Clinical trial NCT01922830: Probiotics and Microbiota in Bariatric Surgery
Official title: Probiotics and Microbiota in Bariatric Surgery
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: NAFLD
Keywords: Sleeve Gastrectomy
NAFLD
gut microbiot
Bariatric surgery
Lead sponsor: Tel-Aviv Sourasky Medical Center
Sponsor class: OTHER_GOV
First posted: 2013-08-14
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a randomized clinical trial with 6 months probiotic supplement vs. placebo treatment and 6 month follow up on 100 NAFLD patients that will undergo sleeve gastrectomy surgery. Measurements will be conducted at: baseline, M3 (3 months after treatment initiation), M6 and M12 and will include: abdominal US, Fibroscan, biochemical tests, anthropometric measurements, glucose breath test for bacterial overgrowth, fecal samples and questionnaires for demographic details, quality of life, food intake, food tolerance and habitual physical activity. 20 subjects will undergo an additional liver-MRI test at baseline and M6.

Additionally, 30 healthy participants will consume probiotic supplement vs. placebo for 28 days and will undergo gastroscopy and colonoscopy before and during consumption.

Detailed description: Background:

Bariatric surgery is an effective and increasingly common treatment for obesity and obesity-related comorbidities. Among patients undergoing bariatric surgery, as many as 96% have NAFLD (Nonalcoholic fatty liver disease) and up to 25% have NASH (Nonalcoholic steatohepatitis). Intestinal microbiota has been shown to play pivotal roles in host mammalian developmental, immune and metabolic functions. Alterations in the gut microbiome, or 'dysbiosis' has been recently linked to the pathogenesis of metabolic disease including obesity, insulin resistance, atherosclerosis and liver diseases. Recent studies show that modulation of gut microbiota may represent a novel way to treat or prevent NAFLD and its progression. Bariatric surgery is associated with major modifications in microbiota composition, quantity and function. Potential mediators to the gut microbiota are probiotics which are considered to be a safe therapy since its microorganisms composition is found naturally in human microflora. Clinical research has shown that probiotic supplementation can induce physiological changes in the intestinal flora (e.g., via the secretion of endogenic antibiotics and other defensins). Moreover, It was shown that probiotic bacteria are assimilated in the gut mucosa, thus replacing and changing the natural bacterial line-up. The biopsies taken in the healthy section of the study will help us evaluate all the above changes, after 4 weeks of probiotic intervention.

To date, there is lack of evidence on the use of probiotics in bariatric surgeries with just 1 randomizes clinical trial in Roux-en-Y gastric bypass surgery patients.

Aims:

To evaluate the effect of 6 months probiotic supplement vs. placebo on clinical and metabolic parameters in patients with NAFLD undergoing sleeve gastrectomy surgery.

Working hypothesis: Modulation of gut microbiota with probiotic will have a beneficial effect on clinical and metabolic parameters in sleeve gastrectomy patients with NAFLD.

To evaluate the effect of 4 weeks probiotic supplement vs. placebo on microbiome composition and function in healthy volunteers.

Methods:

A randomized double blind clinical trial with 6 months treatment and 6 months follow up including 2 treatment arms: probiotic and placebo. One hundred NAFLD patients who will undergo sleeve gastrectomy surgery through the bariatric surgery clinic at the Tel Aviv Assuta medical center will be enrolled during 2013-2016. Baseline and follow up evaluation will be performed at the Tel-Aviv Sourasky Medical center and will include: abdominal US (hepato-renal index-HRI), Fibroscan, biochemical tests, anthropometric measurements, glucose breath test for bacterial overgrowth (BO). Fecal samples will be collected and analyzed for gut microbiota utilizing 'state of the art' molecular methods. All patients will fill out validated questionnaires of demographic details, quality of life, food intake, food tolerance and habitual physical activity. Measurements will be conducted at: baseline, M3 (3 months after treatment initiation), M6 and M12. 20 subjects will undergo an additional liver-MRI test at baseline and M6.

Importance of the study: Almost all morbid obese patients have NAFLD and up to 25% have NASH, leading to major hepatic and extra-hepatic complications. Only limited data are available concerning gut microbiota composition after bariatric surgery and its association with weight reduction, metabolic and hepatic parameters. Moreover, there are no clinical trials on the role of probiotics administration following sleeve gastrectomy bariatric surgery on hepatic parameters. Probiotic supplement after bariatric surgery may improve the therapeutic effect of the surgery on hepatic steatosis and may improve also biochemical tests of vitamins (e.g. B12), inflammatory mediators (e.g. endotoxin levels) and metabolic parameters, reduce bacterial overgrowth and enhance weight loss. The study would help in developing new treatment approaches and will contribute to the understanding of the mechanisms underlying the hepatic, metabolic and inflammatory consequences of bariatric surgery.

