The Microbiome in Mammary Development, and Lacatation

众所周知，遗传背景影响着从正常发育、哺乳到乳房的各个方面的乳腺生物学。 癌症。然而，宿主遗传学只解释了这种变异的一小部分和环境因素，包括那些 可以通过母体遗传，仍然发挥着重要作用。高通量DNA测序技术 已经导致了一种新兴的概念，即微生物群是正常发育和健康的主要贡献者。在 乳腺，现在已知既有组织微生物组，也有牛奶微生物组。也有证据表明 为了支持这样一种观点，即肠道微生物群可以通过“雌激素组”的活动来影响雌激素的动态， 一种微生物酶系统，能够将胆汁中分泌的结合雌激素转化为游离雌激素，这可以是 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到 青春期的开始和乳腺的发育。最近的研究表明，肠道微生物群 可以通过使用粪便微生物组移植(FMT)直接操纵，这可以深刻地影响 不仅是肠道健康，还包括全身的生长和新陈代谢。此外，对小鼠的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可以调节乳腺导管的发育和哺乳。来自我们的最新16年试点数据 团队，这是与阿尔克元基因组学中心的Nadim Ajami和Joseph Petrosino博士合作收集的 和微生物组研究表明，选择乳房发育不同的近交系小鼠 产奶量和产奶量在肠道微生物区系上存在显著差异。这些观察结果支持 假设肠道和乳腺微生物群是环境和环境影响的主要媒介 乳房发育和哺乳的遗传背景，这些影响是通过调节 雌激素、黄体酮和/或IGF-I。我们将首先通过建立 来自不同遗传背景的近交系小鼠的肠道、乳房和乳汁微生物群，其次是 通过FMT检测微生物组多样性对乳房发育和哺乳的直接影响 雌性老鼠。血液和尿液激素浓度的测量将跟踪FMT对儿童发育的影响 与雌激素、孕激素和IGF-I的关系。具体目标是：1)建立多样性和协变性 在已知遗传和表型多样性的近交系小鼠的肠道、乳房和乳汁微生物群中 乳房发育和哺乳，2)决定近交系雌性小鼠FMT的能力 在乳腺导管发育和哺乳过程中不同的表型差异对GnotoBiotic的这些特征的影响 C57BL/6J雌性小鼠。这些研究的完成将对肠道的能力提供前所未有的测试 微生物群直接影响生殖成熟、乳腺发育和哺乳。这些发现也将为 深入了解微生物群形成的生理和分子机制的方法 正常的乳腺生物学。了解这一点也将有助于了解乳房疾病。

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.