Probiotics and Systemic Inflammation in Patients With Metabolic Syndrome and High Cardiovascular Risk

Sponsor

Attikon Hospital (Other)

Overall Status

Withdrawn

CT.gov ID

NCT04232852

Collaborator

(none)

Enrollment

Location

Arms

19.5

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Metabolic Syndrome (MetS) and cardiovascular disease are associated with systemic inflammation (SI). Activation of the mechanisms of inflammation is triggered by the inflammatory cytokines. Τhe NLRP3 inflammasome is activated by microbial-derived low molecular weight (LMW) factors, short chain fatty acids (SCFAs), pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), and monosodium urate crystals. Probiotics can regulate inflammation in two ways: 1) indirectly, by producing SCFAs as well as increasing synthesis of antimicrobial peptides and 2) directly, by binding innate immune system receptors Toll-like (TLR 2, 4, 9) and triggering important signaling pathways associated with activation of NLRs affecting the formation of inflammasome, thus the inflammatory response.

Condition or Disease	Intervention/Treatment	Phase
Metabolic Syndrome Cardiovascular Risk Factor	Dietary Supplement: Probiotic mix Dietary Supplement: Placebo	N/A

Detailed Description

Metabolic Syndrome (MetS) is associated with low-grade systemic inflammation (SI). Activation of the mechanisms of inflammation is triggered by the inflammatory cytokines produced in the adipose tissue. Among them, IL-1β interleukin plays a central role in cardiovascular disease. The active form of IL-1β results by the conversion of its inactive precursor after an infectious/inflammatory stimulus. The Nucleotide-binding Oligomerization Domain (NOD)-like Receptor containing Pyrin domain 3 (NLRP3 or cryopyrin) inflammasome is a multiprotein complex that activates caspase 1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) via the NLRP3/caspase pathway. Τhe NLRP3 inflammasome is activated by microbial-derived Low Molecular Weight (LMW) factors, short chain fatty acids (SCFAs), Pathogen-associated molecular pattern molecules (PAMPs), Damage-associated molecular pattern molecules (DAMPs), and monosodium urate crystals.

It is a randomized, double-blind clinical trial in patients with MetS and cardiovascular disease. Patients will be randomized into two groups: A. those who will receive probiotic supplements and B. placebo-treated patients. Both groups will follow the usual clinical practice as far as drugs and diet concerned.

Τhe primary objective of this study is to investigate the effect of administration of the probiotic mix on IL-1β production by stimulated peripheral blood mononuclear cells (PBMCs) in patients at high cardiovascular risk with MetS at the end of the intervention. Secondly, to investigate the effect of probiotics on endothelial glycocalyx thickness, on hrCRP and on HbA1c levels, on the components of the MetS, on the gut microbiota at the end and 4 weeks after the completion of the intervention.

Time frame 12 weeks.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Care Provider)

Primary Purpose:

Prevention

Official Title:

Probiotics and Systemic Inflammation in Patients With Metabolic Syndrome and High Cardiovascular Risk

Actual Study Start Date :

Jun 12, 2019

Actual Primary Completion Date :

Jan 26, 2021

Actual Study Completion Date :

Jan 26, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Probiotics Demographics, anthropometric measurements (weight, height, waist circumference, BMI) will be recorded, clinical data related to the patient's cardiovascular risk (MI with or without angioplasty, acute coronary syndrome with or without angioplasty). Systolic and diastolic pressure will be measured before and after the 12-week intervention. This group will receive a probiotic mix, which will contain strains of Streptococcus thermophilus, Saccharomyces cerevisiae, Lactobacillus acidophilus, L. rhamnosus L. helveticus, L. gasseri, L. plantarum, Bifidobacterium bifidum, Enterococcus faecium at a daily dose of 7 × 1010 CFU in the form of a capsule. During the intervention, participants will follow their eating habits as well as the physical activity of their personal routine, with the advice not to consume fermented dairy products.	Dietary Supplement: Probiotic mix The probiotic mix will contain strains of Streptococcus thermophilus, Saccharomyces cerevisiae, Lactobacillus acidophilus, L. rhamnosus L. helveticus, L. gasseri, L. plantarum, Bifidobacterium bifidum, Enterococcus faecium at a daily dose of 7 × 1010 CFU in the form of a capsule.
Placebo Comparator: Placebo supplement Demographics, anthropometric measurements (weight, height, waist circumference, BMI) will be recorded, clinical data related to the patient's cardiovascular risk (MI with or without angioplasty, acute coronary syndrome with or without angioplasty). Systolic and diastolic pressure will be measured before and after the 12-week intervention. Patients of this group will receive an identical capsule of maltodextrin (placebo). During the intervention, participants will follow their eating habits as well as the physical activity of their personal routine, with the advice not to consume fermented dairy products.	Dietary Supplement: Placebo Patients in the placebo group will receive an identical capsule of maltodextrin.

