The Effect of Probiotics on Systemic Inflammation and Metabolic Endotoxemia in Patients Undergoing Bariatric Surgery

Study Overview
=================
Brief Summary
-----------------
This study explores the effects of probiotic administration on the outcomes of surgical treatment, and also on the state of the intestinal microbiota and the intestinal barrier. The study protocol is designed as a randomized double-blind placebo-controlled clinical trial. Patients qualified for bariatric surgery will be randomized to receive probiotics or a placebo for 12 weeks. Researchers are going to evaluate changes in intestinal microbiota, epithelial permeability, weight loss, postoperative complications, and serum parameters reflecting inflammation, metabolic profile, and metabolic endotoxemia.

Detailed Description
-----------------
The study is designed as a randomized double-blind placebo-controlled clinical trial with a 12-week probiotics intervention period. Eighty patients qualified for one of 3 types of bariatric surgery Roux-en-Y Gastric Bypass (RYGB), One-Anastomosis Gastric Bypass (OAGB), Laparoscopic Sleeve Gastrectomy (LSG) will be randomized to receive probiotics or a placebo. The time frame for the study is 6 months before and 6 months after surgery. During this time, it is planned to collect stool samples at 5-time points: before the start of the study, before the introduction of probiotic therapy, 2 weeks before the operation, and 3 and 6 months after the operation. Collected fecal samples will be subjected to quantitative and qualitative content of the intestinal microbiota using the new generation sequencing method, as well as intestinal permeability parameters such as I-FABP (Intestinal fatty acid-binding protein), bacterial short-chain fatty acids (SCFA), and lipopolysaccharide (LPS). Simultaneously with the collection of stool samples, an assessment of the patient's nutrition will be performed using the food frequency questionnaire (FFQ) and three-day dietary recall. The blood samples will be collected at 4-time points: before the start of the study, before the operation, and 3 and 6 months after the operation. The following parameters will be marked in the collected blood samples: glucose, insulin, HbA1c, liver tests: ALT (Alanine transaminase), AST (Aspartate transaminase), GGTP (Gamma-glutamyl Transferase), alkaline phosphatase (ALP), bilirubin; lipid profile, CRP (C-reactive protein), total protein, albumin, inflammatory markers: IL-6, IL-10, Tumor necrosis factor-α (TNF-α), IL-8, IL-R2. During the examination, tissue samples will be taken at 2-time points. The first is during routine gastroscopy before surgery. Gastroscopy will be performed before the inclusion of the probiotic. Duodenal and stomach biopsy will be performed during gastroscopy. The second time tissue samples will be collected intraoperatively. Gastric specimens will be collected from patients undergoing LSG. Patients qualified for RYGB and OAGB surgery will undergo gastric and jejunum biopsy. The parameters of the intestinal barrier status will be assessed in the collected tissues: Plasmalemma Vesicle-Associated Protein-1 (PLVAP-1), and Regenerating Islet Derived Protein 3 Alpha (Reg3α).

Official Title
-----------------
The Effect of Probiotic Supplementation on Systemic Inflammation and Metabolic Endotoxemia in Morbidly Obese Patients Undergoing Bariatric Surgery

Conditions
-----------------
Bariatric Surgery Candidate, Dysbiosis

Intervention / Treatment
-----------------
* Dietary Supplement: probiotic supplementation
* Dietary Supplement: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: qualification for LSG, RYGB, OAGB bariatric surgery age over 18 written consent to participate in the study Exclusion Criteria: allergy/intolerance to any of the ingredients of the preparations, inflammatory bowel diseases, current antibiotic therapy, immunosuppression, biological treatment, long-term antibiotic therapy, taking probiotics in the 1 month prior to study enrollment, neurodegenerative diseases.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotic<br>Patients will take 4 capsules of a multi-strain probiotic preparation daily. Product characteristics: 1 capsule of the preparation contains ≥2.5 x 10^9 CFU / g of live bacteria (Bifidobacterium lactis W52, Lactobacillus brevis W63, Lactobacillus casei W56, Lactococcus lactis W19, Lactococcus lactis W58, Lactobacillus acidophilus W37, Bifidobacterium bifidillum W23) | Dietary Supplement: probiotic supplementation<br>* Participants enrolled in the probiotic group will receive probiotics for 12 weeks before surgery.<br>|
| Placebo Comparator: Placebo<br>Patients will take 4 capsules of a placebo preparation daily. | Dietary Supplement: placebo<br>* Participants enrolled in the placebo group will receive a placebo instead of probiotics.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of changes in weight loss of the body | Weight loss will be measured and expressed in kilograms | 3 and 6 months after surgery | 
| Evaluation of changes in inflammation status | The inflammation will be assessed by measuring CRP concentration in the serum | before the intervention, 3 and 6 months after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of changes in the state of the intestinal microbiota - the content of intestinal microbiota | The state of the intestinal microbiota will be measured by quantitative and qualitative content of the intestinal microbiota using the new generation sequencing method (16s rRNA) | before the intervention, 2 weeks before surgery, 3 and 6 months after surgery | 
| Evaluation of changes in the state of the intestinal microbiota - the content of bacterial metabolites short-chain fatty acids (SCFA) | The state of the intestinal microbiota will be measured by the quantitative and qualitative content of bacterial metabolites - short-chain fatty acids (SCFA) | before intervention, 2 weeks before surgery, 3 and 6 months after surgery | 
| Evaluation of changes in the permeability of the intestinal barrier | The permeability of the intestinal barrier will be measured by the presence of increased intestinal permeability parameter - I-FABP in stool | before the intervention, 2 weeks before surgery, 3 and 6 months after surgery | 
| Evaluation of changes in the state of the intestinal barrier | The permeability of the intestinal barrier will be measured by the concentration of PLVAP-1 and Reg3-alfa in collected tissues | before the intervention, in time of surgery | 
| Evaluation of changes in endotoxemia | Endotoxemia will be assessed by measuring lipopolysaccharide in serum. | before the intervention, 3 and 6 months after surgery | 
| Evaluation of changes in inflammation profile in serum | The inflammation profile will be assessed by a concentration of cytokines (IL-6, TNF-alfa, IL-10, IL-8, IL-2R) in the serum. | before the intervention, 3 and 6 months after surgery | 
| Evaluation of changes in intestine inflammation | The intestine inflammation will be measured by the level of calprotectin in the stool | before the intervention, 3 and 6 months after surgery | 
| Evaluation of changes in nutrition - frequency | The assessment of the nutrition will be performed using the food frequency questionnaire (FFQ) | before the intervention and 6 months after surgery | 
| Evaluation of changes in nutrition - quality and quantity | The assessment of the nutrition will be performed using a 3-day food record | two weeks before surgery and 3 months after surgery | 
| Postoperative complications | Postoperative complications will be assessed by the Clavien-Dindo classification of surgical complications (on a scale of 1 to 5, the higher the result, the more intensive treatment is required for the described complication) | During six months after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
microbiota, bariatric surgery, obesity, inflammation, endotoxemia, intestinal permeability