The primary objective of this study is to assess the effect of oral butyrate on blood pressure. Secondary objectives are to assess the effect of oral butyrate on faecal and plasma SCFA levels, gut microbiome composition, diuresis, renin and…
ID
Source
Brief title
Condition
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome is average daytime systolic blood pressure as measured by
24-hour ambulatory blood pressure.
Secondary outcome
Secondary outcomes are other blood pressure measurements, including:
- Average diastolic daytime ambulatory blood pressure, average systolic and
diastolic night-time blood pressure and average systolic and diastolic 24-hour
ambulatory blood pressure;
- Office blood pressure (two-weekly);
- Home blood pressure measurement (weekly).
Other study parameters include:
- Faecal and plasma SCFA levels, including butyrate;
- Gut microbiome composition;
- Parameters of renal fluid and electrolyte balance regulation, including:
weight and total body fluid as measured with body impedance analysis (BIA);
plasma renin activity and aldosterone levels; sodium excretion in 24 hour
urine;
- Baroreceptor activity and pulse wave velocity as measured with Nexfin.
- Dietary intake (mijn.voedingscentrum.nl/nl/eetmeter)
- Change in immunophenotype
Background summary
Hypertension is the leading modifiable risk factor for cardiovascular morbidity
and mortality, and thereby the most important risk factor for preventable death
worldwide.1 The pathogenesis of primary hypertension remains incompletely
understood, but it is currently attributed to a complex interplay of genetic
predisposition and lifestyle.2 Lifestyle factors including diet, salt intake,
and obesity are known to be important for the pathogenesis of hypertension.3-5
A large population-based study in the UK demonstrated that combined lifestyle
factors can modify blood pressure with 4- 5 mmHg.6
The gut microbiota composition is a reflection of life long exposure to dietary
factors. Other important determinants of the gut microbiota are age, body mass
index (BMI), diabetes, antibiotics use and inflammatory bowel diseases.7-10 In
addition, several cross-sectional studies have shown differences in the
composition of the gut microbiota between hypertensive and normotensive
subjects, even after adjusting for important confounders. Higher abundance of
Klebsiella spp. and Prevotella spp. has been associated with higher blood
pressure, while higher abundance of Akkermansia spp. and Ruminococcacae spp.
and Roseburia spp. have been associated with lower blood pressure.11,12
Short chain fatty acids (SCFAs) are key metabolites of the gut microbiome, and
are produced by intestinal gut microbiota, including Akkermansia,
Ruminococcacae and Roseburia spp., in fermentation processes of otherwise
indigestible dietary fibers.13 SCFAs with highest faecal and plasma levels are
acetate, propionate and butyrate. Animal studies have indicated a direct
association between faecal SCFAs and blood pressure by showing that SCFAs
receptors, including free fatty acid receptors (FFAR) 2 and 3 and Olfr78, are
present in kidneys and blood vessels.14 It was suggested that through these
receptors, butyrate has effects on the renin-angiotensin-aldosterone system
(RAAS). In one study, intravenous administration of butyrate to spontaneous
hypertensive rats lowered both blood pressure and renin and angiotensin II
levels.15
In humans, evidence of a direct link between SCFAs and blood pressure is
scarce. Nonetheless, we do know that high fibre intake through the
Mediterranean diet prevents gut dysbiosis by inducing a rise in SCFAs.16 This
diet has been related to reduction of cardiovascular events and lower blood
pressure.17 In addition, butyrate has been administered to human subjects
before in trials at the Amsterdam UMC (2014-084 and 2014-291), which showed
that butyrate was safe and was cardiometabolically active both in the intestine
(alterations in faecal SCFA levels) as well as on insulin sensitivity.18,19 If
faecal butyrate levels are indeed related to blood pressure, this could provide
new perspectives on the pathophysiology and treatment of hypertension. Hence,
in this study, we aim to investigate the effect of oral butyrate treatment on
blood pressure in subjects with mild hypertension.
Study objective
The primary objective of this study is to assess the effect of oral butyrate on
blood pressure.
Secondary objectives are to assess the effect of oral butyrate on faecal and
plasma SCFA levels, gut microbiome composition, diuresis, renin and aldosterone
levels, hemodynamic parameters such as baroreceptor sensitivity and pulse wave
velocity, and immunophenotype. In addition, changes in body weight and body
composition (bioimpedance analysis; BIA) as well as dietary intake will be
monitored.
Study design
Randomized placebo-controlled double-blind trial (parallel design)
Intervention
The investigational products are sodium butyrate (Sensilab) and placebo.
Patients will be randomised over the intervention and control group. In the
intervention group, patients will receive 13 capsules of sodium butyrate twice
daily (total 4 gram), a similar dosage as previously administered to humans
subjects at Amsterdam UMC (2014-084 and 2014-291). In the control group,
patients will receive 13 placebo capsules twice daily filled with sodium
chloride in order to ensure that the administered dosage of sodium is equal
between the intervention and control group (780 mg sodium per day), since
sodium could potentially modify blood pressure levels.
Study burden and risks
There is no direct benefit for participants in this study. Patients need to
make five visits to the AMC for the purpose of this study over the course of
six to nine weeks. Risks associated with procedures in this study, which
include collection of faecal, urine and blood samples, body composition
measurement and several non-invasive blood pressure measurements, are
considered low. The maximum amount of blood that will be drawn over three study
visits is 82,5 ml per patient. Patients could experience side effects of the
butyrate intervention, however, no side effects were reported in intervention
studies with similar dosages.
Meibergdreef 9, D3-316
Amsterdam 1105AZ
NL
Meibergdreef 9, D3-316
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
- Age between 40 and 65 years
- For females: postmenopausal status
- Caucasian
- Mild hypertension (defined as systolic blood pressure range 140-159 mmHg
and/or diastolic blood pressure range 90-100 mmHg) without antihypertensive
medication OR use of 1 antihypertensive drug due to hypertension and willing to
temporarily stop this medication
- Body mass index (BMI) lower than 27 kg/m2
Exclusion criteria
- Insufficient knowledge of the Dutch language
- Use of betablockers
- Known secondary causes of hypertension such as renal artery stenosis, adrenal
or thyroid disease
- History of cardiovascular disease: angina pectoris, myocardial infarction,
cerebrovascular accident, transient ischemic attack, peripheral artery disease,
heart failure.
- History of diabetes mellitus
- Current smoking
- Antibiotics usage within three months before inclusion
- Having a severe disease of the digestive tract, such as celiac disease,
Crohn*s disease, active ulcerative colitis or short bowel syndrome.
- Impaired renal function, defined as an estimated glomerular filtration rate
(eGFR) lower than 60 ml/min/1,73m2 using the CKD-EPI formula within a period of
two years before the screening visit. Participants without an available lab
result on renal function will not be included.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL73625.018.20 |