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，美洲印第安人 (34.1%) 和非西班牙裔黑人 (33.4%) 女性的可能性是其两倍多 怀孕期间肥胖的比例高于非西班牙裔白人女性，其中 16.6% 怀孕期间肥胖。这 高发病率反映了孕产妇肥胖的原因，例如社会经济地位低、犯罪率高、 过度接触空气污染。母亲肥胖对后代有广泛的不利影响，包括 增加她们死于乳腺癌的风险。产妇肥胖也会永久破坏相互之间的关系 后代和后代肠道微生物群之间的有益相互作用，导致肠道菌群失调。肠道菌群失调 后代的特点是产生粪便短链脂肪酸的肠道细菌减少 （SCFA）。 SCFA 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着关键作用 功能。这些化合物主要通过其受体 GPR43 和 GPR41 发挥作用，这些受体表达于 免疫细胞和多种其他细胞类型。在这里，我们将检验中心假设，即 肥胖母猪后代中的共生肠道微生物是导致后代体重增加的原因 对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 通过进行粪便微生物群转移（FMT）来发现因果关系。 GPR43 和 GPR41 在介导 将使用 CRISPR/Cas9 敲除小鼠测试母亲肥胖对后代的影响。的潜力 我们的研究结果的临床转化将通过向肥胖怀孕母鼠补充商业药物来建立 产生 SCFA 的肠道细菌和膳食纤维的益生菌混合物可增加 SCFA 的产量。这样的 早期发现一种组合对于逆转健康肠道关键微生物的丧失最为有效 来自多代人食用不健康西方饮食的个体的微生物群。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 大约3个月大。鸟枪法宏基因组测序和质谱分析将用于研究肠道 分别是微生物群及其代谢物。将测量免疫细胞浸润和活性的变化 并与免疫细胞中 GPR43 和 GPR41 的表达进行比较。我们的研究可以 制定有效、安全的预防策略，预防乳腺癌及其在肥胖女儿中的生长 母亲们，并且对遭受健康差距的社区特别有益。