Clinical trial NCT04415333: Gut Butyrate and Blood Pressure in African Americans
Official title: Effect of Gut Butyrate Delivery on Blood Pressure in African Americans With Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypertension
Keywords: African American
Blood pressure
Gut Microbiome
Short-chain fatty acid
Butyrate
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: North Carolina Translational and Clinical Sciences Institute
name: North Carolina Agriculture & Technical State University
First posted: 2020-06-04
Enrollment: 20
Sex: ALL
Minimum age (years): 30
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mean Daytime Blood Pressure
timeFrame: approximately 16 hours post enema
measure: Mean Nighttime Blood Pressure
timeFrame: approximately 8 hours post enema
Secondary outcomes:
measure: Blood Butyrate Concentrations
timeFrame: up to 1 hour post enema
measure: Interleukin-1 Beta (IL-1β) Concentration
timeFrame: up to 1 hour post enema
Other outcomes:
Locations:
city: Greensboro
country: United States
facility: NC A&T State University
state: North Carolina
Study officials:
affiliation: North Carolina A&T State Univeristy
name: Marc D Cook, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.
citation: 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.