The Role of Gut Microbiota in Hypertension

Study Overview
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Brief Summary
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Hypertension is the single most prevalent risk factor for heart diseases, heart failure, kidney failure and stroke. About 1 in 3 adults in the United States have hypertension. Approximately 28-30% of hypertensive patients suffer from resistant hypertension (RH). Inflammation has been implicated in the pathogenesis of the hypertension. Additional data suggests the involvement of gut microbiota in host normal cardiovascular functions and pathophysiology. Accumulating evidence demonstrates that antibiotic treatment benefits patients with acute coronary syndromes and reduces the incidence of ischemic cardiovascular events. Even though these studies did not address effects of antibiotic treatment on the gut microbiota, it is possible that gut microbiota could affect neurologic inflammation. Finally, intestinal microbiota has recently been proposed to modulate blood pressure (BP) through production of short-chain fatty acids. In order to investigate this, the investigators hypothesize that gut microbiota is involved in the neuroinflammation-mediated initiation and establishment of RH, and targeting gut microbiota by minocycline would produce beneficial outcomes in RH.

Detailed Description
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This is a prospective cohort design. This study will enroll 388 subjects: 81 patients without HTN as a reference group, 81 patients with controlled HTN, 55 patients with uncontrolled HTN, 55 with remodeled RH, and 81 patients with RH to characterize gut microbiota composition. Subjects will provide stool samples for analysis. Subjects will also provide a blood sample for inflammatory marker and stem cell analysis.

Official Title
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The Role of Gut Microbiota in Hypertension: Brain-Gut Microbiome-Immune Axis in Hypertension

Conditions
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Hypertension

Intervention / Treatment
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* Other: Stool Sample and Blood Sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age >18 and <80 is competent and willing to provide consent Inclusion criteria for each subject group: Control subjects will have a systolic BP <140mmHg with no cardiovascular disease Patients with controlled hypertension Patients with uncontrolled hypertension Resistant hypertension subjects will have systolic blood pressure (BP) ≥140 mmHg despite ≥3 anti-hypertensive medications of different classes one of which should be a diuretic Patients who are no longer RH subjects and have normal blood pressure Subjects participating in NCT 02133872 will be eligible to participate Exclusion Criteria: currently pregnant or have been pregnant in the last 6 months; antibiotic treatment within 2 months of study enrollment; currently taking a medication (e.g., antibiotic, anti-inflammatory agents, glucocorticoids or other immune modulating medications); unwilling to discontinue vitamin or supplements, including probiotics, potentially affecting gut microbiota (vitamins/supplements and medications that possibly affect the gut microbiota should be discontinued for at least 2wks prior to stool collection); history of intestinal surgery, inflammatory bowel disease, celiac disease, lactose intolerance, chronic pancreatitis or other malabsorption disorder.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Normal controls without hypertension<br>Control subjects will have a systolic BP <140mmHg with no cardiovascular disease. These subjects will provide a one time stool sample and a blood sample. | Other: Stool Sample and Blood Sample<br>* All subjects will provide a stool sample and a blood sample at baseline. Subjects in NCT02133872 will provide a second stool sample and blood sample at their 3 month visit.<br>|
| Controlled hypertension<br>Subjects with controlled hypertension will provide a one time stool sample and a blood sample. | Other: Stool Sample and Blood Sample<br>* All subjects will provide a stool sample and a blood sample at baseline. Subjects in NCT02133872 will provide a second stool sample and blood sample at their 3 month visit.<br>|
| Resistant hypertension<br>Resistant hypertension subjects will have systolic blood pressure (BP) ≥140 mmHg despite ≥3 anti-hypertensive medications of different classes. These subjects will provide a one time stool sample and a blood sample. | Other: Stool Sample and Blood Sample<br>* All subjects will provide a stool sample and a blood sample at baseline. Subjects in NCT02133872 will provide a second stool sample and blood sample at their 3 month visit.<br>|
| Prior enrolled in NCT 02133872<br>These subject will be asked to provide two stool samples and two blood samples. One at baseline and one after 3 months of therapy. | Other: Stool Sample and Blood Sample<br>* All subjects will provide a stool sample and a blood sample at baseline. Subjects in NCT02133872 will provide a second stool sample and blood sample at their 3 month visit.<br>|
| Remodeled Resistent Hypertension<br>Subjects with controlled hypertension will provide a one time stool sample and a blood sample. | Other: Stool Sample and Blood Sample<br>* All subjects will provide a stool sample and a blood sample at baseline. Subjects in NCT02133872 will provide a second stool sample and blood sample at their 3 month visit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize gut microbiota composition at phylum level | Stool samples to analyze the composition of the microbiota, extracted bacterial genomic DNA will be used as a template for PCR reactions targeting the V4-V5 variable regions of the 16S rRNA gene. Amplicons generated from the PCR will be run on the Illumina MiSeq sequencing platform available in our laboratory to profile microbial communities at phylum level. | 24 hours | 
| Characterize gut microbiota composition at genus level | Stool samples to analyze the composition of the microbiota, extracted bacterial genomic DNA will be used as a template for PCR reactions targeting the V4-V5 variable regions of the 16S rRNA gene. Amplicons generated from the PCR will be run on the Illumina MiSeq sequencing platform available in our laboratory to profile microbial communities at genus level. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in BP is associated with changes in gut microbiota composition in RH subjects. | Stool samples from patients enrolled in NCT 02133871 that received minocycline medication for resistant hypertension. Will be used to analyze the composition of the microbiota and data (taxonomic assignment) will be analyzed using QIIMEv1.3 pipeline to enumerate microbial population between samples derived from the cohorts. | Baseline, 3 months | 
| IS hypertension associated with increased sympathetic activity and decreased parasympathetic activity and whether minocycline or other tetracyclines are effective to improve this balance | Stool samples from patients enrolled in NCT 02133871 that received minocycline | Baseline and 3 months | 
| To determine if characterization of gut microbiota in at risk patients predicts long term care utilization and/or cardiovascular outcomes | Stool samples | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Resistant Hypertension (RH), Uncontrolled Hypertension