The human microbiome varies by anatomic site, physiologic state, and time as it responds to internal and external stimuli. While accumulating data show associations with type 2 diabetes, there is a paucity of data on the progression from normal glycemia to prediabetes and diabetes. The longitudinal study proposed here will allow evaluating relationships of the microbiome with prediabetes development and progression to type 2 diabetes while separating the confounding effects of temporality. This study will evaluate 600 Mexican American individuals from Starr County, Texas at baseline and 3, 6, 12, 24, and 36 months later. Most importantly, these individuals will be composed of 300 with normal glycemia and 300 with prediabetes. Stool and nasal microbiomes will be evaluated. Evaluating 600 Mexican Americans in Starr County, Texas at 6 points in time over 3 years and from two microbiome sites will generate 7,200 samples and associated data to achieve the following:
Aim 1. Determine the influence of time and seasonality on nasal and gut microbiome diversity, relative abundance, and change through 16S ribosomal RNA sequencing of stool and nasal samples from 600 Mexican American individuals without diabetes - half with prediabetes and half with normal glycemia.
Aim 2. Test hypotheses that the development of prediabetes and progression to type 2 diabetes will be correlated with and impacted by the diversity and abundance of the gut and nasal microbiomes and that these microbiomes interact.
Aim 3. From stool and nasal samples of incident cases of prediabetes and type 2 diabetes and from those with the greatest changes in relative abundance and diversity from one time point to the next, determine the species driving the changes through whole genome sequencing metagenomics on 680 specimens. We also propose two exploratory/opportunistic aims. One, because species level determinations in Aim 3 will provide data on the DNA virome and two, because all individuals have been previously genotyped and whole exome sequenced. The sample sizes for these opportunistic aims are modest, but the uniqueness of the data merit evaluation.
Aim 4 : Conduct a preliminary evaluation of the distribution, abundance, and diversity of the DNA virome from those samples being sequenced to the species level in Aim 3.
Aim 5. Determine the effects of rare and common human genetic variation on the composition and dynamics of the nasal and gut microbiomes over time. The proposed longitudinal analyses are paramount to better understanding the impact of the microbiome on the development of prediabetes, progression to type 2 diabetes, and their reciprocal relationships. They will identify genera most associated with change and will identify those species that drive changes in relative abundance and/or diversity. Perhaps most significant is that the microbiome offers a readily modifiable target. However, before that, there must be an understanding of normal variation over time and its relationship to the development of prediabetes and type 2 diabetes.
The bacteria that live in our gut are key to how we metabolize food and are associated with type 2 diabetes. This project will determine the role of these bacteria (known collectively as the microbiome) on the development of prediabetes and type 2 diabetes. Because the microbiome can be manipulated, it is possible that by understanding its role in the development of diabetes that new strategies will be developed to slow the development of diabetes or even prevent and reverse the current trends where type 2 diabetes seems to keep increasing in an unchecked manner.
