The complex relationship between humans and their microbiome and the changes of the microbiome during the onset of human disease are poorly understood. We propose to form a Center for the detailed longitudinal analysis of both the microbiome, its activity, and its interconnected relationship with the host during healthy and disease states by omics profiling. Building upon our broad expertise, we will analyze several human microbiomes (fecal, nasal, and exogenous viral) in conjunction with host blood and urine components. Samples will be collected and analyzed during healthy and viral infections from the same individuals over the course of at least three years.

Through analysis of the microbiome and host biological activities as measured through a variety of omics approaches (metagenome, genome, transcriptome, proteome, metabolome), we will follow the dynamic changes in the microbiome and host pathways that occur during viral infections and other potential stresses, and obtain an unprecedented view of the molecular pathways that change during this period. We will focus on subjects at risk for diabetes, and we will correlate the molecular changes in microbiome (endogenous and viral) activity with changes in host glucose levels and diabetes onset.

Overall, more than 1080 different physiological states will be analyzed in omic detail and the microbiome and corresponding host information will be deposited in public repositories and serve as an invaluable resource to the scientific community. To accomplish this goal we have assembled a uniquely qualified team.

Specifically our Center will be involved in:

Specific Aim 1 - Cohort establishment, recruitment and sample acquisition

Collect microbiome and host samples from a cohort of 100 consented individuals at risk for diabetes. Dense sampling (at 1-to-4-day intervals) will occur during infected and other stress states and less sampling (every ~3 months) will occur during healthy periods, with a minimum of 27 timepoints sampled per subject.



Specific Aim 3 - Integrative analyses of microbiome omes and microbiome-host omes.

The different viral and fecal microbiome omes (genome, transcriptome and proteome) will be analyzed individually and in a combined fashion to determine the dynamic pathways that change during viral infection.

In addition we will correlate microbiome omic temporal profiles with those of the host omics profiles to obtain an unprecedented view of the global microbiome-host changes that occur during viral infections.

Specific Aim 2 - Omics analysis of longitudinal microbiome and host samples

Microbiome genetic, transcriptome and proteome content will be determined in fecal, nasal samples and PBMC samples (for viral and endogenous microbiome population).

Host genomic, transcriptomic, and proteomic data will be concurrently analyzed in blood components (PBMCs for genome and transcriptome; plasma for proteome). Combined microbiome and host metabolites will be analyzed in serum and urine. Anti-virome antibodies will also be analyzed.

Specific Aim 4 - Data release and outreach

All omics data will be deposited in accessible databases. For “open volunteers”, data will be deposited in an open access database. For partially restricted volunteers, data will be deposited in dbGaP.

Overall our longitudinal study is expected to reveal global changes in the microbiome and host at an unprecedented level and frequency, and identify the molecules and pathways that change during viral infections and diabetic onset and progression.