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| Name | Class |
|---|---|
| North Carolina Translational and Clinical Sciences Institute | OTHER |
| North Carolina Agriculture & Technical State University | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sodium Butyrate [5 mmol] first, then Sodium Butyrate [80 mmol] | Experimental | 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-days 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). |
|
| Sodium Butyrate [80 mmol] first, then Sodium Butyrate [5 mmol] | Experimental | 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). |
|
| Control | No Intervention | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sodium Butyrate 5 mmol | Drug | Enema-based delivery of 5 mmol butyrate in 0.9% saline, (60 mL total) |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | approximately 16 hours post enema |
| 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. | approximately 8 hours post enema |
| Measure | Description | Time Frame |
|---|---|---|
| Blood Butyrate Concentrations | Measure blood butyrate concentrations before, 30 minutes post, and 60 minutes post self-administration of the butyrate enemas | up to 1 hour post enema |
| Interleukin-1 Beta (IL-1β) Concentration |
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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):
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):
Exclusion Criteria for both groups:
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| Name | Affiliation | Role |
|---|---|---|
| Marc D Cook, PhD | North Carolina A&T State Univeristy | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| NC A&T State University | Greensboro | North Carolina | 27411 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8899080 | Background | Steinhart AH, Hiruki T, Brzezinski A, Baker JP. Treatment of left-sided ulcerative colitis with butyrate enemas: a controlled trial. Aliment Pharmacol Ther. 1996 Oct;10(5):729-36. doi: 10.1046/j.1365-2036.1996.d01-509.x. | |
| 19460106 | Background | Vanhoutvin SA, Troost FJ, Kilkens TO, Lindsey PJ, Hamer HM, Jonkers DM, Venema K, Brummer RJ. The effects of butyrate enemas on visceral perception in healthy volunteers. Neurogastroenterol Motil. 2009 Sep;21(9):952-e76. doi: 10.1111/j.1365-2982.2009.01324.x. Epub 2009 May 19. |
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| ID | Type | URL | Comment |
|---|---|---|---|
| De-identified data set | View IPD |
The investigators will share the informed consent and de-identified data set including fecal microbiome sequencing, blood pressure data, circulating butyrate levels in an online repository (Carolina Digital Repository).
3-5 years after the completion of the primary endpoint.
Contact Dr. Marc Cook (mdcook@ncat.edu) at NC A&T State University. The data set will be shared in the Carolina Digital repository.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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). |
| FG001 | 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). |
| FG002 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (Single 1-Day Visit) |
| |||||||||||||
| Washout (1 Week) |
| |||||||||||||
| Second Intervention (Single 1-Day Visit) |
|
No participants received random assignment to the 80 mmol intervention first.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | mmHg | approximately 16 hours post enema |
|
During each 1-Day study visit through 24 hours post intervention administration and an additional 7 days after the final 1-Day study visit.
All-Cause Mortality, Serious, and Other (Not Including Serious) Adverse Events were not monitored/assessed for the control participants.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sodium Butyrate (5 mmol) | 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). |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Marc Cook, PhD | North Carolina A&T State University | 336-285-3547 | mdcook@ncat.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 31, 2018 | Jun 14, 2022 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jul 1, 2021 | Feb 18, 2022 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D020148 | Butyric Acid |
| ID | Term |
|---|---|
| D002087 | Butyrates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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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.
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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.
| Sodium Butyrate 80 mmol | Drug | Enema-based delivery of 80 mmol butyrate in 0.9% saline, (60 mL total) |
|
Blood biomarker samples were collected for the inflammatory cytokine IL-1β.
| up to 1 hour post enema |
| 20471725 | Background | Hamer HM, Jonkers DM, Vanhoutvin SA, Troost FJ, Rijkers G, de Bruine A, Bast A, Venema K, Brummer RJ. Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission. Clin Nutr. 2010 Dec;29(6):738-44. doi: 10.1016/j.clnu.2010.04.002. Epub 2010 May 15. |
| 24343275 | Background | Krokowicz L, Stojcev Z, Kaczmarek BF, Kociemba W, Kaczmarek E, Walkowiak J, Krokowicz P, Drews M, Banasiewicz T. Microencapsulated sodium butyrate administered to patients with diverticulosis decreases incidence of diverticulitis--a prospective randomized study. Int J Colorectal Dis. 2014 Mar;29(3):387-93. doi: 10.1007/s00384-013-1807-5. Epub 2013 Dec 18. |
| 40736085 | Derived | Hogue T, Das P, Reczek S, Hampton-Marcell J, Ford Y, Raval D, Carroll I, Cook MD. Effect of Acute Gut Butyrate Delivery on Blood Pressure in Black Individuals With Hypertension: A Proof-of-Concept Randomized Controlled Study. J Am Heart Assoc. 2025 Sep 2;14(17):e039759. doi: 10.1161/JAHA.124.039759. Epub 2025 Jul 30. |
Data will be accessible at the above Carolina Data Repository for the UNC library system. |
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| NOT COMPLETED |
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| BG001 | 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). |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG002 |
| 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. |
|
|
| 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. | Posted | Mean | Standard Deviation | mmHg | approximately 8 hours post enema |
|
|
|
| Secondary | Blood Butyrate Concentrations | Measure blood butyrate concentrations before, 30 minutes post, and 60 minutes post self-administration of the butyrate enemas | 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. | Posted | Mean | Standard Deviation | ng/mL | up to 1 hour post enema |
|
|
|
| Secondary | Interleukin-1 Beta (IL-1β) Concentration | Blood biomarker samples were collected for the inflammatory cytokine IL-1β. | 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. | Posted | Mean | Standard Deviation | pg/mL | up to 1 hour post enema |
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|
| 0 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | Sodium Butyrate (80 mmol) | 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). | 0 | 10 | 0 | 10 | 0 | 10 |
| EG002 | 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. | 0 | 0 | 0 | 0 | 0 | 0 |
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| D005232 |
| Fatty Acids, Volatile |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| 30 Minutes Post |
|
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| 60 Minutes Post |
|