Prospective Study of the Serological Microbial-Viral Interactome and Gut Microbiome-Virome in Type 2 Diabetes

About This Grant

PROJECT SUMMARY Type 2 diabetes (T2D) affects over 30 million US adults and remains a pressing public health challenge. While the gut microbiome is increasingly recognized as a contributor to T2D pathogenesis, the role of the human virome, including eukaryotic viruses and bacteriophages, has been largely overlooked, despite compelling mechanistic evidence and recent advances in sequencing and serological technologies, and computational tools that now enable comprehensive virome profiling. Moreover, most human microbiome studies have focused on species- or genus-level taxa, failing to capture strain-level functional differences that can have distinct metabolic and immunological consequences. This project will comprehensively characterize the “serological microbial-viral interactome”—the host’s systemic antibody response to microbial and viral exposures—and investigate its relationship with T2D development. Using Phage ImmunoPrecipitation Sequencing (PhIP-Seq), we will profile antibody responses to a large antigen library spanning bacteria, viruses, bacteriophages, and fungi. These data will be integrated with shotgun metagenomic and metatranscriptomic sequencing of fecal samples to assess microbial composition, strain-level diversity, gene functions, and active microbial transcription. State-of-the-art bioinformatic tools will be used to analyze both the gut microbiome and virome, including functional and strain-resolved profiling. We will apply this multi-omics framework in a prospectively designed, nested case-control study of 1,200 participants from two large US cohorts, the Hispanic Community Health Study/Study of Latinos (SOL) and the Nurses’ Health Study II (NHSII), comprising 600 healthy individuals who later developed incident T2D and 600 matched controls. We will test three key hypotheses: (1) antibody responses to microbial and viral antigens are associated with T2D risk; (2) strain-specific microbial features and their functions contribute to T2D pathogenesis; and (3) gut microbiome and virome features modify host immune responses and their links to T2D. Findings will be validated in an independent cohort, LifeLines DEEP, a population-based prospective study of 1,272 individuals who were free from T2D at baseline. By integrating serological and multi-omics data in a rigorously designed, prospective, multi-cohort study, this project will provide the first comprehensive systems-level assessment of how microbial and viral exposures shape host immunity and influence T2D risk. Results will advance the identification of novel microbial pathways and immune biomarkers, paving the way for microbiome-informed prediction, prevention, and therapeutic strategies for T2D.