Bacteriophage-mediated microbiota modification to prevent colorectal cancer development

噬菌体介导的微生物群修饰可预防结直肠癌的发展

• 批准号: 10467179
• 负责人: Lynn El Haddad
• 金额: $ 17.82万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467179
• 关键词: Adverse effects; Antibiotics; ApcMin/+ mice; Applied Research; Bacteria; Bacterial Infections; Bacteriophages; Buffers; Cancer Cell Growth; Cessation of life; Clinical; Colitis; Colitis associated colorectal cancer; Colonic Neoplasms; Colorectal Cancer; Data; Development; Disease; Equilibrium; Escherichia coli; Evaluation; Feces; Future; Germ-Free; Human; Immune response; Immune system; In Vitro; Individual; Infection; Inflammation; Inflammatory Bowel Diseases; Intervention; Intestines; Island; Klebsiella pneumoniae; Knowledge; Laboratories; Malignant Neoplasms; Mediating; Mission; Modeling; Modification; Monitor; Mus; Necrotizing Enterocolitis; Outcome; Pathogenicity; Phase I Clinical Trials; Pre-Clinical Model; Prevention strategy; Preventive; Randomized; Research; Ribosomal DNA; Role; Safety; Sterility; Testing; Therapeutic; Time; Tissues; Translating; United States National Institutes of Health; Virus; antimicrobial; bacteriome; base; carcinogenesis; colorectal cancer prevention; commensal bacteria; drinking water; fighting; germ free condition; gut colonization; gut inflammation; gut microbiota; host microbiota; improved outcome; innovation; insight; microbial composition; microbiome; microbiota; microorganism; murine colitis; neonate; normal microbiota; pathobiont; pathogen; polyketide synthase; prevent; restoration; tool; treatment response; tumor; tumor growth; tumorigenesis

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.

项目概要 结直肠癌仍然是第二大致命癌症和第三大流行恶性肿瘤 全世界。携带致病性聚酮合酶的肺炎克雷伯菌在肠道定植 Jobin博士实验室证明(pks)岛可单独诱发肠道炎症并影响结直肠 临床前模型中的癌症。恢复肠道菌群的正常平衡并减少或控制 K. 肺炎链球菌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，目前消除传染性微生物的策略几乎完全依赖抗生素 策略，这会显着破坏微生物群平衡并经常造成不利影响。 一种创新方法，可实现精确干预并恢复肠道微生物组平衡 菌群是噬菌体（即噬菌体）的使用。噬菌体是能够裂解特定噬菌体的自然实体 病原体，而不干扰宿主的正常菌群，同时避免抗菌药物的附带损害 用法。我们的初步数据表明，分离的噬菌体可以特异性根除 pks 阳性 K. 体外培养肺炎克雷伯菌，但不感染其他肺炎克雷伯菌和大肠杆菌等共生菌 菌株。此外，随着时间的推移，噬菌体在小鼠肠道中的存在得以维持，并且不会触发 任何炎症。尽管如此，目前还不清楚噬菌体如何影响细菌微生物组、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群： 减少炎症，控制肺炎克雷伯菌定植，并防止宿主体内肿瘤生长。这 当前应用程序的目标是定义噬菌体、细菌微生物组、 结肠炎小鼠模型中的炎症和结肠肿瘤形成以及结肠炎相关的肿瘤发生。 拟议研究的基本原理是，结果将为未来提供支持性证据 对肺炎克雷伯菌定植的人类进行基于噬菌体的干预的开发和评估。我们的目标 (1) 评估噬菌体在选择性控制小鼠肺炎克雷伯菌定植中的作用，以及 (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。 这项研究完成后，我们期望获得关于噬菌体在控制 K. 噬菌体中的作用的新见解。 肺炎链球菌定植并防止结肠肿瘤形成和炎症，而不会造成大规模破坏 微生物群网络。定义噬菌体、细菌微生物组、炎症和细菌之间的相互作用 临床前模型中结肠肿瘤的形成可以使我们更接近于识别噬菌体的安全性和有效性 人类细菌定植和肿瘤生长的有效精确调节剂。