Saturday, November 23, 2024
11/23/2024
Project Summary Hypertension is the single prominent risk factor of epidemic proportions leading to cardiovascular disease and stroke, which comprise the top two reasons for mortality of humans in the modern age. Genetics and dietary salt intake are the most investigated factors for susceptibility to hypertension. We recently discovered a novel link between the composition of gut microbiota and hypertension in the Dahl Salt-Sensitive (S) rat, a rodent model of human disease. However, except for a few metabolites such as short chain fatty acids, the mechanisms by which microbiota trigger hypertension is largely unknown. Microbiota collaborates with the host to produce key metabolites required for host health. Conjugated bile acids are one such class of bile acids. They are generated by the host in the liver and deconjugated by microbiota in the gut. A bile acid targeted metabolomics study led us to discover that conjugated bile acids are significantly depleted in hypertension, rescuing which ameliorated hypertension. Thus, the overarching hypothesis of this proposal is that conjugated bile acids are novel antihypertensive metabolites. To test this hypothesis, experiments are proposed to address two important questions: First, why are conjugated bile acids depleted in hypertension? Aim 1 will address this question. Preliminary data show that specific gut microbiota which are known to deconjugate bile acids expand during hypertension. We propose to investigate whether such microbiota are the culprits responsible for depleting the circulating pool of conjugated bile acids. Using novel S rats which lack gut microbiota, studies are proposed to introduce specific microbiota to test its effect on enhancing the circulating levels of the antihypertensive metabolites, conjugated bile acids. Aim 2 will address the second important question, ‘What is the mechanism by which conjugated bile acids provide protection against the development of hypertension?’ Focusing on taurocholic acid, which is a specific conjugated bile acid depleted during hypertension, Aim 2 will test the hypothesis that taurocholic acid lowers hypertension by targeting the gut FXR-ceramide pathway. Specifically, taurocholic acid antagonizes the bile acid receptor Farnesyl X receptor (FXR) in the gut to inhibit the transcription of key genes required for the synthesis of the known prohypertensive metabolite, ceramide. A novel Villin-Cre rat knock-in rat and a second novel FXR knockout rat have been constructed and proposed as tools to study this gut-specific mechanism. Overall, this work expands our current limited knowledge beyond the host factors and sheds important new light on how microbiota critically modify bile acid biochemistry to amplify hypertension. Our proposal not only identifies this problem, but also interrogates a means to mitigate it by a simple solution of enhancing circulating conjugated bile acids as a novel putative clinical therapeutic strategy to lower hypertension.
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