Immunoepigenetic-gut microbiome axis in the social networks of health disparate youth

项目摘要/摘要 这项研究的主要目标是赋予健康不同社区的年轻人权力，以降低患上 通过评估社会网络之间的免疫表观遗传-肠道微生物组相互作用来研究心脏代谢疾病。 夏威夷原住民和太平洋岛民(NHPI)的患病率高得不成比例，而且更早 2型糖尿病(DM)的发病率高于美国其他种族/民族。这些健康差距可能 社交网络对塑造个人健康行为/生活方式和暴露于 肥胖环境，以及糖尿病进展背后的基因-环境相互作用。这个 社会环境的有害影响可能包括全身炎症的增加，这是 心脏代谢疾病，其中免疫系统的单核细胞起主要作用。事实上，我们观察到一种 邻里社会环境与不同健康人群炎症之间的关系。 包括DNA甲基化在内的表观遗传机制调节促炎症基因的转录 单核细胞，炎症的关键介质，并对肠道微生物群的变化做出反应 生活方式。肠道微生物区系失调可能是炎症相关疾病的潜在属性，如 DM，这也影响表观遗传过程所必需的底物的生物利用度。我们的初步数据 揭示DNA甲基化和促炎性基因表达状态在全基因组范围内的显著变化 糖尿病合并NHPI患者单核细胞炎症活性和血糖控制的相关基因 一种生活方式干预。此外，我们观察到大鼠肠道微生物群组成发生了显著变化 NHPI年轻人与糖尿病风险降低相关，糖尿病聚集在他们的社交网络中。我们的数据 表明社会环境影响肠道微生物群和单核细胞的表观基因组图景， 这可能会使他们的炎症状态启动，并导致炎症，从而导致破坏 葡萄糖动态平衡。我们试图探索这一“免疫表观遗传-肠道微生物组轴” NHPI网络面临糖尿病的风险。我们独特的多学科团队将测试假设 邻里社会环境条件下的单核细胞表观基因组景观 炎症，它(1)增加糖尿病的风险，(2)在社交网络中传播，(3)通过 以社区为基础的生命发展计划，影响免疫表观遗传-肠道微生物群轴。在两分钟内- 部分研究，我们将确定与邻里水平相关的DM风险的免疫表观遗传学特征 在嵌套病例对照研究设计中使用多民族队列(MEC)的因素，并将其与以下变化联系起来 一年中NHPI青年社会网络中DM的肠道微生物群和亚临床测量 以社区为基础的纵向研究。响应PAR-16-355，本研究旨在推动 表观基因组学关注健康差异并扩展理解表观遗传机制的方法 通过这些社会因素导致生物变化，从而影响卫生政策机构之间的健康差距。

PROJECT SUMMARY/ABSTRACT The primary goal of this study is to empower youth in health disparate communities to ameliorate risk for cardiometabolic diseases by evaluating immunoepigenetic-gut microbiome interactions among social networks. Native Hawaiians and Pacific Islanders (NHPIs) experience a disproportionately higher prevalence and earlier onset of Type-2 diabetes mellitus (DM) than other U.S. racial/ethnic groups. These health disparities may result from social network influences on shaping an individual's health behaviors/lifestyle and exposure to an obesogenic environment, as well as from gene-environment interactions underlying DM progression. The detrimental effects of social environments may include an increase in systemic inflammation, a hallmark of cardiometabolic diseases where monocytes of the immune system play a major role. Indeed, we observed an association between neighborhood social environments and inflammation in health disparate populations. Epigenetic mechanisms including DNA methylation regulate transcription of pro-inflammatory genes of monocytes, a key mediator of inflammation, and respond to changes in the gut microbiome associated with lifestyle. Dysbiosis of gut microbiota may be an underlying attribute of inflammatory-related conditions such as DM, which also affects bioavailability of substrates essential for epigenetic processes. Our preliminary data reveal significant genome-wide changes to DNA methylation and gene expression states of pro-inflammatory genes that associated with monocyte inflammatory activity and glycemic control in NHPIs with DM undergoing a lifestyle intervention. Additionally, we observed significant changes to the gut microbiome composition of NHPI youth that associated with reduced risk for DM, which clustered in their social networks. Our data suggest that social environments influence the gut microbiome and the epigenomic landscape of monocytes, which may prime their inflammatory state and contribute to inflammation that consequently lead to disrupted glucose homeostasis. We seek to explore this “immunoepigenetic-gut microbiome axis” among the social networks of NHPIs at risk for DM. Our unique multidisciplinary team will test the hypotheses that the neighborhood social environment conditions the monocyte epigenomic landscape associated with inflammation, which (1) increases DM risk, (2) propagates among social networks, and (3) is ameliorated by a community-based life development program that impacts the immunoepigenetic-gut microbiome axis. In a two- part study, we will identify an immunoepigenetic signature of DM risk associated with neighborhood level factors using the Multiethnic Cohort (MEC) in a nested case-control study design, and link this with changes to the gut microbiome and subclinical measures of DM in the social networks of NHPI youth over time in a community-based longitudinal study. Responsive to PAR-16-355, this study seeks to advance the science of epigenomics focused on health disparities and expand approaches for understanding epigenetic mechanisms by which social factors lead to biological changes that affect health disparities among NHPIs.