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

• 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
• 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

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，美国印第安人（34.1%）和非西班牙裔黑人（33.4%）的妇女有超过两倍的可能性， 非西班牙裔白色妇女中有16.6%在怀孕期间肥胖。这 高发病率反映了母亲肥胖的原因，如社会经济地位低，犯罪率高， 过度暴露于空气污染。母亲肥胖对后代有广泛的不良影响，包括 增加她们死于乳腺癌的风险。母亲的肥胖也永久性地破坏了 后代和后代肠道微生物群之间的有益相互作用，导致肠道生态失调。肠道生态失调 在后代中的特点是减少肠道细菌产生粪便短链脂肪酸 （SCFA）。SCFAs在维持健康的免疫功能、细胞代谢和其他关键功能方面发挥关键作用。 功能协调发展的这些化合物主要通过它们的受体GPR 43和GPR 41起作用，所述受体在细胞中表达。 免疫细胞和多种其他细胞类型。在这里，我们将测试的中心假设， 肥胖母鼠后代的肠道微生物是导致后代体重增加的原因 乳腺肿瘤发生的易感性，这种影响可能也反映了免疫力的改变。我们将测试这个 通过执行粪便微生物群转移（FMT）的因果关系。GPR 43和GPR 41在介导细胞凋亡中的作用 将使用CRISPR/Cas9敲除小鼠测试母体肥胖对后代的影响。的潜力 我们的研究结果的临床翻译将通过补充肥胖妊娠母鼠与商业 可获得的益生菌混合物的SCFA生产肠道细菌和膳食纤维，增加SCFA的生产。等 早期发现的一种组合在逆转健康肠道关键微生物的损失方面最有效 来自几代人食用不健康的西方饮食的个体的微生物群。我们将使用 同种异体移植E0771和Py 230乳腺肿瘤模型和MMTV-PyMT小鼠， 大约3个月大。鸟枪宏基因组测序和质谱将应用于肠道研究 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 并与免疫细胞中GPR 43和GPR 41的表达进行比较。我们的研究可以 导致有效和安全的预防乳腺癌及其在肥胖的女儿的增长策略 这将使妇女和母亲受益，并特别有益于健康不平等的社区。