Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04398693 |
| Other study ID # |
VALORIS |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2019 |
| Est. completion date |
January 2022 |
Study information
| Verified date |
February 2021 |
| Source |
Hospital de Base |
| Contact |
José F Vilela-Martin, MD PhD FAHA |
| Phone |
+55 (17) 3201-5727 |
| Email |
vilelamartin[@]uol.com.br |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The gastrointestinal tract begins its colonization shortly after birth. During the first two
years of life, gut microbiota is unstable and less diverse than in adulthood. Its complexity
and diversity are modified by external factors that shall influence the composition of gut
microbiota, especially the diet, the personal hygiene and the food cleansing, as well as the
chronic use of antibiotics. Some recent evidence suggests that the microbiome may affect the
likelihood of various diseases, including obesity, diabetes and cardiovascular disease. Among
cardiovascular diseases, hypertension (HT) accompanied with increased cardiovascular
morbidity and mortality. Hypertensive individuals may present controlled blood pressure (use
of up to 03 antihypertensive drugs) or resistant without blood pressure control, even in the
use of 03 or more antihypertensive drugs. Objectives: Evaluating gut microbiota of resistant
hypertensive individuals, we shall compare it with those of normotensive and controlled
hypertensive individuals. The resistant hypertensive ones will also receive a therapeutic
intervention with prebiotics to determine if the changes in microbiota and in the production
of microbiota metabolites can lower blood pressure. Methods: The study will be composed of
two phases, one observational and one interventional. The observational phase will be
composed of adults of both genders, aged between 40 and 70 years old, divided into three
groups: normotensive, controlled hypertensive and resistant hypertensive individuals.
Nutritional assessment, biochemistry and stool analysis will be performed to study the
microbiota in all groups, in addition to the evaluation of peripheral and central hemodynamic
parameters. The intervention phase will consist of a, randomized, double-blinded,
placebo-controlled crossover study using a prebiotic formula during 04 weeks in the resistant
hypertensive group. After a washout period of 4 weeks, the protocol will be repeated in the
other arm. Participants will visit the clinic in 4 occasions, which shall include biochemical
tests [for small chain fatty acids (SCFAs), noradrenaline, gut dysbiosis, immunomodulation]
and fecal sample collection (for SCFAs and gut microbiome determination), besides the
evaluation of flow-mediated dilation and peripheral and central hemodynamic parameters.
Description:
The gastrointestinal tract begins its colonization shortly after the birth. During the first
two years of life, microbiota is unstable and less diverse than in adulthood, when its
complexity and diversity are modified. There are more than 100 trillion microorganisms hosted
in the gut, mostly as phylae, Bacteroidetes and Firmicutes. These microorganisms help in
various functions, and their balance is of great importance to control diseases and metabolic
disorders. The lack of homeostasis of gut microbiota, results in gut dysbiosis, known by the
imbalance of Firmicutes and Bacteroidetes concentration, but also with the presence of other
phylae. Hypertension (HT) is characterized by blood pressure (BP) ≥ 140/90 mmHg HT can
manifest itself with chronic or acute elevation of BP. Among the situations of BP chronic
elevation, there is resistant hypertension (RH), defined by BP ≥ 140/90 mmHg, even with the
use of three or more antihypertensive drugs in appropriate doses, preferably including a
diuretic. Certain gut microbial strains may play either a pathogenic or protective role in
the development hypertension. Changes in gut microbiota were observed in the hypertension
with significant decrease in microbial richness, diversity and uniformity, in addition to an
increased Firmicutes/Bacteroidetes ratio, characterizing intestinal dysbiosis. These changes
have been accompanied by decreases in acetate and butyrate producing bacteria.
Thus, one of the mechanisms by which the gut microbiota may interfere with control of the BP
is related to the production of metabolites produced by fermentation of fibers like resistant
starch, known as short chain fatty acids (SCFAs). These metabolites have vasodilating
property (acetate, butyrate and propionate), which may influence vascular tone. Acetate and
the propionate are able to reduce the levels of BP in animal models, and that independent
models of hypertension (SHR rats and Ang II), have less SCFAs producing bacteria than the
normotensive controls. The SCFA butyrate, bacterial metabolic product, is produced from
dietary fibers by bacteria found in lumen and hosts multiple beneficial properties for the
host. Studies in animal models show that diet high in fiber and acetate supplementation
correct gut dysbiosis, increase the abundance of acetate/butyrate producing bacteria and are
associated with lower BP in hypertension animal model.
