phages impact the bacterial microbiome, the host immune system, or tumor growth. Hence, the central hypothesis for this project is that phages can balance the gut microbiota by decreasing inflammation, controlling K. pneumoniae colonization, and preventing tumor growth in the host. The objective of the current application is to define the interaction between phages, bacterial microbiome, inflammation, and colonic tumor formation in a mouse model of colitis and a colitis-associated tumorigenesis. The rationale for the proposed research is that the outcomes will provide supportive evidence for future development and evaluation of a phage-based intervention in humans colonized with K. pneumoniae. We aim to (1) evaluate the role of phages in selectively controlling K. pneumoniae colonization in mice and (2) determine the therapeutic value of phages in K. pneumoniae-mediated colitis-associated tumorigenesis. At the completion of this research, we expect to obtain new insights on the role of phages in controlling K. pneumoniae colonization and preventing colonic tumor formation and inflammation without massive disruption of microbiota network. Defining the interaction between phages, bacterial microbiome, inflammation, and colonic tumor formation in a pre-clinical model can bring us a step closer to identifying phages as safe and effective precise modulators of bacterial colonization and tumor growth in humans.