Probiotic supplement vs. placebo will be given to 30 healthy participants. participants will undergo gastroscopy (upper GI endoscopy) + colonoscopy (lower GI endoscopy) before the probiotics intervention and after 3 to 4 weeks of probiotic intervention. During the procedure, biopsies will be taken from different segments of the GI tract. The study samples will be frozen performing the microbial tests. In addition, participants will collect fecal samples. In this section, participants will be followed-up for 3 months.

Eligibility criteria: Inclusion Criteria:

* Subjects 18-65 years old
* BMI \> 40 kg/m² or BMI \> 35 kg/m² with comorbidities (See Appendix 1 for the Ministry of health indications for bariatric surgeries) that got the bariatric commission approval of Assuta private hospitals to undergo sleeve gastrectomy surgery
* Willingness to take a probiotic/placebo supplement once a day for 6 months
* Ultrasound diagnosed NAFLD patients
* Reading and speaking Hebrew

Healthy volunteers:

* Subjects 18-65 years old
* Healthy subjects

Exclusion Criteria:

* Subject with mental illness or cognitive deterioration
* Use of probiotic/antibiotic 3 mounts before surgery
* Use of other antibiotic for more than 1 week during the study
* Drug addiction
* Excessive alcohol consumption (≥ 30 g/day in men or ≥ 20 g/day in women)
* Treatment with drugs known to cause hepatic steatosis or elevation of liver enzymes (e.g. Corticosteroids, HAART, Amiodarone, high dose estrogens) (see Appendix 2)
* Treatment with drugs or supplements that may improve hepatic steatosis or liver enzymes (Vitamin E, Milk thistle, ω-3 fatty acid, Ursodeoxycholic acid) 3 months prior to the initiation of the study
* Other causes of chronic liver disease ( e.g. viral hepatitis: HBV/HCV +, autoimmune hepatitis, Hemochromatosis, Wilson's disease)
* Diabetic patients who are treated with antidiabetic medications, except diabetic patients who are treated for at least 6 months exclusively with Metformin at a stable dose
* Subjects who began a new lipid reduction medications less than 6 months prior to the initiation of the study
* Subjects with chronic conditions that could interfere with our study: active cancer, organ transplant subjects, advanced kidney or liver disease, inflammatory bowel disease and other systemic inflammatory conditions
* Bariatric surgery in the past

Primary outcomes:
measure: Hepato-Renal Index (HRI) method by abdominal US
timeFrame: 36 months
Secondary outcomes:
measure: Liver fibrosis - by Fibroscan (transient elastography)
timeFrame: 36 months
measure: Anthropometric measurements
timeFrame: 36 months
measure: Biochemical fasting blood tests
timeFrame: 36 months
measure: The fecal microbiota composition
timeFrame: 6 years
measure: Quality of life (QoL)
timeFrame: 36 months
measure: Food tolerance after bariatric surgery
timeFrame: 36 months
measure: Liver MRI
timeFrame: 6 months
measure: Hand grip
timeFrame: 36 months
measure: Microbiome composition and function
timeFrame: 6 years
Other outcomes:
Locations:
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
Study officials:
affiliation: Tel-Aviv Sourasky Medical Center
name: Oren Shibolet, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sherf-Dagan S, Zelber-Sagi S, Buch A, Bar N, Webb M, Sakran N, Raziel A, Goitein D, Keidar A, Shibolet O. Prospective Longitudinal Trends in Body Composition and Clinical Outcomes 3 Years Following Sleeve Gastrectomy. Obes Surg. 2019 Dec;29(12):3833-3841. doi: 10.1007/s11695-019-04057-2.
citation: Shenhar-Tsarfaty S, Sherf-Dagan S, Berman G, Webb M, Raziel A, Keidar A, Goitein D, Sakran N, Zwang E, Shapira I, Zeltser D, Berliner S, Rogowski O, Shibolet O, Zelber-Sagi S. Obesity-related acetylcholinesterase elevation is reversed following laparoscopic sleeve gastrectomy. Int J Obes (Lond). 2019 Feb;43(2):297-305. doi: 10.1038/s41366-018-0014-4. Epub 2018 Feb 3.
citation: Sherf Dagan S, Zelber-Sagi S, Webb M, Keidar A, Raziel A, Sakran N, Goitein D, Shibolet O. Nutritional Status Prior to Laparoscopic Sleeve Gastrectomy Surgery. Obes Surg. 2016 Sep;26(9):2119-2126. doi: 10.1007/s11695-016-2064-9.