The spontaneously hypertensive rats prone to stroke (stroke-prone SHR) show gut dysbiosis and
fecal microbiota transplant of these rats to normotensive Wistar-Kyoto rats increases the BP
in normotensive rats. On the other hand, the intimate association between inflammation and
chronic hypertension is well known. The control of inflammation by the sympathetic nervous
system plays a central role in hypertension. Therefore, the gut receives significant
sympathetic innervation, it is densely populated with a diverse microbial ecosystem, and
contains immune cells that cause great impact overall inflammatory homeostasis. This
influence can be demonstrated in germ-free mice subjected to the model of hypertension with
infusion of Ang II. They showed mitigated inflammatory signs (smaller vascular leukocyte
adhesion, smaller neutrophils and monocytes infiltration in the arterial wall), as well as
smaller endothelial dysfunction and increased attenuation of the BP as a response to Ang II
compared to conventionally raised mice, indicating systemic protection of inflammatory
cardiovascular stress. Thus, the gut microbiota plays a key role in the immune system and can
also influence the inflammatory response, by changing the endothelial function and,
consequently, BP. Hypertension causes a vascular endothelium injury, triggering an
inflammatory response that is accompanied with an increase in C-reactive protein, which can
induce the PAI-1.
The use of Prebiotics to treat hypertension Epidemiological studies suggest that dietary
components, such as fiber, may reduce the development of HT. A high fiber diet consumption
increases gut microbiota populations which generate SCFAs such as acetate and butyrate.
Recently, Marques et al. have shown that a high-fiber diet or supplementation with the
short-chain fatty acid acetate modulated gut microbiota and prevented BP elevation and the
development of cardio-renal complications in DOCA-salt hypertension rats. The authors
validated these findings in hypertensive model induced by angiotensin II infusion (Ang II),
showing that other SCFA, butyrate, also reduced the BP and accompanied with lower levels of
inflammatory cytokines in the large bowel (data not published). Hypertensive subjects also
show an abnormal gut microbiota and lower production of acetate and butyrate. Prebiotics
modified diets based on high-amylose corn starches, which release large amounts of SCFAs
(acetate and butyrate) into the gut and into peripheral tissues, have the ability to
successfully reduce the predisposition to develop diabetes type 1 in mice and improve type II
diabetes mellitus control in humans. Dietary supplements, which produce high acetate and
butyrate levels, have the ability to positively intervene in gut microbiota and in
chronic-metabolic diseases such as HT and diabetes, being able to be used as a new strategy
to reduce the BP. Therefore, we need further investigation to assess the behavior of
microbiota in controlled hypertensive and resistant hypertensive individuals and show that
modulate gut microbiota can bring health benefits.
JUSTIFICATION With the high prevalence of hypertension in the globalized world and the
consumption increase of industrialized foods, fast-food, ultra-processed foods and physical
inactivity, there is a strong trend to the exponential growth of cardiovascular
complications. Over 60 years ago, Dr. Irvine Page proposed the Mosaic Theory of Hypertension,
which states that multiple factors interdigitate to blood pressure elevation. This fostered
establishment of cellular, molecular, and physiological mechanisms altered in HT. However,
However, how these diverse factors integrate to impair BP control remains a challenge.
Furthermore, why some factors are prohypertensive in one individual and not in another, and
where prohypertensive signals originate, remains an enigma. In this viewpoint, the gut
microbiota can be one missing link and provide a potential unifying concept, occupying a
prominent place in the mosaic theory. The latest evidence shows the involvement of the gut
microbiota in BP control and its interference in HT in animal and in humans' models. Thus,
addressing knowledge gaps in order to determine whether the gut microbiota is related to HT
and if the change of the microbiota might help in HT treatment constitutes in an opportunity
to develop new evidence to advance in this field, mainly in cases of resistant hypertension.
