Effect of maternal obesity on breast cancer among offspring: role of the gut microbiota

母亲肥胖对后代乳腺癌的影响：肠道微生物群的作用

基本信息

批准号：
10734892
负责人：
LEENA A. HILAKIVI-CLARKE
金额：
$ 35.46万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734892
关键词：
Address Adverse effects Affect Age Agonist Air Pollution Allografting American Indians Antibiotics Bacteria Biological Biological Sciences Birth Black race Breast Cancer Cell Breast Cancer Model Breast Cancer Risk Factor C57BL/6 Mouse CD8-Positive T-Lymphocytes CRISPR/Cas technology Cell physiology Cells Child Clinical Clostridiaceae Cognitive Communities Consumption Crime Daughter Diabetes Mellitus Dietary Fiber Dietary Intervention Discipline of Nursing Emotional Endocrinology Etiology Exposure to FFAR2 gene FFAR3 gene Female Female of child bearing age Fetal Tissues Fiber Functional disorder Generations Goals Growth Human Immune Immunity Impairment Incidence Individual Inflammation Inflammatory Intervention Intervention Studies Inulin Knock-out Knockout Mice Life Link Long-Term Effects Mammary Neoplasms Mammary Tumorigenesis Mass Spectrum Analysis Measures Mediating Metabolism Microbe Minnesota Mouse Mammary Tumor Virus Mus Not Hispanic or Latino Obesity Obesity Epidemic Organ Outcome Play Predisposition Pregnancy Pregnant Women Prevention strategy Prevotella Probiotics Production Public Health Reporting Risk Role Shotguns Signal Transduction Testing Tissues Transplantation Tumor-infiltrating immune cells Volatile Fatty Acids Whole Blood Woman anti-tumor immune response cell type clinical translation diet-induced obesity dietary dietary control drinking water effective intervention fecal microbiota fecal transplantation gut bacteria gut dysbiosis gut microbes gut microbiota health disparity immune cell infiltrate immune function inflammatory marker low socioeconomic status malignant breast neoplasm mammary maternal obesity metagenomic sequencing mitochondrial metabolism mortality obese mothers obesity in pregnancy offspring polyoma middle tumor antigen pregnant prevent programs receptor stem cell differentiation western diet

项目摘要

In Minnesota, American Indian (34.1%) and non-Hispanic Black (33.4%) women are over twice as likely to be obese during pregnancy than non-Hispanic White women of whom 16.6% are obese during pregnancy. This high incidence reflects the causes of maternal obesity such as low socioeconomic status, high crime rate, and excess exposure to air pollution. Maternal obesity has widespread adverse effects on the offspring including increasing their risk of dying from breast cancer. Maternal obesity also permanently disrupts the mutually beneficial interaction between the offspring and offspring’s gut microbiota, causing gut dysbiosis. Gut dysbiosis in the offspring is characterized by a reduction in the gut bacteria that produce fecal short-chain fatty acids (SCFA). SCFAs play pivotal roles in maintaining healthy immune functions, cellular metabolism, and other critical functions. These compounds act mostly through their receptors GPR43 and GPR41, which are expressed in immune cells and multiple other cell types. Here, we will test the central hypothesis that the composition of commensal gut microbes in the offspring of obese dams is causally responsible for an offspring’s increased susceptibility to mammary tumorigenesis, an effect that likely also reflects altered immunity. We will test this causal link by performing fecal microbiota transfers (FMTs). The role of GPR43 and GPR41 in mediating the impact of maternal obesity on offspring will be tested using CRISPR/Cas9 knockout mice. The potential for clinical translation of our findings will be established by supplementing obese pregnant dams with a commercially available probiotic mix of SCFA-producing gut bacteria and dietary fiber that increases SCFA production. Such a combination has been earlier found to be most effective in reversing loss of critical microbes of healthy gut microbiota from individuals who have consumed an unhealthy Western diet for multiple generations. We will use allografted E0771 and Py230 mammary tumor models and MMTV-PyMT mice developing mammary tumors at about age 3 months. Shotgun metagenome sequencing and mass spectrometry will be applied to study gut microbiota and their metabolites, respectively. Changes in immune cell infiltration and activity will be measured in multiple tissues and compared with the expression of GPR43 and GPR41 in immune cells. Our studies could lead to effective and safe prevention strategies against breast cancer and its growth in the daughters of obese mothers, and be particularly beneficial for communities suffering from health disparities.

在明尼苏达州，美洲印第安人（34.1％）和非西班牙裔黑人（33.4％）妇女的可能性超过两倍怀孕期间的肥胖比非西班牙裔白人妇女，其中16.6％的怀孕期间肥胖。这高事件反映了孕产妇肥胖的原因，例如社会经济状况低，犯罪率高和过度暴露于空气污染。孕产妇肥胖对后代有不利影响，包括增加他们因乳腺癌而死的风险。孕产妇肥胖也永久破坏相互破坏后代和后代的肠道微生物群之间的有益相互作用，导致肠道营养不良。在后代中的特征是减少产生粪便短链脂肪酸的肠道细菌（SCFA）。 SCFA在维持健康的免疫功能，细胞代谢和其他关键方面发挥关键作用功能。这些化合物主要通过其受体GPR43和GPR41作用免疫细胞和其他多种细胞类型。在这里，我们将测试中心假设，即肥胖大坝后代的共生肠道微生物有时是造成后代增加的原因对乳腺肿瘤发生的敏感性，这种作用也可能反映出免疫力改变。我们将测试这个通过进行粪便微生物群转移（FMT）来因果关系。 GPR43和GPR41在中介孕产妇肥胖对后代的影响将使用CRISPR/CAS9敲除小鼠进行测试。潜力我们的发现的临床翻译将通过用商业上补充肥胖的孕妇大坝来确定可用的产生SCFA的肠道细菌和饮食纤维的可用益生菌混合物，可增加SCFA的产生。这样的早些时候发现一种组合在逆转健康肠道临界微生物的损失方面最有效从几代人食用不健康的西方饮食的人的微生物群。我们将使用同种异体移植的E0771和PY230乳腺肿瘤模型以及MMTV-PYMT小鼠在乳腺肿瘤上发育于大约3个月大。 shot弹枪元基因组测序和质谱法将用于研究肠道微生物群及其代谢产物。将测量免疫细胞浸润和活性的变化在多个时序中，与免疫细胞中GPR43和GPR41的表达进行了比较。我们的研究可以导致针对乳腺癌的有效和安全的预防策略及其在肥胖女儿中的成长母亲，对患有健康差异的社区特别有益。