Bacteriophage-mediated microbiota modification to prevent colorectal cancer development

项目总结 结直肠癌仍然是第二大致命性癌症和第三大最常见的恶性肿瘤 全世界。肺炎克雷伯菌携带致病聚酮合酶的肠道定植 Jobin博士的实验室发现(PKS)岛可以单独引起肠道炎症并影响结直肠 处于临床前模型的癌症。恢复肠道菌群的正常平衡，减少或控制K。 肺炎杆菌的浓度可能会抑制结直肠癌细胞的生长，并改善宿主的预后。 不幸的是，目前消灭传染性微生物的策略几乎完全依赖于抗生素。 战略，这严重扰乱了微生物区系平衡，并经常造成不利影响。 一种创新的方法，在干预中带来精确度，并恢复肠道微生物群平衡 植物群是对噬菌体(即噬菌体)的使用。噬菌体是自然实体，能够裂解特定的 在不干扰寄主正常菌群的同时避免抗菌剂的附带损害 用法。我们的初步数据表明，分离的噬菌体可以特异性地清除PKS阳性的K。 体外培养肺炎克雷伯菌，不感染其他肺炎克雷伯菌和大肠杆菌等共生菌 菌株。此外，噬菌体在小鼠肠道中的存在随着时间的推移而保持不会触发 任何炎症。尽管如此，尚不清楚噬菌体如何影响细菌微生物群、宿主免疫系统或 肿瘤生长。因此，该项目的中心假设是噬菌体可以通过以下方式平衡肠道微生物区系 减轻炎症，控制肺炎克雷伯菌在宿主体内的定植，防止肿瘤生长。这个 当前应用的目的是定义噬菌体、细菌微生物组 结肠炎小鼠模型中的炎症和结肠癌的形成以及结肠炎相关的肿瘤发生。 提出这项研究的理由是，研究结果将为未来提供支持性证据。 肺炎克雷伯菌定植人群中基于噬菌体的干预方法的发展和评价。我们的目标是 目的(1)评价噬菌体在小鼠体内选择性控制肺炎克雷伯菌定植的作用和(2) 确定噬菌体在肺炎克雷伯菌介导的结肠炎相关肿瘤发生中的治疗价值。 在这项研究完成后，我们希望对噬菌体在控制K。 肺炎杆菌的定植和预防结肠肿瘤形成和炎症的无大规模破坏 微生物区系网络。定义噬菌体、细菌微生物群、炎症和 临床前模型中的结肠肿瘤形成可以使我们更接近于确定噬菌体是安全的和 有效的精确调节细菌在人体内的定植和肿瘤生长。

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.