The Hispanic/Latino population is the fasting growing segment of the US population. Diabetes disproportionately affects this group. National US 2007-09 data found that >20 yr old Hispanics (11.8%) have a 66% higher rate of diabetes compared to non-Hispanic whites (7.1%). In the population-based Hispanic Community Health Study (HCHS)/Study of Latinos (SOL), diabetes had a baseline prevalence of approximately 17%. Very recent data implicates the gut microbiome (GMB) as a key determinant of diabetes. Since different ancestral populations harbor different diabetes-associated sets of GMBs, it is necessary to study Hispanic/Latino populations with high rates of diabetes to determine the relationship between the GMB and diabetes. Understanding the relationship of the GMB to diabetes is anticipated to lead to a new era of prevention and treatment options, especially since therapeutic interventions are available that target the GMB. Nevertheless, there are major gaps in understanding the epidemiology of the GMB in the population and its role in the development of diabetes. The proposed study will leverage the HCHS/SOL study that will re-examine the participants in 2014-2017. This study has a major focus on diabetes including a fasting 2h glucose tolerance test (GTT), a standardized and universally accepted metric of glucose metabolism, in addition to specific other laboratory and clinical measurements. This proposed ancillary study will test the hypothesis that specific patterns of the gut microbiome will be significantly associated with pre-diabetes and diabetes, building upon recent advances in understanding the importance of the GMB in human health and metabolic diseases. This project will collect and determine the genetic composition of the fecal microbiome from 2,000 cohort members. The proposed study has developed a unique multidisciplinary team to address the following specific aims: (1) to investigate epidemiological factors affecting the gut microbiome in the sample of Hispanic/Latino individuals of diverse background who have normal indices of carbohydrate metabolism. We will test the association of geographic/ancestral background (e.g., Mexican, Puerto Rican), US birth status, gender, age, BMI, shared household and relatedness, and other variables with the GBM composition; (2) to utilize a cross-sectional design to evaluate the association of the gut microbiome (GMB) with the presence of disorders of carbohydrate metabolism including diabetes and prediabetes; and (3) to examine the longitudinal association of the GMB with risk of developing diabetes. We will use the active follow-up in the entire cohort to identify individuals who develop diabetes and estimate the relative risk of disease associated with different microbiomes. We hypothesize that the microbiomes found to be cross-sectionally associated with diabetes in Aim 2 will be predictive of the development of diabetes among initially pre-diabetic and normoglycemic individuals. 1

PUBLIC HEALTH RELEVANCE STATEMENT Diabetes and prediabetes are a major cause of morbidity and mortality and disproportionately affect individuals of Hispanic/Latino origins. This study will investigate the role of the gut microbiome on the development of diabetes in the Hispanic Community Health Study (HCHS)- Study of Latinos (SOL) cohort. This study should provide evidence to support the development of new therapeutic approaches to prevent and treat diabetes through targeting the gut microbiome.