Arm

Intervention/Treatment

Active Comparator: Probiotics

Demographics, anthropometric measurements (weight, height, waist circumference, BMI) will be recorded, clinical data related to the patient's cardiovascular risk (MI with or without angioplasty, acute coronary syndrome with or without angioplasty). Systolic and diastolic pressure will be measured before and after the 12-week intervention. This group will receive a probiotic mix, which will contain strains of Streptococcus thermophilus, Saccharomyces cerevisiae, Lactobacillus acidophilus, L. rhamnosus L. helveticus, L. gasseri, L. plantarum, Bifidobacterium bifidum, Enterococcus faecium at a daily dose of 7 × 1010 CFU in the form of a capsule. During the intervention, participants will follow their eating habits as well as the physical activity of their personal routine, with the advice not to consume fermented dairy products.

Dietary Supplement: Probiotic mix

The probiotic mix will contain strains of Streptococcus thermophilus, Saccharomyces cerevisiae, Lactobacillus acidophilus, L. rhamnosus L. helveticus, L. gasseri, L. plantarum, Bifidobacterium bifidum, Enterococcus faecium at a daily dose of 7 × 1010 CFU in the form of a capsule.

Placebo Comparator: Placebo supplement

Demographics, anthropometric measurements (weight, height, waist circumference, BMI) will be recorded, clinical data related to the patient's cardiovascular risk (MI with or without angioplasty, acute coronary syndrome with or without angioplasty). Systolic and diastolic pressure will be measured before and after the 12-week intervention. Patients of this group will receive an identical capsule of maltodextrin (placebo). During the intervention, participants will follow their eating habits as well as the physical activity of their personal routine, with the advice not to consume fermented dairy products.

Dietary Supplement: Placebo

Patients in the placebo group will receive an identical capsule of maltodextrin.

Outcome Measures

Primary Outcome Measures

IL-1β production by stimulated peripheral blood mononuclear cells. [12 weeks]
We will measure IL-1β concentrations in cell supernatants and consequently the NLRP3 inflammasome activation via the alteration in cytokine production in the presence of a different stimulants.
TNFα expression [12 weeks]
Reverse Transcription Polymerase Chain Reaction (RT-PCR) will be used to quantify gene expression of tumor necrosis factor alpha (TNFα)
Caspase 1 (CASP1) expression [12 weeks]
Reverse Transcription Polymerase Chain Reaction (RT-PCR) will be used to quantify CASΡ-1 as a key modulator of IL-1b bioactivity.

Secondary Outcome Measures

Glycocalyx thikness. [12 weeks]
The Perfused Boundary Region (PBR) of the hypoglossal vessels will be calculated using a high-resolution special lens using the Sideview DarkField (SDF) Imaging technique (Microscan, Glucockeck).
Change of biochemical exams related to MetS [12 weeks]
Insulin resistance (IR) will be quantified using the HOMA-IR index (HOmeostatic Model Assessment, HOMA-IR index), calculated as the product of fasting plasma insulin. Blood lipids (Total Cholesterol, LDL-C, HDL-C, TRG) will be measured by enzymatic methods.
Alterations of hsCRP levels. [12 weeks]
Hs-CRP will be measured by the Immunoturbidimetry method with a polyclonal antibody.
Alterations in gut microbiota [12 weeks]
Stool specimen will be collected before and after intervention. Stool samples will be frozen (-80 ° C) immediately after collection, in order to study changes in the gut microbiota by the technique of deep sequencing at a second time.
Alterations of HbA1C [12 weeks]
HbA1C will be measured by the HPLC.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients≥50 years old, with diagnosed MetS and history of Myocardial Infarction (MI), angioplasty, acute coronary syndrome with or without angioplasty, after written consent.
MetS syndrome defined by fulfilling at least 3 of the 5 following criteria: (NCEP-ATP-III) and "at high cardiovascular risk" as aforementioned.

Exclusion Criteria:

Body Mass Index (BMI) ≥ 40 (morbid obesity - difficult to manage, comorbidities)
Probiotic intake three months prior to intervention
Antibiotic intake three months prior to intervention
Presence of inflammatory disease
Inability to comply with study procedures