The Microbiome in Mammary Development, and Lacatation

乳腺发育和哺乳中的微生物组

• 批准号: 9430549
• 负责人: DARRYL L HADSELL
• 金额: $ 21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9430549
• 关键词: Affect; Bile fluid; Biology; Blood; Breast Cancer Risk Factor; Breast Diseases; Catalogs; Collaborations; Conjugated Estrogens; Data; Development; Developmental Biology; Disease; Ductal Epithelium; Environment; Environmental Risk Factor; Enzymes; Estrogens; Evaluation; Female; Future; Genetic; Genetic Variation; Gnotobiotic; Gold; Growth; Growth and Development function; Health; High-Throughput DNA Sequencing; Hormones; Inbred Strains Mice; Inbreeding; Inherited; Insulin-Like Growth Factor I; Intestines; Lactation; Link; Mammary Duct; Mammary Gland Parenchyma; Mammary gland; Measurement; Measures; Mediator of activation protein; Metabolism; Metagenomics; Molecular; Mus; Organism; Personal Satisfaction; Phenotype; Physiological; Play; Population; Process; Progesterone; Puberty; Regulation; Research; Role; Sexual Maturation; Shapes; Somatomedins; System; Technology; Testing; Time; Tissues; Variant; Work; breast milk microbiome; fecal transplantation; gut microbiome; malignant breast neoplasm; mammary gland development; microbial; microbiome; microbiome research; milk microbiome; novel; prepuberty; reproductive; trait; transmission process; urinary

Genetic background is known to influence all aspects of mammary biology from normal development and lactation to breast cancer. However, host genetics only explains a fraction of this variation and environmental factors, including those that could be inherited through maternal transmission, still play a major role. High-throughput DNA sequencing technologies have led to an emerging concept that the microbiome is a major contributor to normal development and health. In the mammary gland, there is now known to be both a tissue microbiome as well as a milk microbiome. There is also evidence to support the idea that the intestinal microbiome can influence estrogen dynamics through the activity of the “estrobolome”, a system of microbial enzymes capable of converting conjugated estrogens secreted in bile to free estrogen, which can be reabsorbed to elevate circulating concentrations. In prepubertal females this elevation would be expected to influence both the onset of puberty and the development of the mammary gland. Recent work has shown that the intestinal microbiome can be directly manipulated through the use of fecal microbiome transplantation (FMT), which can profoundly affect not only intestinal health, but also whole body growth and metabolism. In addition, FMT studies in mice suggest that the microbiome regulates the insulin-like growth factor system, a system that is linked to the regulation of sexual maturation, and that our own lab has shown to regulate mammary ductal development and lactation. Recent 16s pilot data from our team, that was collected in collaboration with Drs. Nadim Ajami and Joseph Petrosino of the Alkek Center of Metagenomics and Microbiome Research, has demonstrated that select inbred mouse strains with differences in mammary development and lactation capacity have striking differences in their intestinal microbiomes. These observations support the hypothesis that the intestinal and mammary microbiomes are dominant mediators of the effects of environment and genetic background on mammary development and lactation, and that these effects occur through modulation of estrogen, progesterone, and/or IGF-I. We will test this hypothesis first by establishing the range of variability in the intestinal, mammary, and milk microbiomes from inbred mouse strains of varying genetic background, and second by measuring the direct impact of microbiome diversity on mammary development and lactation through FMT into gnotobiotic female mice. Measurement of blood and urinary hormone concentrations will track the developmental effects of FMT in relationship to estrogen, progesterone, and IGF-I. The specific aims will be: 1) Establish the diversity and covariance among the gut, mammary, and milk microbiomes in inbred mouse strains with known genetic and phenotypic diversity in mammary development and lactation, 2) Determine the ability of FMT derived from inbred female mice that are genetically distinct and phenotypically divergent in mammary ductal development and lactation to influence these traits in gnotobiotic C57BL/6J female mice. The completion of these studies will provide an unprecedented test of the capacity for the intestinal microbiome directly impact reproductive maturation, mammary development and lactation. These findings will also pave the way for in-depth work to understand the physiological and molecular mechanisms through which the microbiome shapes normal mammary biology. Gaining this understanding will also contribute to understanding breast diseases.

已知遗传背景影响乳腺生物学的各个方面，从正常发育和哺乳到乳房 癌然而，宿主遗传学只能解释这种变异和环境因素的一小部分，包括那些 可以通过母体传播，仍然发挥着重要作用。高通量DNA测序技术 已经导致了一个新兴的概念，即微生物组是正常发育和健康的主要贡献者。在 在乳腺中，现在已知存在组织微生物组以及乳汁微生物组。还有证据 为了支持肠道微生物组可以通过“雌激素组”的活性影响雌激素动力学的观点， 一种能够将胆汁中分泌的结合雌激素转化为游离雌激素的微生物酶系统， 重吸收以提高循环浓度。在青春期前的女性中，这种升高预计会影响 青春期的开始和乳腺的发育。最近的研究表明， 可以通过使用粪便微生物组移植（FMT）直接操作，这可以深刻地影响非 不仅肠道健康，而且整个身体的生长和代谢。此外，小鼠FMT研究表明， 微生物组调节胰岛素样生长因子系统，该系统与性成熟的调节有关， 我们自己的实验室已经证明它可以调节乳腺导管的发育和泌乳。我们最近的16 s飞行员数据 该研究小组与Alkek宏基因组学中心的Nadim Ajami和Joseph Petrosino博士合作收集了这些数据 和微生物组研究，已经证明，选择乳房发育差异的近交系小鼠品系， 和泌乳能力在肠道微生物组中有显著差异。这些观察结果支持了 假设肠道和乳腺微生物组是环境影响的主要介质， 遗传背景对乳腺发育和泌乳的影响，这些影响是通过调节 雌激素、孕酮和/或IGF-I。我们将首先通过确定 肠道、乳腺和乳汁微生物组来自不同遗传背景的近交系小鼠品系，其次是 通过FMT测量微生物组多样性对乳腺发育和泌乳的直接影响， 雌性老鼠血液和尿液激素浓度的测量将跟踪FMT对发育的影响， 与雌激素、孕激素和IGF-I的关系。具体目标是：1）建立多样性和协方差 在具有已知遗传和表型多样性的近交系小鼠品系中， 乳腺发育和泌乳，2）测定来自遗传上 在乳腺导管发育和泌乳中不同的和表型上不同的，以影响这些特征， C57 BL/6 J雌性小鼠。这些研究的完成将为肠道的能力提供前所未有的测试。 微生物组直接影响生殖成熟、乳房发育和泌乳。这些发现也将为 深入了解微生物组形成的生理和分子机制的方法 正常的乳腺生物学获得这种理解也将有助于了解乳腺疾病。