Exercise Training Influences Gut Microbiota and Cardiovascular Health Through Inflammation Control in Adult Hypertensive Population: the MicroFit Study

Cardiovascular diseases are the number 1 cause of death globally, taking an estimated 17.9 million lives each year (31% of deaths worldwide). Hypertension, with 1.13 billion people affected worldwide, is the leading risk factor for global mortality. Physical inactivity is among the modifiable cardiovascular risk factors. While the beneficial effects of physical activity on cardiovascular system are widely known, the mechanisms involved are not completely understood. Both exercise training and hypertension are linked to inflammation. Furthermore, there is evidence that gut microbiota regulates inflammatory patterns. Recent investigations showed a relationship between exercise training and the composition/functionality of the gut microbiota. Anyway, the modification of the composition and functionality of the gut microbiota in hypertension due to the exercise training and the relative involvement of oxidative stress and inflammation are not completely understood.

In literature an association between gut microbiota composition and arterial stiffness is described, in particular, the investigators observed both a direct correlation between arterial stiffness and abundances of bacteria associated with altered gut permeability and inflammation; and an inverse relationship between arterial stiffness, microbiota diversity, and abundances of bacteria associated with most fit microbiota composition. Anyway, while these association were stable in animal studies, in human studies none of the identified interventional trials was able to demonstrate this relationship. Of note, only half of human studies measured BP, and very few adjusted the vascular analyses for BP variation, which is a major determinant of arterial stiffness.

This is a non-profit, monocentric, non-pharmacological interventional study, a randomized controlled trial with three intervention arms, partial double-blind, aiming to verify the hypothesis that, in hypertensive patients in primary prevention with cardiovascular risk factors, physical exercise favorably modifies the intestinal bacterial flora compared to the probiotic, with a positive impact on cardiovascular health, and to demonstrate that this involves inflammation modulation. There will be 3 intervention arms, with 1:1:1 stratified randomization by gender: 1. Administration of controlled physical activity training; 2. Administration of probiotic; 3. Administration of placebo. Arms 2 and 3 will be double-blind. The intervention will last for three months, followed by a 6-month follow-up period. Afterwards, the medical team may be contacted for further tests/assessments or simply for information about the participant's health status, for a total duration of 24 months.

The investigators hypothesize that hypertensive patients in cardiovascular primary prevention have a dysbiotic gut microbial signatures, that could be a new marker of early vascular aging. Secondly, the investigators anticipate that exercise training will modify both gut microbiota and hemodynamic profile, and that a relationship exists between gut microbiota and hemodynamic modifications. Thirdly, the investigators expect that the beneficial effects of exercise training are driven by positive changes in the inflammatory modulators.

Study Overview

• Status: Recruiting
• Conditions: Hypertension; Microbiota
• Intervention / Treatment: Behavioral: exercise training; Other: Probiotics; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Davide Agnoletti, PhD; Phone Number: 00390512145597; Email: davide.agnoletti2@unibo.it

Study Locations

• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • University of Bologna
    • Contact: Davide Agnoletti, PhD; Phone Number: 00390512145579; Email: davide.agnoletti2@unibo.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Arterial hypertension*;
• Stable antihypertensive therapy in the last 2 months, with controlled blood pressure values;
• Age 40-65 years;
• Willing to sign the written informed consent;
• Written and spoken Italian language comprehension.

Exclusion Criteria:

• Atrial fibrillation;
• Diabetes mellitus either type I or II;
• Active cancer;
• Inflammatory bowel disease;
• Heart failure NYHA class III to IV;
• Recent antibiotic or probiotic treatment in the previous month for any reason;
• Recent myocardial infarction or hospital admission for any other reason in the previous 6 months;
• Any other condition that the medical doctor (MD) considers to contraindicate the participation in an exercise program of High intensity;
• Pulmonary disease requiring oxygen therapy;
• Relevant neurological condition impairing motor or cognitive function;
• Severe depressive disorder;
• Pregnancy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise training; high intensity interval training: thrice a week	Behavioral: exercise training; high intensity interval training
Active Comparator: Probiotics; VSL#3# probiotic: twice daily	Other: Probiotics; VSL#3# Probiotic
Placebo Comparator: Placebo; Comparator of the Probiotics arm	Other: Placebo; Probiotic Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To describe the modification of the gut microbiota composition and function after the exercise training compared to probiotic supplements and to placebo.	Changes in measures of gut microbiota composition and function from time 0 to 3 months (alpha diversity, beta diversity, taxonomy, relative abundance of microbial genes and pathways)	time 0 and 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To describe the association between gut microbiota patterns with impaired central hemodynamics	To measure the association of gut microbiota diversity indexes, taxonomy, relative abundance of microbial genes and pathways, with central hemodynamics parameters (central blood pressure, aortic stiffness, pulse pressure amplification, augmentation index).	time 0 and 3 months
To test the association of the systemic inflammation with the modification of gut microbiota composition/functionality.	To test the association between inflammatory markers (alpha-1-acid glycoprotein, high-sensitive c-reactive protein) and gut microbiota diversity indexes, taxonomy, relative abundance of microbial genes and pathways.	time 0 and 3 months
To test the modification of endothelial function after the exercise training in comparison to probiotic supplements and placebo.	To measure variation in endothelial glycocalyx thickness before and after 3-mo intervention	time 0, and 3 months
To identify the variation of the gut microbiota composition and function in the long term follow up after the intervention	Measures of gut microbiota diversity indexes, taxonomy, relative abundance of microbial genes and pathways at the end of the intervention (3 months) and after the 9-mo follow up.	from 3 to 9 months.
To describe the association between gut microbiota patterns with impaired central hemodynamics in the long term follow up 6 months after the intervention	To measure the association of gut microbiota diversity indexes, taxonomy, relative abundance of microbial genes and pathways, with central hemodynamics parameters (central blood pressure, aortic stiffness, pulse pressure amplification, augmentation index)	at 9-mo follow up
To test the association of the systemic inflammation with the modification of gut microbiota composition/functionality, after the long term follow up 6 months after the intervention.	To test the association between inflammatory markers (alpha-1-acid glycoprotein, high-sensitive c-reactive protein) and gut microbiota diversity indexes, taxonomy, relative abundance of microbial genes and pathways, at 9-mo follow up.	at 9-mo follow up
To test the modification of endothelial function after the exercise training in comparison to probiotic supplements and placebo, after the long term follow up 6 months after the intervention	To measure variation in endothelial glycocalyx thickness at 9-mo follow up	at 9-mo follow up

Collaborators and Investigators

• Sponsor: University of Bologna
• Collaborators: Actial Farmaceutica S.r.l.

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2023
• Primary Completion (Estimated): April 2, 2026
• Study Completion (Estimated): April 2, 2026

Study Registration Dates

• First Submitted: June 16, 2023
• First Submitted That Met QC Criteria: July 21, 2023
• First Posted (Actual): August 1, 2023

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 21, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: physical activity; hypertension; exercise training; gut microbiota; pulse wave velocity; arterial stiffness; central hemodynamics
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Hypertension; Inflammation
• Other Study ID Numbers: MicroFit

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No