Abstract: The role of metabolites produced by gut microbiota in chronic inflammatory diseases is established; however, new evidence indicates a link between GI microbiota dysbiosis and hypertension (HTN). Recent evidence in human and animal models suggests that GI dysbiosis may be one of the mechanisms contributing to treatment-resistant neurogenic hypertension. Our preliminary data demonstrate that circulating bacterial metabolites, for example butyrate, are reduced in the spontaneously hypertensive rat (SHR) and in mice fed a moderately high salt diet prior to the development of high blood pressure, i.e. in the symptom free stage. This continues through established hypertension stage in the SHR. We also show that central administration of butyrate is able to reduce blood pressure, but to a lower extent in the SHR compared to normotensive animals. Thus, bacterial metabolites may play a significant role in maintaining cardiovascular homeostasis, and their imbalance may contribute to treatment-resistant neurogenic hypertension. This is particularly pertinent considering that up to 20% of patients remain either resistant or refractory to antihypertensive treatments. Moreover, HTN is a silent disease and relatively symptom free. Thus, there is a pressing need to identify microbiome-related metabolite biomarkers (Aim 1), that can be tested in a clinical environment which lead to preemptive and personalized therapeutics. We aim to measure these metabolites in brain cardioregulatory regions and to examine the functional relationship between metabolite and neurogenic hypertension (Aim 2). We propose that the gut dysbiosis-associated imbalance of microbial end products is present during the early symptom free stages of HTN. Two rodent models of neurogenic hypertension, the SHR and the Schlager mouse, and the inclusion of borderline hypertensive rats, will be used to identify predictive biomarkers in the symptom free stages of neurogenic HTN which can also indicate the severity of disease later on in life. Comparison with data from salt sensitive angiotensin II hypertension, also characterized by a significant neurogenic component, will yield biomarkers of environmentally induced hypertension as opposed to one influenced by genetic background. Alignment with human metabolomics data from literature using a meta-analysis approach will provide a clinical aspect that can be further explored in subsequent proposals. Functionally, we propose that the imbalance in gut bacterial metabolites will contribute to exaggerated central immune responses, mitochondrial dysfunction, and dysregulation of transcripts related to the renin- angiotensin system and major neurotransmitters (e.g. glutamate) in cardioregulatory regions of the brain, thus contributing to neurogenic hypertension. If this hypothesis is supported, our proposed studies will validate metabolite biomarkers predictive of severity of hypertension, and will contribute to the improvement and/or development of novel therapeutic approaches for the treatment of neurogenic hypertension.