Hypertension
Conditions
Keywords
African American, Blood pressure, Gut Microbiome, Short-chain fatty acid, Butyrate
Brief summary
African Americans have the greatest burden of hypertension. Recently, the short-chain fatty acid, butyrate, has been reported to have some effect on blood pressure. Butyrate is not normally ingested since it is made by bacteria in the gut as a byproduct of fiber fermentation. In this proof of concept study, the investigators will investigate the effect of butyrate absorbed in the gut (via the participant self-administering an enema with butyrate) has on blood pressure.
Detailed description
Description: African Americans (AA) have the greatest burden of hypertension. Recently, gut microbial dysbiosis (a term that describes a poorly diverse gut microbial profile and lower short-chain fatty acid (SCFA) production) has been linked to hypertension and may be involved in the pathogenesis of hypertension in African Americans. African Americans have been reported to have lower gut SCFA and SCFA can reduce blood pressure. This is a proof of concept pilot study to determine the relationship between gut SCFA and blood pressure (BP). Delivery of butyrate to the gut will be via enema. Objectives: The objectives of this research are to 1. Identify gut microbial taxa (SCFA butyrate-producing microbes) and circulating butyrate levels associated with hypertension via a cross-sectional design in AA without and with hypertension. 2. Quantify the relationship between SCFA (butyrate) absorption into the bloodstream and subsequent changes in blood pressure in a 24-hour period after delivering butyrate into the gut via enema. Participants: African Americans males and females ages of 30-50 without hypertension (normal BP/healthy control; systolic BP: 90-129/ diastolic BP: 60-89mmHg) and with hypertension (systolic BP: 130-159 mmHg/ diastolic BP: 80-99 mmHg) that do not take anti-hypertension medication will be recruited. Description of Study: There are 2 groups; control (without hypertension; BP: 90-129/60-89mmHg; 5 male/5 female, n=10) and experimental (with hypertension; BP 130-159/80-99 mmHg; 5 male/5 female, n=10). Normotensive participants (control group) will be age (±1 year) and sex-matched to hypertensive group participants. All participants (control and experimental groups; 5 male/5 female) will provide stool and blood samples, and complete 24-hour (hr) ambulatory blood pressure (ABP) monitoring to compare the abundance of fecal butyrate-producing microbes, circulating (blood) butyrate concentrations, and average blood pressure responses during the day and overnight. Individuals in the control group will only participate in donating stool (1-time) and a blood sample (1-time) and wearing a 24-hr ABP monitor (1-day). In a crossover blinded randomized controlled pilot study, the 10 hypertensive AA subjects (5 male/5 female) will be randomized to self-administer a sodium butyrate (80mmol butyrate in 0.9% saline, 60 ml total) or control (low dose) butyrate (5mmol butyrate 0.9%, 60 ml total) enema 1 week apart (7 days). Subjects will provide a stool sample before each study day (2 total), have their BP measured via ABP monitor, submit to a blood draws (pre-enema-baseline), self-administer the randomized enema, submit to a 30 min & 60 min post-enema blood draw, and wear the 24-hour ABP monitor for the remainder of that day. Subjects will be provided with written and verbal instructions on how to self-administer the enema. The dietary supplement (sodium butyrate) will be compounded by a local pharmacy (Custom Care Pharmacy - 109 Pisgah Church Rd. Greensboro, NC) into an enema at the concentrations listed above.
Interventions
DRUGSodium Butyrate 5 mmol
Enema-based delivery of 5 mmol butyrate in 0.9% saline, (60 mL total)
DRUGSodium Butyrate 80 mmol
Enema-based delivery of 80 mmol butyrate in 0.9% saline, (60 mL total)
Sponsors
North Carolina Translational and Clinical Sciences Institute
North Carolina Agriculture & Technical State University
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Only the participants with hypertension will perform the enema in a randomized order. The participants, nursing research staff (e.g., care providers), nor the PI's will know which enema the subjects are receiving. The study Biostatistician (e.g., statistical outcome assessor) will only be given the treatment IDs and not be given the sodium butyrate concentrations during statistical analyses. Randomization will be performed by 1 member of the research team at the beginning of the study who is also not involved in any informed consent process. Enemas will be assigned a letter (e.g., A or B) and each letter will be placed in an envelope (blinded allocation concealment). The research team member will reveal the key upon the conclusion of the study.
Intervention model description
In this blinded study, participants with Hypertension will self-administer a \[5 mmol\] and a \[80 mmol\] sodium butyrate enema in a randomized order 1 week (7 days) apart.
