Role of mouse microbiome in cancer and inflammation

小鼠微生物组在癌症和炎症中的作用

基本信息

批准号：
9343818
负责人：
GIORGIO TRINCHIERI
金额：
$ 80.92万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9343818
关键词：
Address Adipose tissue Adverse reactions Affect Anorexia Antibiotic Therapy Antibiotics Attenuated Bacteria Bacterial Typing Bioinformatics Birth CCR Cachexia Cancer Control Cell Proliferation Cell physiology Cells Chemotherapy-Oncologic Procedure Chronic Cisplatin Clinical Colitis Comorbidity Crohn&apos s disease Cutaneous Development Disease Disease Outcome Distal Distant Epithelial Eukaryota Experimental Models Exposure to Fluorescent in Situ Hybridization Genes Genetic Germ-Free Gnotobiotic Health Hepatocarcinogenesis Homeostasis Housing Human Human body Immune Immune response Immune system Immunity Immunotherapy Individual Inflammation Inflammatory Interleukin-1 Receptors Interleukin-18 Intestinal Mucosa Intestines Invaded Label Life Liver Lung Lymphocyte Function Maintenance Malignant Neoplasms Mediating Metabolic Control Metabolism Metagenomics Methods Microbe Microbiology Molecular Mus Muscle Mutation Myelogenous Myeloid Cells Necrosis Obesity Oligonucleotides Pathogenesis Physiological Physiology Platinum Play Predisposition Production Prokaryotic Cells RNA Reactive Oxygen Species Regulation Resistance to infection Role Science Signal Transduction Site Skin Sterility T-Lymphocyte TNF gene Time Tissues Toxic effect base cancer immunotherapy cancer therapy carcinogenesis chemical carcinogenesis chemotherapy colitis associated cancer commensal microbes cytokine fecal transplantation fortification genotoxicity gut microbiome gut microbiota improved insight irradiation microbial microbial host microbiome microbiota microorganism monocyte mouse model mutualism nephrotoxicity pathogen programs reconstitution response stem subcutaneous tumor tumor microenvironment

项目摘要

In the Section of Cancer Immmunobiology as well as in a few other Sections within the Cancer and Inflammation Program as well as other part of CCR there is great need to understand the role of the gut microbiota in the pathogenesis of inflammatory and immune colitis and in mouse models of colitis-associated cancer. We extensively use mice deficient for immune or inflammation-related genes and it is always difficult to distinguish a direct effect of those genes on the colitis or cancer, or an indirect one through the regulation of the intestinal flora. Other collaborative studies in the program are directed to the study of the role of the liver immune response in controlling liver carcinogenesis and it is likely that the inflammatory-immunological microenvironment in the liver is also significantly affected by the composition of the intestinal flora. Overall these studies will greatly benefit by the access to a germ free facility that we are establishing in Frederick and particularly by the availability of committed expertise in gut microbiology based on state of the art sequencing and bioinformatics, expertise that is provided by the microbiome core that we have established in Bethesda. We have established methods for the determination of mouse microbioma using 454 sequencing or MiSeq sequencingof 16 RNA, metagenomic analysis using NextSeq sequencing, and cytofluorimetric analysis of FISH labeling of specific bacterial types. We also initiated studies with germ free mice, gnotobiotic mice with defined intestinal flora, and mice reconstitute after antibiotic treatment. Initially we studied the role of the intestinal microbiota in experimental models of colitis and colitis-associated cancer using mice genetically deficient for inflammation-controlling genes such as MyD88, IL-18, TNF, TLRs, and others. In this mice the genetic defects induce a dysbiosis that can be transferred to normal mice by co-housing or fecal transplant and enhance susceptibility to chemical carcinogenesis. The bacterial species responsible of this increased susceptibility to carcinogenesis and their mechanism of action are being investigated. The role of commensal microbiota in energetic alteration associated with cancer (i.e. obesity, cachexia, anorexia, cancer treatment, irradiation) has been initiated in murine experimental models and in observational clinical experimentation. Compartmentalized control of skin immunity by resident commensals (Science. 2012;337:1115-9). Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota has an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment (Science 342:967-970). The gut microbiome influences both local and systemic inflammation. Although the role of inflammation in cancer is well documented, whether commensal bacteria can exert distant effects on the inflammation in the sterile tumor microenvironment remains unclear. Here we show that microbiota perturbation impairs the response of subcutaneous cancers to CpG-oligonucleotide-immunotherapy or platinum chemotherapy. In antibiotic-treated or germ-free mice, decreased cytokine productionfrom tumor-infiltrating monocyte-derived cells following CpG-ODN treatment reduced tumor necrosis, whereas deficient chemotherapy-induced production of reactive oxygen species by myeloid cells impaired genotoxicity and tumor destruction. Thus, optimal response to cancer immunotherapy and chemotherapy requires an intact commensal microbiota that acts distantly by modulating myeloid-derived cell function in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment. The toxicity mediated by cisplatin (intestinal mucosa damage, nephrotoxicity, decrease of adipose and muscular tissues (cachexia)) require the presence of gut microbiota. The participation of different microbial species and the mechanisms by which they allow the cisplatin toxicity are being investigated.

