Gut microbiome, aging and cardiometabolic diseases in American Indians

项目摘要 衰老和与年龄相关的心脏代谢疾病（CMD），如肥胖、2型糖尿病、高血压， 心血管疾病和慢性肾病，沿着它们的风险因素（例如，胰岛素抵抗， 炎症、血脂异常等），这是由遗传、生活方式和 环境因素美国印第安人（AI）不成比例地患有这些慢性心脏代谢疾病。 条件肠道微生物群（我们肠道中的细菌、病毒、真菌、多细胞寄生虫和古细菌） 作为一种新的、代谢活跃的"器官"出现，它调节许多关键的生物过程， 生理功能。肠道生态失调（肠道微生物群落失衡，例如，微生物多样性的丧失或 有益微生物、病原微生物的扩增）与慢性代谢紊乱有关。 然而，存在着一些基本的知识差距，例如，什么是关键的微生物特征 随着衰老和CMD？什么样的宿主因素塑造了肠道植物群，又是如何塑造的？具体的微生物或 人类肠道中的微生物种类，以及它们的组成和功能在不同的 人口/民族？人类肠道微生物群的变化是否受宿主基因组的影响，如果是， 什么程度？尽管存在这些未知因素，但人们普遍认为，肠道微生物组在不同的人群中存在显著差异。 其组成在很大程度上取决于个人的年龄，性别，地理，饮食偏好， 生活方式、健康状况等。由于人工智能患有肥胖症和糖尿病的比例很高， 其他部落的土地，吃传统的食物和药物，并实行其他独特的生活方式，有可能，他们 与其他人群/种族相比，具有不同的疾病和健康相关肠道微生物组 组本研究的目标是通过生成第一个 人类肠道微生物组的完整图谱，并确定与衰老相关的关键微生物特征， 美国印第安人的CMD。为了实现这一目标，我们将利用母公司SHS第七阶段（由NHLBI资助， 合同，2019 - 2026年），将在2020 - 2024年重新检查所有活着的参与者（N~= 3，000），以收集粪便样本 来自1,500名表现型良好的人工智能参与者。我们将进行全基因组鸟枪法宏基因组测序 并进行创新的统计分析，以：（1）确定与年龄相关的关键肠道微生物组特征， 与生物老化（通过白细胞端粒长度评估）和CMD（目标1）;（2）确定宿主因素， 塑造AI中的人类肠道微生物群（目标2）;（3）探索肠道生态失调，衰老， CMDs（目标3）。我们的长期目标是了解肠道微生物相互作用的机制 与主机因素导致加速老化和CMD，最终目标是开发新的，精密 治疗干预（例如，饮食、药物、活生物体、粪便微生物群移植），以促进健康 老化和改善心脏代谢健康。

Project Summary Aging and age-related cardiometabolic diseases (CMDs) such as obesity, type 2 diabetes, hypertension, cardiovascular disease, and chronic kidney disease, along with their risk factors (e.g., insulin resistance, inflammation, dyslipidemia, etc.), result from the complex interplay between genetic, lifestyle, and environmental factors. American Indians (AIs) suffer disproportionately from these chronic cardiometabolic conditions. Gut microbiota (bacteria, viruses, fungi, multicellular parasites, and archaea in our intestine) has emerged as a novel, metabolically active “organ” that regulates many key biological processes and physiological functions. Gut dysbiosis (imbalance in gut microbial community, e.g., loss of microbial diversity or beneficial microbes, expansion of pathogenic microbes) has been associated with chronic metabolic disorders. However, several fundamental knowledge gaps exist, e.g., what are the key microbial signatures associated with aging and CMDs? What host factors shape the gut flora and how? What are the specific microbes or microbial species in human gut, and how does their composition and function differ across different populations/ethnic groups? Is the variation in human gut microbiota influenced by host genome, and if so, to what extent? Despite these unknowns, it is well accepted that the gut microbiome varies significantly among individuals and its composition heavily depends on an individual’s age, gender, geography, dietary preference, lifestyle, health status, etc. Since AIs suffer from high rates of obesity and diabetes, live on reservations or other tribal lands, eat traditional food and medicine, and practice other unique lifestyles, it is possible that they harbor different sets of disease- and health-associated gut microbiomes compared to other populations/ethnic groups. The objectives of this study are to address these fundamental questions by generating the first complete map of the human gut microbiome and identifying key microbial features associated with aging and CMDs in American Indians. To achieve this, we will leverage the parent SHS Phase VII (funded by NHLBI as a contract, 2019-2026) that will re-exam all living participants (N~=3,000) in 2020-2024 to collect stool samples from 1,500 well-phenotyped AI participants. We will conduct whole-genome shotgun metagenomic sequencing and perform innovative statistical analyses to: (1) identify key age-related gut microbiome features associated with biological aging (assessed by leukocyte telomere length) and CMDs (Aim 1); (2) identify host factors that shape the human gut microbiota in AIs (Aim 2); (3) explore the mechanistic links between gut dysbiosis, aging, and CMDs (Aim 3). Our long-term goal is to understand the mechanisms through which gut microbes interact with host factors in leading to accelerated aging and CMDs, with an ultimate goal to develop novel, precision therapeutic interventions (e.g., diet, drugs, live organisms, fecal microbiota transplantation) to promote healthy aging and improve cardiometabolic health.