Tuesday, February 4, 2025
2/4/2025
Project Summary Periodontitis and Type II Diabetes (T2D) are co-occurring diseases and among the most prevalent chronic illnesses in the United States with an estimated 46.5% of adults suffering from the former, 9.4% adults suffering from the latter, and 62.3% of diabetic adults older than 65 burdened by both. T2D, characterized by a state of chronic systemic inflammation, can lead to periodontitis via dysregulated host immune responses and a positive feedback loop between systemic inflammation and oral dysbiosis. The observation that periodontitis adversely affects glycemic control, insulin resistance, and diabetic complications like neuropathy, cardiovascular disease, and even death is well accepted, but the underlying mechanism is unknown. Periodontitis has emerged as a potential modifier of the gut microbiome, whose role in regulating systemic and metabolic health is increasingly being recognized. Multiple studies point to gut microbiome dysbiosis as a contributor to metabolic disorders, inflammatory bowel disease (IBD), colorectal cancer and rheumatoid arthritis. Combined with evidence oral dysbiosis is associated with gut microbiome compositional changes, and, that oral microbes make up gut microbiome signatures in T2D, rationale exists for the oral-gut microbiome axis as a link between periodontitis and diabetes. The goal of this NRSA F30 proposal is to evaluate the effect of periodontitis, and its associated mouth microbiome dysbiosis, on metabolic pathways of the gut microbiome important to metabolic disorders and T2D. The overarching hypothesis of this proposal is that periodontitis alters the gut microbiome vis oral-to-gut strain transmission to contribute to metabolic dysfunction and inflammation in T2D. The purpose of Aim 1 is to determine if microbial specific strain-level genetic variation and oral dysbiosis are associated with functional changes in the gut microbiome. The purpose of Aim 2 is to test oral-to-gut strain transmission as a mechanism by which periodontitis alters the gut microbiome, and contributes to poor outcomes related to T2D. Using subject-matched plaque and feces samples, the oral and gut microbiomes will be characterized at strain- level resolution, and metabolic profiles will be reconstructed for each microbiome. The experiments outlined in this proposal will determine the role of specific oral strains and oral-to-gut strain transmission in contributing to the pathologic systemic effects of periodontitis seen in T2D. This work will take place at the University at Buffalo, School of Dental Medicine, in the laboratory of Dr. Patricia Diaz, who is an expert in microbiome research. The training plan is tailored for development as a physician-scientist in the field of infectious disease, and will include clinical preceptorships in infectious disease and endocrinology in order to gain cross-disciplinary experience, reflecting the research goals of this proposal. These longitudinal clinical preceptorships will be with successful physician-scientists, who also will be directly involved in the proposed research, thereby providing integrated mentorship over the course of the fellowship.
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