在癌症和炎症计划中的其他一些部分以及CCR的其他部分中，在癌症免疫生物学部分以及CCR的其他部分中，非常需要了解肠道菌群在炎症和免疫结肠炎的发病机理以及与结肠炎相关癌症的小鼠模型中的作用。我们广泛使用缺乏免疫或炎症相关基因的小鼠，总是很难区分这些基因对结肠炎或癌症的直接作用，或通过调节肠道菌群的调节而间接的。该计划中的其他协作研究针对研究肝癌在控制肝癌中的作用的研究，肝脏中炎症性免疫学微环境很可能也受到肠道菌群组成的显着影响。总的来说，这些研究将通过我们在弗雷德里克（Frederick）建立的无菌设施的访问，尤其是基于肠道微生物学专业知识的可用性，这将在很大程度上受益，这将是基于艺术测序和生物信息学的肠道微生物学专业知识，这是由微生物组提供的专业知识，这些专业知识是我们在贝塞斯达（Bethesda）建立的。我们已经建立了使用454个测序或Miseq测序16 RNA，使用NextSeq测序的元基因组分析以及对特定细菌类型的鱼类标记的细胞基因组分析的方法来确定小鼠微生物瘤的方法。我们还开始使用无菌小鼠，具有定义的肠菌群的gnotobiotic小鼠以及抗生素治疗后重新构成的小鼠。最初，我们研究了肠道微生物群在结肠炎和结肠炎相关癌症实验模型中的作用，使用小鼠在遗传上缺乏炎症控制基因，例如MyD88，IL-18，IL-18，TNF，TNF，TLR和其他。在这只小鼠中，遗传缺陷会诱发营养不良，可以通过共屋或粪便移植并增强对化学癌变的敏感性转移到正常小鼠。正在研究这种细菌物种增加对致癌作用及其作用机理的敏感性。共生微生物群在与癌症（即肥胖症，恶病质，厌食症，癌症治疗，辐射）相关的能量改变中的作用已在鼠实验模型和观察性临床实验中启动。居民共生对皮肤免疫的隔离控制（Science。2012; 337：1115-9）。肠道细菌会诱导维持宿主微生物互助的保护性和调节反应。但是，尚未解决组织居民份额对其他屏障部位的免疫和炎症的贡献。我们发现，在小鼠中，皮肤微生物群在控制局部炎症环境和调整居民T淋巴细胞功能方面具有自主作用。发现对皮肤病原体的保护性免疫与皮肤微生物群有关，而不是肠道微生物群。此外，皮肤分别以依赖白介素-1受体下游的信号传导的方式调整了局部T细胞的功能。这些发现强调了微生物群作为组织隔室化的独特特征，并洞悉了居民在健康和疾病中的共生壁nike的免疫系统调节机制。共生细菌通过调节肿瘤微环境来控制癌症对治疗的反应（科学342：967-970）。肠道微生物组影响局部和全身性炎症。尽管炎症在癌症中的作用有充分的文献证明，但共生细菌是否可以对无菌肿瘤微环境的炎症产生遥远的影响。在这里，我们表明微生物群扰动会损害皮下癌症对CPG-寡核苷酸免疫疗法或铂化化疗的反应。在抗生素治疗或无菌小鼠中，CpG-ODN治疗后，细胞因子降低的单核细胞衍生细胞降低了细胞因子的细胞，降低了肿瘤坏死，而缺乏化学疗法诱导的基因毒性细胞损害了基因诺毒性和肿瘤的肿瘤细胞产生的活性氧的产生。因此，对癌症免疫疗法和化学疗法的最佳反应需要完整的共生菌群，该菌群通过调节肿瘤微环境中的髓样细胞功能而远处起作用。这些发现强调了微生物群在疾病治疗结果中的重要性。顺铂介导的毒性（肠粘膜损伤，肾毒性，脂肪降低和肌肉组织（Cachexia））需要存在肠道微生物群。正在研究不同微生物物种的参与及其允许顺铂毒性的机制。