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.

项目摘要 结直肠癌仍然是第二大致死性癌症和第三大常见恶性肿瘤 国际吧携带致病性聚酮合酶的肺炎克雷伯菌在肠道定植 (pks)Jobin博士实验室证明，岛单独诱导肠道炎症并影响结直肠 癌症的临床前模型。恢复肠道植物群的正常平衡，减少或控制K. pneumoniae的浓度可以减少结肠直肠癌细胞的生长并改善宿主的结果。 不幸的是，目前消除感染性微生物的策略几乎完全依赖于抗生素 这种策略会严重破坏微生物群平衡，并经常造成不良影响。 一种创新的方法，可以精确干预并恢复肠道的微生物组平衡 植物群是使用噬菌体（即，）。噬菌体是能够裂解特异性 病原体而不干扰宿主的正常植物群，同时避免抗微生物剂的附带损害， 使用.我们的初步数据表明，分离的pkS可以特异性地根除pkS阳性的K。 pneumoniae在体外不感染其它克雷伯氏菌等肠道细菌。和大肠埃希菌 菌株此外，随着时间的推移，小鼠肠道中的E2的存在得以维持，并且不会触发 任何炎症。尽管如此，目前还不清楚细菌对细菌微生物组、宿主免疫系统或 肿瘤生长因此，该项目的中心假设是，益生菌可以通过以下方式平衡肠道微生物群： 减轻炎症，控制K.肺炎定殖，并防止宿主中的肿瘤生长。的 本申请的目的是定义细菌，细菌微生物组， 炎症和结肠肿瘤形成以及结肠炎相关的肿瘤发生。 拟议研究的理由是，这些结果将为未来的研究提供支持性证据。 开发和评估基于噬菌体的干预人类定殖与K。肺炎。我们的目标 （1）研究了水稻根际土壤中的根际土壤在选择性控制K.小鼠中的肺炎菌定殖和（2） 确定了白藜芦醇K的治疗价值。肺炎介导的结肠炎相关的肿瘤发生。 本研究的完成，将为进一步了解水稻根际光合作用对钾素的调控作用提供新的思路。 肺炎定殖和预防结肠肿瘤形成和炎症，而不会造成大规模破坏 微生物网络。定义细菌，细菌微生物组，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结肠癌是安全的， 在人类中的细菌定植和肿瘤生长的有效精确调节剂。