Targeting Gut Microbiota Metabolites to Prevent Liver Cancer

针对肠道微生物代谢物预防肝癌

• 批准号: 10557785
• 负责人: Rachel M. Golonka
• 金额: $ 1.27万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-13 至 2023-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557785
• 关键词: 16S ribosomal RNA sequencing; Abate; Ablation; Acids; Ally; Anhydrides; Antibiotics; Antitumor Response; Attenuated; BAY 54-9085; Back; Bacteria; Bile Acids; Biological Markers; Breeding; Butyrates; Cancer Biology; Cancer Etiology; Carcinoma; Cell Separation; Cells; Cessation of life; Childhood Liver Cancer; Cytotoxic T-Lymphocytes; Data; Diagnostic; Diet; Dietary Intervention; Disease; Doctor of Philosophy; Elderly; Environmental Risk Factor; Fiber; Flow Cytometry; Fostering; Future; G-Protein-Coupled Receptors; Gammaproteobacteria; Gastrointestinal tract structure; Genetic; Goals; Growth; Hepatic; Hepatocarcinogenesis; Histone Deacetylase Inhibitor; Human; Humulus; Hydrolase; Immune; Immunologic Surveillance; Immunologics; Immunology; Immunosuppression; Immunotherapy; Impairment; Intervention; Intestines; Inulin; Knowledge; Laboratories; Literature; Liver neoplasms; Malignant neoplasm of liver; Mediating; Metagenomics; Microbe; Modeling; Monitor; Mus; Natural Immunity; Natural Killer Cells; Nature; Nutritional Biochemistry; Oral; Pathogenesis; Patients; Phenotype; Physiology; Primary carcinoma of the liver cells; Process; Production; Publications; Reaction; Regimen; Regulatory T-Lymphocyte; Reporting; Repression; Research; Resistance; Role; Serum; Severities; Survival Rate; T-Lymphocyte; Technical Expertise; Therapeutic; Therapeutic Intervention; United States; United States Department of Agriculture; Universities; Volatile Fatty Acids; Wild Type Mouse; adaptive immunity; bile salts; dehydroxylation; diagnostic tool; dysbiosis; feeding; gene therapy; germ free condition; gut dysbiosis; gut microbiota; inhibitor; insight; male; metabolomics; microbial products; microbiota; microbiota metabolites; mortality; mouse model; new therapeutic target; novel; opportunistic pathogen; pathogenic bacteria; pharmacologic; prebiotics; prevent; receptor; side effect; therapeutic target; therapeutically effective; translational therapeutics; tumor

PROJECT SUMMARY/ABSTRACT Hepatocellular carcinoma (HCC) has emerged as a leading cause of cancer-related deaths globally and in the United States. Metagenomic studies are unveiling that gut microbiota dysbiosis may possess diagnostic potential for HCC patients. Intriguingly, our previous Cell publication highlights that a diet enriched with the fermentable fiber inulin can act as the trigger to induce HCC in mice with preexisting gut dysbiosis. Ablation of the gut microbiota through antibiotics and germ-free conditions completely eradicated inulin-induced HCC, which leads to question HOW does the gut microbiota contribute to HCC and, on the therapeutic standpoint, WHAT within the gut microbiota can be specifically targeted to impede HCC. Accordingly, we first found this HCC phenotype in genetically altered mice but for this proposal we have generated gut dysbiotic wild-type (WTDYS) mice through extensive breeding and cross fostering to study specifically the role of gut microbiota in inulin-induced HCC. Through 16S rRNA sequencing, we found that WTDYS mice recapitulated the HCC-associated microbiota, which includes an overgrowth of short chain fatty acid (SCFA)- and secondary bile acid (2° BA)-producing Clostridia species and opportunistic pathogens like γ-Proteobacteria. While the fecal and serum contents from WTDYS mice fed on inulin containing diet are in the process for metabolomics analysis, we expect to have a striking elevation of SCFA and 2° BA based on the associated bacterial blooms, which would be analogous to our original model with genetic deficiency. Intriguingly, both gut metabolites have been recently delineated in the literature to cause a severe reduction of invariant natural killer T (iNKT) cells but expand regulatory T (Treg) cell abundance, which would downregulate anti-tumor responses and favor immunosuppression, respectively. From this recent insight, we performed hepatic immune cell isolation and characterization via flow cytometry in WTDYS mice and identified mitigated levels of iNKT but overpopulated Treg cells. Our previous study and preliminary data lead us to the central hypothesis that gut microbiota-dependent immunosuppression is a main contributor to inulin-induced HCC. In Aim 1, we will implement pharmacologic and genetic interventions to blockade SCFA production and activation of SCFA receptors, while Aim 2 will apply pharmacologic and dietary interventions to inhibit 2° BA production, which we posit will be two independent, but inter-related, approaches to abate inulin- induced HCC by restoring anti-tumor immunosurveillance.

项目摘要/摘要 肝细胞癌（HCC）已成为癌症相关的主要原因 全球和美国的死亡。宏基因组学揭示了该肠道 菌群营养不良可能对HCC患者具有诊断潜力。有趣的是，我们的 以前的细胞出版物强调，富含可发酵纤维的饮食 可以充当诱导伴有肠道营养不良的小鼠中HCC的触发因素。消融 通过抗生素和无菌条件完全消除了肠道菌群 诱导的HCC，这导致肠道微生物群如何有助于 HCC，从治疗的角度来看，肠道菌群中的什么 专门针对障碍HCC。彼此之间，我们首先在 基因改变的小鼠，但对于此提案，我们产生了肠道不良生物野生型 （WTDYS）小鼠通过广泛的繁殖和交叉养育，专门研究角色 肌蛋白诱导的HCC中的肠道微生物群。通过16S rRNA测序，我们发现 WTDYS小鼠概括了与HCC相关的微生物群，其中包括过度生长 短链脂肪酸（SCFA）和次级胆汁酸（2°BA） - 产生梭状芽胞杆菌 物种和机会性病原体，例如γ-蛋白酶细菌。而粪便和系列 来自含丁素饮食的WTDYS小鼠的含量正在进行中 代谢组学分析，我们希望SCFA和2°BA的罢工升高 在相关的细菌血液上，这将类似于我们的原始模型 遗传缺陷。有趣的是，两种肠道代谢物最近都被描述 文献导致严重减少不变的天然杀手t（inkt）细胞，但扩展 调节性t（treg）细胞抽象，将下调抗肿瘤反应和 分别支持免疫抑制。从最近的见解中，我们进行了肝 通过WTDY小鼠的流式细胞仪进行免疫细胞分离和表征，并鉴定 减轻inkt的水平但人口过多的Treg细胞。我们以前的研究和初步 数据导致我们提出了一个中心假设，即肠道微生物群依赖性免疫抑制 是诱导的HCC的主要贡献者。在AIM 1中，我们将实施药理学 和遗传干预措施，以阻止SCFA的生产和激活SCFA接收器， 虽然AIM 2将采用药理和饮食干预措施来抑制2°BA的产生，但 我们将是两个独立但相互关联的方法，以减轻菊粉 - 通过恢复抗肿瘤免疫监视来诱导HCC。