It would be important to establish metabolites signatures and the microbiota that could be
used to predict the development of HT or biomarkers for resistant hypertension. Despite great
advances in drug therapy, HT continues to be the main modifiable risk factor for
cardiovascular morbidity and mortality development, due to lack of BP proper control in
resistant hypertension, which corresponds to about 10 to 20% of hypertensive subjects, this
group is exposed to higher cardiovascular risk. Thus, this study will assess whether the gut
microbiota is associated with BP levels of resistant hypertensive individuals compared to
hypertensive controlled and whether the microbiota alteration with Prebiotics may help BP
control and, consequently, decrease the prevalence of CVD in hypertensive patients.
Additionally, this study compares the microbiota of two different global regions, Brazil and
Australia, in relation to BP. Our hypothesis is that the gut microbiota and its metabolites
acetate and butyrate play a role in the hypertension prevention and that medical diets
("Nutrigenomics") can be used to reduce the BP. Initially, the study will evaluate the
microbiota of 3 different groups: normotensive, hypertensive controlled and resistant
hypertensive individuals. In a second phase of this project, we propose the establishment of
a randomized, blinded, placebo-controlled cross-over study using a prebiotic (dietary
modified supplement). The use of Prebiotic is justified because it is a cheap, safe and
simple therapy, constituting a new therapeutic approach that can increase BP control in
resistant hypertensive patients who cannot control it with traditional drugs.
OBJECTIVES General objective The aim of this study is to evaluate the gut microbiota of
resistant hypertensive patients, compared to normotensive and hypertensive ones, and also to
evaluate the gut microbiota response to medical intervention (Prebiotics) in resistant
hypertensive patients.
Specific objectives
- To analyze which bacteria, colonize the resistant hypertensive intestine, comparing them
to the microbiota bacteria of normotensive and hypertensive controlled patients;
- To assess the patients' nutritional status studied and correlate it with their
microbiota;
- To correlate metabolic-biochemistry profile (including inflammatory markers) and
peripheral and central hemodynamic parameters of the patients who will be studied with
the results of their microbiota evaluation;
- To carry out the intervention with the Prebiotics formula and reassess the gut
microbiota after the treatment of the hypertensive controlled and the resistant
hypertensive group.
- To compare the microbiota of normotensive, hypertensive controlled and resistant
hypertensive of Brazilian population studied with Australians.
MATERIALS AND METHODS The study shall be divided into two phases. The first phase will be a
descriptive, observational cross-sectional study. The collection of material shall be carried
out at the Hypertension Clinic of State Medical School at São José do Rio Preto (FAMERP),
with the aim of evaluating the gut microbiota of normotensive, hypertensive controlled and
resistant hypertensive patients. The second study will be a randomized, blinded,
placebo-controlled crossover study, using prebiotics in resistant hypertensive patients
during two periods of 4 weeks with a wash-out interval of 4 weeks.
Characteristics of the participants
Patients who are being monitored will be assessed at the Hypertension Clinic. The study will
consist of 3 groups of participants:
1. 40 normotensive patients with systolic BP (SBP) < 140 mmHg and diastolic BP (DBP) < 90
mmHg at the office, without the use of antihypertensive drugs and evaluated through
ambulatory blood pressure monitoring (ABPM) to confirm normotension (BP < 130/80 mmHg)
and the exclusion of possible masked hypertension.
2. 40 controlled hypertensive patients using up to three antihypertensive drugs with SBP <
130 mmHg and DBP < 80 mmHg evaluated through ambulatory blood pressure monitoring
(ABPM).
3. 40 resistant hypertensive patients defined by an uncontrolled BP in doctor's office (≥
140/90 mmHg), despite the use of three or more antihypertensive drugs in appropriate
doses, including preferably a diuretic, or the use of four or more drugs with blood
pressure control. Patients will also be evaluated by the ABPM, which should present in
SBP ≥130 mmHg and DBP ≥ 80 mmHg to be considered resistant hypertensive, otherwise they
will be classified as controlled hypertensive. Resistant hypertension will be defined
after the exclusion of causes of pseudo-resistance, i.e., inaccurate blood pressure
measurement, white coat effect, non-therapeutic adherence, the use of drugs that can
increase BP and secondary causes of arterial hypertension.
