The Role of the Bifidobacterium Gut Microbiome Guild in Pathophysiology of Chronic Heart Failure with Reduced Ejection Fraction

PROJECT SUMMARY/ABSTRACT The candidate’s long-term career goal is to lead an independent research program focused on defining mechanisms that govern gut microbiome-host interactions in chronic heart failure and to translate this knowledge into novel preventative and therapeutic targets. This research program will pave the path for gut microbiome-focused precision medicine approaches in heart failure. The candidate will use the structured environment of the K08 award to acquire advanced research expertise in microbiome meta-transcriptomic and time-series analyses, integrative multi-omic data analysis, clinical research methods, as well as targeted professional development skills in mentorship, scientific communication, grantsmanship, and leadership. This will be accomplished in the context of investigating longitudinal gut microbiome-host interactions in chronic heart failure and how these relate to disease pathophysiology and progression. The candidate will leverage a longitudinal multi-omic and clinical dataset from a cohort of 60 patients with chronic heart failure with reduced ejection fraction, previously recruited by the candidate as part of her NHLBI-funded F32. The first aim will examine the relationship between gut microbial Bifidobacterium- based functional guild and heart failure severity and outcomes. The second aim will elucidate shifts in the host immune profile, gut microbiome composition and function, and heart failure disease status following a targeted Bifidobacterium probiotic intervention. A new cohort of patients with stable chronic heart failure with reduced ejection fraction will be recruited for this aim. This project will uncover mechanisms by which the gut microbiome interacts with different facets of host biology, which is expected to provide novel insight into disease pathophysiology and explain heterogeneity in heart failure progression. This knowledge will translate into better disease risk stratification and identify new therapeutic targets in heart failure. The proposed project will be performed under the guidance of an expert mentorship team comprised of world- leading experts in host-microbiome multi-omics (Dr. Snyder), mechanistic microbiome research (Drs. Sonnenburg and Tang), and heart failure translational research and clinical trials (Drs. Tang and Khush). They will provide complementary expertise in skills applied in this project and support the candidate's career development. The rich multidisciplinary environment at Stanford is optimal for this research proposal and provides an ideal setting for the candidate’s development into an independent researcher. At the culmination of this proposal, the candidate will gain the necessary expertise and preliminary data for an R01 proposal to identify synergistic microbiome-host pathways that underlie heart failure pathophysiology. As an independent physician-scientist, the candidate will use gut microbiome-based precision medicine approaches to improve the outcomes of patients she cares for as a heart failure physician.