Eligibility
Sex/Gender
ALL
Age
30 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
Normotensive (control subjects without hypertension): In order to be eligible to participate in this study, an individual must meet all of the following criteria (which will be assessed after an initial telephone interview and at Visit 1 (screening and consent visit): * Provision of signed and dated informed consent form * Be an African American adult (man or woman) between 30 - 50 years of age with normal blood pressure (never diagnosed with hypertension) (systolic: 90-129 and diastolic: 60-89 mmHg). * Body Mass Index of 18.5-30 kg/m\^2 * Not have any other diagnosed cardiovascular disease * Not exercise regularly (Participate in less than 60 minutes of exercise/week) * Not be pregnant or be lactating * Be free of active diseases that affect your intestines (i.e., chronic constipation, diarrhea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diverticulosis, stomach or duodenal ulcers, diabetes, hepatitis, HIV, and cancer) * Have not taken antibiotics in the past 3 months * Have not been regularly taking medications that impact intestinal function (i.e., laxatives, enemas, anti-diarrheal agents, narcotics, antacids, antispasmodics, antidepressants, anticonvulsants, antibiotics, herbals, homeopathy, and home remedies) or fiber supplements. * Have no plans of travel out of town during the study periods. * Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration Hypertension subjects not on anti-hypertension medication (intervention group). The pool of subjects that do not take hypertension medication may be limited. If a heavily medicated subject population is encountered, the investigators may include subjects taking diuretics only: In order to be eligible to participate in this study, an individual must meet all of the following criteria (which will be assessed after an initial telephone interview and at Visit 1 (screening and consent visit): * Provision of signed and dated informed consent form. Letter of clearance or signature of PCP on informed consent. * Be an African American adult (man or woman) between 30 - 50 years of age with stage-1 to stage-2 hypertension (systolic: 130-159 and diastolic: 80-99 mmHg). * Not taking any anti-hypertension medications (although the investigators may enroll individuals only taking a diuretic where resting BP levels are within the range of stage-1 hypertension: systolic BP 130-140 mmHg. Subjects can resume taking the diuretic after they remove the monitor). * Body Mass Index of 18.5-30 kg/m\^2 * Not have any other diagnosed cardiovascular disease * Not exercise regularly (Participate in less than 60 minutes of exercise/week) * Not be pregnant or be lactating * Be free of active diseases that affect your intestines (i.e., chronic constipation, diarrhea, Crohn's disease, ulcerative colitis, irritable bowel syndrome, diverticulosis, stomach or duodenal ulcers, diabetes, hepatitis, HIV, and cancer) * Have not taken antibiotics in the past 3 months * Have not been regularly taking medications that impact intestinal function (i.e., laxatives, enemas, anti-diarrheal agents, narcotics, antacids, antispasmodics, antidepressants, diuretics, anticonvulsants, antibiotics, herbals, homeopathy, and home remedies) or fiber supplements. * Have no plans of travel out of town during the study periods. * Agreement to adhere to Lifestyle Considerations throughout study duration
Exclusion criteria
for both groups: * Exercise more than 60 minutes per week for more than 4 consecutive weeks. * Diagnosed with stroke, history of myocardial infarction (heart attack); liver, lung, or kidney diseases; peripheral vascular disease or cancer within the last 6 months. * Presence of metabolic disease (diabetes mellitus), inflammatory diseases (e.g., inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematosus); kidney stones or gallbladder problems; diagnosed liver, lung or kidney diseases; * Pregnancy, lactation, or actively trying to conceive. * Taking anti-hypertension medications (i.e., calcium channel blockers, ACE inhibitors, angiotensin- receptor blockers, β-blockers, vasodilators, etc.) other than diuretics (e.g., hydrochlorothiazide, chlorothiazide, furosemide, etc) or medications known to affect inflammation or metabolic function (anti-inflammatories, statins, thyroid medication) in the past 1 month. If diuretics are used, subjects may able to participate if they agree to refrain from taking their diuretic the day of the experiment. In this instance, resting systolic BP while on their medication will still need to be greater than 130 mmHg. * Current smoker or tobacco use within the last 10 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Daytime Blood Pressure | approximately 16 hours post enema | Immediately following self-administration of butyrate enema, participants will be fitted with an ambulatory blood pressure monitor to be worn for 24 hours. |
| Mean Nighttime Blood Pressure | approximately 8 hours post enema | Immediately following self-administration of butyrate enema, participants will be fitted with an ambulatory blood pressure monitor to be worn for 24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Butyrate Concentrations | up to 1 hour post enema | Measure blood butyrate concentrations before, 30 minutes post, and 60 minutes post self-administration of the butyrate enemas |
