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.

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.

Only for the "probiotics" and "placebo" arms