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). Recentevidence in human and animal models suggests that GI dysbiosis may be one of the mechanisms contributingto treatment-resistant neurogenic hypertension. Our preliminary data demonstrate that circulating bacterialmetabolites, for example butyrate, are reduced in the spontaneously hypertensive rat (SHR) and in mice fed amoderately high salt diet prior to the development of high blood pressure, i.e. in the symptom free stage. Thiscontinues through established hypertension stage in the SHR. We also show that central administration ofbutyrate 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, andtheir imbalance may contribute to treatment-resistant neurogenic hypertension. This is particularlypertinent considering that up to 20% of patients remain either resistant or refractory to antihypertensivetreatments. Moreover, HTN is a silent disease and relatively symptom free. Thus, there is a pressing need toidentify microbiome-related metabolite biomarkers (Aim 1), that can be tested in a clinical environment whichlead to preemptive and personalized therapeutics. We aim to measure these metabolites in braincardioregulatory regions and to examine the functional relationship between metabolite and neurogenichypertension (Aim 2). We propose that the gut dysbiosis-associated imbalance of microbial end productsis 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 identifypredictive biomarkers in the symptom free stages of neurogenic HTN which can also indicate the severity ofdisease later on in life. Comparison with data from salt sensitive angiotensin II hypertension, also characterizedby a significant neurogenic component, will yield biomarkers of environmentally induced hypertension asopposed to one influenced by genetic background. Alignment with human metabolomics data from literatureusing a meta-analysis approach will provide a clinical aspect that can be further explored in subsequentproposals. Functionally, we propose that the imbalance in gut bacterial metabolites will contribute to exaggeratedcentral 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, thuscontributing to neurogenic hypertension. If this hypothesis is supported, our proposed studies will validatemetabolite biomarkers predictive of severity of hypertension, and will contribute to the improvement and/ordevelopment of novel therapeutic approaches for the treatment of neurogenic hypertension.