| Interleukin-1 Beta (IL-1β) Concentration | up to 1 hour post enema | Blood biomarker samples were collected for the inflammatory cytokine IL-1β. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sodium Butyrate [5 mmol] First, Then Sodium Butyrate [80 mmol] After a randomized assignment in the crossover design, participants with hypertension will come to the testing office to self-administer the first enema with a concentration of 5 mmol sodium butyrate in a 0.9% saline solution (60 ml total). After a 7-day washout period, they will return to testing office to self-administer the other enema with a concentration of 80 mmol sodium butyrate in a 0.9% saline solution (60 ml total). | 10 |
| Sodium Butyrate [80 mmol] First, Then Sodium Butyrate [5 mmol] After a randomized assignment in the crossover design, participants with hypertension will come to the testing office to self-administer the first enema with a concentration of 80 mmol sodium butyrate in a 0.9% saline solution (60 ml total). After a 7-day washout period, they will return to the testing office to self-administer the other enema with a concentration of 5 mmol sodium butyrate in a 0.9% saline solution (60 ml total). | 0 |
| Control African Americans with normal blood pressure (control group) will not perform self-administration of the enema. They will submit to 1 blood draw and wear the 24-hour ambulatory blood pressure monitor for 1-day. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Sodium Butyrate [5 mmol] First, Then Sodium Butyrate [80 mmol] | Sodium Butyrate [80 mmol] First, Then Sodium Butyrate [5 mmol] | Control | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 0 Participants | 10 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 0 Participants | 10 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 0 Participants | 10 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 10 Participants | 0 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Female | 5 Participants | 0 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Male | 5 Participants | 0 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 0 |
| other Total, other adverse events | 0 / 10 | 0 / 10 | 0 / 0 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 0 |
Outcome results
Primary
Mean Daytime Blood Pressure
Immediately following self-administration of butyrate enema, participants will be fitted with an ambulatory blood pressure monitor to be worn for 24 hours.
Time frame: approximately 16 hours post enema
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sodium Butyrate [5 mmol] | Mean Daytime Blood Pressure | 137.5 mmHg | Standard Deviation 13.47 |
| Sodium Butyrate [80 mmol] | Mean Daytime Blood Pressure | 132.9 mmHg | Standard Deviation 12.64 |
| Control | Mean Daytime Blood Pressure | 128.2 mmHg | Standard Deviation 16.31 |
Primary
Mean Nighttime Blood Pressure
Immediately following self-administration of butyrate enema, participants will be fitted with an ambulatory blood pressure monitor to be worn for 24 hours.
Time frame: approximately 8 hours post enema
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sodium Butyrate [5 mmol] | Mean Nighttime Blood Pressure | 123.2 mmHg | Standard Deviation 13.5 |
| Sodium Butyrate [80 mmol] | Mean Nighttime Blood Pressure | 116.2 mmHg | Standard Deviation 10.9 |
| Control | Mean Nighttime Blood Pressure | 114.0 mmHg | Standard Deviation 12.8 |
Secondary
Blood Butyrate Concentrations
Measure blood butyrate concentrations before, 30 minutes post, and 60 minutes post self-administration of the butyrate enemas
Time frame: up to 1 hour post enema
Population: Unable to perform venipuncture for 1 participant in the control arm. Only baseline data are reported for the control arm for reference purposes as this group did not receive the intervention. Unable to collect blood at the 60-minute time point due to consistent antecubital vein rupturing after repeated venipuncture efforts.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Butyrate [5 mmol] | Blood Butyrate Concentrations | 30 Minutes Post | 138.64 ng/mL | Standard Deviation 11.29 |
| Sodium Butyrate [5 mmol] | Blood Butyrate Concentrations | Baseline | 143.88 ng/mL | Standard Deviation 20.62 |
| Sodium Butyrate [80 mmol] | Blood Butyrate Concentrations | Baseline | 138.60 ng/mL | Standard Deviation 16.84 |
| Sodium Butyrate [80 mmol] | Blood Butyrate Concentrations | 30 Minutes Post | 151.57 ng/mL | Standard Deviation 36.12 |
| Control | Blood Butyrate Concentrations | Baseline | 149.89 ng/mL | Standard Deviation 45.47 |
Secondary
Interleukin-1 Beta (IL-1β) Concentration
Blood biomarker samples were collected for the inflammatory cytokine IL-1β.
Time frame: up to 1 hour post enema
Population: Insufficient sample collected to allow for analysis for 1 participant in the sodium butyrate (80 mmol) group and unable to perform venipuncture for 1 participant in the control arm.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sodium Butyrate [5 mmol] | Interleukin-1 Beta (IL-1β) Concentration | NA pg/mL |
| Sodium Butyrate [80 mmol] | Interleukin-1 Beta (IL-1β) Concentration | NA pg/mL |
| Control | Interleukin-1 Beta (IL-1β) Concentration | NA pg/mL |