Hypertension (HTN) is the most prevalent modifiable risk for cardiovascular disease (CVD) and disorders directly influencing CVD (i.e. diabetes, chronic kidney disease, obstructive sleep apnea, etc.). Despite lifestyle changes and advances in drug therapy, ~20% of all HTN patients are resistant to (or require ?3) antihypertensive drugs Resistant HTN (R-HTN) is generally neurogenic in origin and associated with a dysfunctional autonomic nervous system. Few treatment options remain available following the recent failure of percutaneous renal artery sympathetic denervation (SYMPLICITY HTN-3, PRAUGE-15). Thus, a mechanism- based breakthrough is imperative to develop novel strategies to control and potentially cure R-HTN. We believe that our evidence of gut dysbiosis and dysfunctional brain-gut-bone marrow (BM) interaction in R-HTN represents this breakthrough. We propose a brain-gut-BM dysfunctional interaction hypothesis: HTN risk factors increase sympathetic drive by influencing autonomic brain regions, setting in motion a sequence of critical signaling events key to establishing neurogenic R-HTN. This includes increased gut stiffness, permeability and inflammation leading to gut microbial dysbiosis. Dysbiosis-associated changes increase BM production of myeloid progenitors and other proinflammatory cells. This contributes to increased peripheral inflammation, and neuroinflammation, as some BM-derived myeloid progenitors migrate to the paraventricular nucleus (PVN), and differentiate into microglia. Therefore, we hypothesize that establishment of R-HTN is caused by an increased SNA-mediated gut dysbiosis, activity of BM proinflammatory cells, and neuroinflammation.
Three specific aims are proposed to support/refute this dysfunctional brain-gut-BM linked neuroinflammation hypothesis in R-HTN:
Aim 1 will investigate the hypothesis that increased gut SNA is critical in enhanced intestinal permeability, proinflammatory conditions, and microbial dysbiosis in HTN.
Aim 2 will define how gut dysbiosis increases production of proinflammatory progenitors and neuroinflammation in HTN.
Aim 3 will evaluate the hypothesis that human R-HTN is linked to profound gut microbial dysbiosis and that treatment with minocycline will reverse the dysbiosis and lower BP. These studies will utilize state-of-the-art integrative physiological genomic techniques and will be conducted by an exceptional team of investigators. Thus, the outcome of this mechanism-based translational study spanning from mice to humans will provide the basis for development of paradigm-changing therapeutic approaches for R-HTN without involving more anti-hypertensive drugs.

Public Health Relevance

Hypertension (HTN) is the most prevalent risk for cardiovascular disease, diabetes, obesity, chronic kidney disease and obstructive sleep apnea. Despite campaigns for lifestyle changes and drug therapy, ~20% of HTN patients are resistant. HTN is neurogenic in origin, and is characterized by dysfunction of the autonomic nervous system (ANS), which heightens inflammation. We propose that increased ANS to the gut increases gut susceptibility, which induces microbial dysbiosis and increases neuroinflammation. This process causes drug resistance. We aim to determine if imbalances in the gut microbes can control neuroinflammation in resistant HTN (R-HTN). We will carry out two studies to determine if patients with R-HTN exhibit gut dysbiosis, and if minocycline's rebalancing of gut microbiota would lower blood pressure in R-HTN patients. We believe that the outcome of this study will be valuable for development of therapeutic approaches for R-HTN.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132448-04
Application #
9671954
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
OH, Youngsuk
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Walejko, Jacquelyn M; Kim, Seungbum; Goel, Ruby et al. (2018) Gut microbiota and serum metabolite differences in African Americans and White Americans with high blood pressure. Int J Cardiol 271:336-339
Smith, Steven M; Gurka, Matthew J; Calhoun, David A et al. (2018) Optimal Systolic Blood Pressure Target in Resistant and Non-Resistant Hypertension: A Pooled Analysis of Patient-Level Data from SPRINT and ACCORD. Am J Med 131:1463-1472.e7
Stevens, Bruce R; Goel, Ruby; Seungbum, Kim et al. (2018) Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut 67:1555-1557
Shah, Chintan; Gong, Yan; Szady, Anita et al. (2018) Unanticipated Cardiotoxicity Associated with Targeted Anticancer Therapy in Patients with Hematologic Malignancies Patients: Natural History and Risk Factors. Cardiovasc Toxicol 18:184-191
Kim, Seungbum; Goel, Ruby; Kumar, Ashok et al. (2018) Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure. Clin Sci (Lond) 132:701-718
Zubcevic, Jasenka; Santisteban, Monica M; Perez, Pablo D et al. (2017) A Single Angiotensin II Hypertensive Stimulus Is Associated with Prolonged Neuronal and Immune System Activation in Wistar-Kyoto Rats. Front Physiol 8:592
Santisteban, Monica M; Qi, Yanfei; Zubcevic, Jasenka et al. (2017) Hypertension-Linked Pathophysiological Alterations in the Gut. Circ Res 120:312-323
Yang, Tao; Ahmari, Niousha; Schmidt, Jordan T et al. (2017) Shifts in the Gut Microbiota Composition Due to Depleted Bone Marrow Beta Adrenergic Signaling Are Associated with Suppressed Inflammatory Transcriptional Networks in the Mouse Colon. Front Physiol 8:220
Richards, Elaine M; Pepine, Carl J; Raizada, Mohan K et al. (2017) The Gut, Its Microbiome, and Hypertension. Curr Hypertens Rep 19:36
Qi, YanFei; Goel, Ruby; Kim, Seungbum et al. (2017) Intestinal Permeability Biomarker Zonulin is Elevated in Healthy Aging. J Am Med Dir Assoc 18:810.e1-810.e4

Showing the most recent 10 out of 15 publications