Elucidating the role of the gut metagenome in hypertension.

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Project Summary Cardiovascular disease (CVD) is the leading cause of death world-wide. The primary modifiable risk factor for CVD is hypertension (HTN), which is exacerbated by high sodium intake. One third of Americans are hypertensive, of which half exhibit salt-sensitive HTN. Additionally, 12% of HTN patients do not respond to treatment using standard medications. Taken together, these statistics highlight the critical need to elucidate the mechanisms involved in the development of HTN for the design of alternative treatment options. The gut microbiome has been implicated in many diseases including HTN. This project is designed to identify HTN- exacerbating or protective bacteria and their associated metabolic genes to inform the design of microbiome-based therapeutics for the treatment of HTN. Our preliminary results demonstrate that severe HTN induced by salt consumption correlates with shifts in the gut microbial community of Dahl salt-sensitive (SS) rats. Therefore, we tested the potential for the gut microbiota to affect HTN by performing a fecal material transfer (FMT) from hypertensive Dahl SS into HTN-resistant rats. We demonstrated that the microbiome was sufficient to exacerbate HTN in recipients and corresponded with statistically significant shifts in the gut microbiome. These results lead us to hypothesize that the gut microbiota directly influences HTN. Aim 1 will evaluate the role of bacterial supplementation during onset of HTN in the Dahl SS rat model. Predetermined strains identified from our preliminary experiments will be grown in vitro and transferred into SS Dahl rats and the effect on blood pressure and kidney damage will be evaluated. Potential mechanisms through which the bacteria influence the severity of HTN will be explored by measuring metabolite production, evaluating gut barrier function, and identifying shifts in the gut microbiome. Aim 2 will utilize machine learning to identify specific gut bacteria and metabolic genes that serve as signatures for the severity of HTN. Experiments in this aim will exploit shotgun metagenomic sequencing and computational approaches to identify specific bacteria and metabolic genes associated with HTN. Their use as predictive biomarkers for HTN will be validated by PCR-based analysis. This work will take place in the laboratory of Dr. John Kirby in the Department of Microbiology & Immunology (M&I) at the Medical College of Wisconsin, a highly collaborative and stimulating environment that is well equipped to perform the proposed aims. The Department of M&I offers a state-of-the-art educational program and various opportunities to explore alternative career pathways. We have designed a complementary training plan for my scientific and professional growth that will position me to reach my goal of becoming an independent biomedical scientist. In all, this project is critical for my advancement as a Latina woman in biomedical research, the field of HTN research, and the generation of microbiome-based therapeutics for CVD.