Targeting Gut Microbiota Metabolites to Prevent Liver Cancer

针对肠道微生物代谢物预防肝癌

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要肝细胞癌 (HCC) 已成为癌症相关疾病的主要原因全球和美国的宏基因组研究揭示了这种肠道。有趣的是，微生物群失调可能对 HCC 患者具有诊断潜力。之前的《细胞》杂志强调，富含可发酵纤维菊粉的饮食可以作为诱发肠道菌群失调的小鼠患肝癌的触发因素。通过抗生素和无菌条件彻底消灭肠道微生物群菊粉诱导的 HCC，这引发了一个问题：肠道微生物群如何促进 HCC 以及在治疗上，肠道微生物群中的什么可以专门针对阻止 HCC 因此，我们首先在中发现了这种 HCC 表型。基因小鼠，但对于这个提议，我们已经产生了肠道菌群失调的野生型 (WTDYS)小鼠通过广泛繁育和杂交培育来研究特异性作用通过 16S rRNA 测序，我们发现肠道微生物群在菊粉诱导的 HCC 中的作用。 WTDYS 小鼠重现了与 HCC 相关的微生物群，其中包括过度生长产生短链脂肪酸 (SCFA) 和仲胆汁酸 (2° BA) 的梭菌种和机会性病原体，如 γ-变形菌，而粪便和血清。正在研究以含有菊粉的饮食喂养的 WTDYS 小鼠的内容物代谢组学分析，我们预计 SCFA 和基于 2° BA 的显着升高相关的细菌繁殖，这类似于我们最初的模型有趣的是，这两种肠道代谢物最近都在文献导致恒定自然杀伤 T (iNKT) 细胞严重减少，但扩大调节性 T (Treg) 细胞丰度，这会下调抗肿瘤反应并根据最近的见解，我们分别进行了肝脏治疗。通过流式细胞术在 WTDYS 小鼠中分离和表征免疫细胞并鉴定我们之前的研究和初步研究表明，iNKT 水平降低，但 Treg 细胞数量过多。数据使我们得出一个中心假设：肠道微生物群依赖性免疫抑制是菊粉诱发 HCC 的一个主要因素。在目标 1 中，我们将实施药物治疗。以及通过基因干预来阻断 SCFA 的产生和 SCFA 受体的激活，而目标 2 将应用药理和饮食干预来抑制 2° BA 的产生，我们认为这将是两种独立但相互关联的减少菊粉的方法通过恢复抗肿瘤免疫监视诱发肝癌。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor-deficient mice.

Toll 样受体 5 的缺失会增强法尼醇 X 受体缺陷小鼠的自发性肝癌发生。

DOI：
发表时间：
2023-06-01
期刊：
影响因子：
5.1
作者：
Golonka, Rachel M;Yeoh, Beng San;Saha, Piu;Gohara, Amira;Tummala, Ramakumar;Stepkowski, Stanislaw;Tiwari, Amit K;Joe, Bina;Gonzalez, Frank J;Gewirtz, Andrew T;Vijay
通讯作者：
Vijay