Gut microbiome, aging and cardiometabolic diseases in American Indians

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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.