Clinical trial NCT02972567: Evaluation of the Effects of a L.Reuteri Strain on Markers of Inflammation, Cardiovascular Risk and Fatty Liver Disease
Official title: Evaluation of the Effect of a Lactobacillus Reuteri Strain on Markers of Inflammation, Cardiovascular Risk and Fatty Liver Disease in Obese Subjects With Insulin Resistance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Metabolic Syndrome X
Keywords: probiotics
metabolic syndrome
non-alcoholic fatty liver disease
Lead sponsor: Biosearch S.A.
Sponsor class: INDUSTRY
Collaborators: name: Universidad de Granada
name: Complejo Hospitalario de Jaen
First posted: 2016-11-23
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is the evaluation of the effects in obese patients with metabolic syndrome on the composition of the intestinal microbiota, markers of the syndrome (hypertension, dyslipidemia, inflammation biomarkers, risk cardiovascular and hepatic steatosis) and other possible metabolites involved.

Detailed description: Randomized double blind crossover placebo controlled intervention study

The proposed study will be conducted by members of the Endocrinology and Nutrition Services (ENCHJ), and Gastroenterology (ADCHJ), of the Hospital of Jaen and members of the Department of Biochemistry and Molecular Biology II of the University of Granada (UGR) and members of Microbiology Department of the University Hospital San Cecilio of Granada (MHUSC).

The selection, clinical and anthropometric control, general biochemical parameters and the determination of hepatic steatosis by ultrasound will be performed by members of ENCHJ.

The determination of the composition of the intestinal microbiota will be carried out by members of the UGR together with members form the MHUSC. Inflammation and steatosis biomarkers as well as metabolic profile will be performed by members of the UGR.

The study will be conducted according to the Helsinki Rules and will be previously approved by the Ethics Committee of Research of Jaen. The study will follow the rules of international, national and regional research The biological samples will be managed and processed in accordance with the research protocols by the Biobanco del Sistema Sanitario Público de Andalucía. At the end of the project, samples will be stored within the framework of Biobank from Public Health Organization of Andalusia .

The present study involves access and use of information confidential, so all the data will be treated anonymously.

• Sample size assessment to specify the number of participants or participant years necessary to demonstrate an effect.

Based on the range and median value on plasma lipopolysaccharide (LPS), and assuming a power of 90% and a type error alpha of 5%, the minimum number of subjects was 32. To avoid possible bias caused by gender and taking into account the withdrawal, will be recruited 60 subjects.

The missing data will be considered as unavailable data.

All statistical analyses will be performed using the statistical package SPSS (Statistical Product and Service Solutions). Normally distributed data will be expressed as the mean and standard error of the mean, whereas median and ranges will be used for data not normally distributed.

Eligibility criteria: Inclusion Criteria:

* Patients with a diagnosis of insulin resistance syndrome, according to Criteria of the International Diabetes Federation (IDF)
* BMI\>30 kg/m2 or Waist Circumference ≥ 94cm (men) WC≥ 80cm (women)
* Serum Triglycerides ≥ 150 mg/dl
* HDLcholesterol \< 40 mg/dl (1,03 mmol/l) in men and \< 50 mg/dl (1,29 mmol/l) in women
* Systolic blood pressure ≥ 130 mmHg or diastolic ≥ 85 mmHg
* Glucose ≥ 100 mg/dl (5,6 mmol/l) (not previous diagnostic of diabetes II)

Exclusion Criteria:

* Patients with renal or hepatic impairment
* Patients with a diagnosis of diabetes
* Patients with diseases that condition immunosuppression
* Patients presenting positive serologies for liver viruses
* Being on antihypertensive treatment: beta-blockers, Angiotensin 2 receptor antagonists (ARA 2), enzyme inhibitors, Angiotensin converting enzyme (ACE) inhibitors.
* Patients receiving lipid-lowering and / or hypoglycemic agents
* Patients on treatment with drugs that increase hepatic enzymes,such as Amiodarone, perhexiline, maleate and 4,4'-diethylaminoethoxyhexestrol, synthetic estrogens, Tamoxifen, corticosteroids, acetylsalicylic acid, Valproic acid, tetracyclines, viral agents (zidovudine, zalcitabine, didanosine), among others.
* Exhibiting high values of C-reactive protein (CRP) or Sedimentation (ESR)
* Consuming alcohol in quantities greater than 40 g / d or other hepatotoxic.

Primary outcomes:
measure: Change from basal plasma lipopolysaccharide (LPS) at 12 weeks
timeFrame: Basal (T0), 12 weeks
Secondary outcomes:
measure: Change from basal Blood pressure at 12 weeks
timeFrame: Basal (T0), 12 weeks
measure: Change from basal HOMA ( homeostatic model assessment ) index at 12 weeks
timeFrame: Basal (T0), 12 weeks
measure: Change from basal plasma cholesterol level (total, LDL and HDL) at 12 weeks
timeFrame: Basal (T0), 12 weeks
measure: Change from basal plasma Inflammatory markers (sVCAM, sICAM, myeloperoxidase selectin, adiponectin, plasminogen activator inhibitor and resistin, and interleukines Il-6, Il-8, tumor necrosis factor, HGF, leptin and Multicopper oxidase-1) at 12 weeks
timeFrame: Basal (T0), 12 weeks
measure: Change from basal Hepatic Steatosis markers (arginase, prolidase and RBP-4(Retinol binding protein-4)) at 12 weeks
timeFrame: Basal (T0), 12 weeks
measure: Changes from basal fecal microbiota at 12 weeks
timeFrame: Basal (T0), 12 weeks
Other outcomes:
Locations:
city: Jaen
country: Spain
facility: Complejo Hospitalario Universitario de Jaen
Study officials:
affiliation: University of Granada (Spain)
name: Gil Ángel, Prof. Ph.D
role: STUDY_DIRECTOR
References:
citation: Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006 Dec 21;444(7122):1027-31. doi: 10.1038/nature05414.
citation: Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):979-84. doi: 10.1073/pnas.0605374104. Epub 2007 Jan 8.
citation: Bermudez-Brito M, Munoz-Quezada S, Gomez-Llorente C, Matencio E, Bernal MJ, Romero F, Gil A. Human intestinal dendritic cells decrease cytokine release against Salmonella infection in the presence of Lactobacillus paracasei upon TLR activation. PLoS One. 2012;7(8):e43197. doi: 10.1371/journal.pone.0043197. Epub 2012 Aug 14.
citation: Tenorio-Jimenez C, Martinez-Ramirez MJ, Tercero-Lozano M, Arraiza-Irigoyen C, Del Castillo-Codes I, Olza J, Plaza-Diaz J, Fontana L, Migueles JH, Olivares M, Gil A, Gomez-Llorente C. Evaluation of the effect of Lactobacillus reuteri V3401 on biomarkers of inflammation, cardiovascular risk and liver steatosis in obese adults with metabolic syndrome: a randomized clinical trial (PROSIR). BMC Complement Altern Med. 2018 Nov 20;18(1):306. doi: 10.1186/s12906-018-2371-x.