Intestinal Microbiota and NAFLD Pre and Post Bariatric Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by University Health Network, Toronto
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Johane Allard, University Health Network, Toronto
ClinicalTrials.gov Identifier:
NCT01856465
First received: May 14, 2013
Last updated: January 10, 2014
Last verified: January 2014
  Purpose

Non-alcoholic fatty liver disease (NAFLD) includes benign hepatic simple steatosis (SS) and steatohepatitis (NASH), which is characterised by inflammation leading to fibrosis and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, and the prevalence is 74-98% in morbidly obese individuals undergoing bariatric surgery. Although steatosis improves post bariatric surgery, hepatic inflammation and fibrosis do not consistently improve. Alterations of the human gut flora (intestinal microbiota; IM) may play a role. One mechanism linking IM to obesity, insulin resistance (IR), and NAFLD is through translocation of bacterial lipopolisaccharide (LPS=endotoxin) into the blood stream (=endotoxemia), causing chronic inflammation. Morbidly obese subjects have different IM compared to lean controls, and the IM structure is significantly altered after bariatric surgery, probably due to a combination of anatomic changes, diet, and weight loss. For example, the ratio of Firmicutes/Bacteroidetes may be lower in obese subjects compared to lean controls and lower numbers of Faecalibacterium prausnitzii were reported in some obese subjects before bariatric surgery, which increased 3 months post-surgery. This is of interest since, in animal studies, low abundance of F. prausnitzii, a butyrate producing bacterium, is associated with increased intestinal permeability, endotoxemia, and inflammation. To our knowledge, only two studies are available describing IM in patients pre and post bariatric surgery, and no data have been published on the relationship between IM and NAFLD in these patients.


Condition
Morbid Obesity
Non-alcoholic Fatty Liver Disease

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Role of Intestinal Microbiota in Non-alcoholic Fatty Liver Disease Pre and Post bAriatric Surgery

Resource links provided by NLM:


Further study details as provided by University Health Network, Toronto:

Primary Outcome Measures:
  • Firmicutes/Bacteroides ratio in feces [ Time Frame: Baseline, 6, 12 months ] [ Designated as safety issue: No ]
    16S rRNA sequencing will be performed on the Ion Torrent platform


Secondary Outcome Measures:
  • Overall microbiota composition, amount of selected groups of microorganisms and concentration of Short Chain Fatty Acid (SCFA) in stool sample [ Time Frame: 8 months ] [ Designated as safety issue: No ]
    Lower fecal butyrate concentration in NASH vs SS

  • The amount of endotoxin, TNF-alfa and IL-6 in plasma/serum [ Time Frame: 8 months ] [ Designated as safety issue: No ]
    Higher plasma endotoxin and pro-inflammatory markers (TNF-alfa and IL-6) in NASH vs SS.

  • The change in inflammation, fibrosis, steatosis in liver histology [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Change in the number of F. prausnitzii in stool between baseline and 12 months related with the change in liver histology

  • NAFLD activity score [ Time Frame: baseline, 12 months ] [ Designated as safety issue: No ]
    NAFLD Activity score (Kleiner) on liver histology


Biospecimen Retention:   Samples With DNA

Liver biopsy and stool samples


Estimated Enrollment: 120
Study Start Date: June 2013
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts
Bariatric surgery of morbid obese
Morbid obese patient who undergo Bariatric surgery with NAFLD (NASH or SS) status

Detailed Description:

Study Design: A. Cross-sectional study: Sixty patients with morbid obesity undergoing bariatric surgery diagnosed with NAFLD on liver biopsy (30 SS, 30 NASH). Main hypothesis: The ratio of Firmicutes/Bacteroidetes is higher in stool samples from morbidly obese subjects with NASH compared to SS. Other differences in IM composition exist. Objective: to compare bacterial dynamics using Illumina technology to assess the IM. The relative abundance of the dominant fecal microorganisms (including Firmicutes, Archaea, Bacteroides, Bifidobacteria, Mollicutes, Enterobacteriaceae, Clostridia clusters, F. prausnitzii, Roseburia, and Lactobacilli) will also be assessed by real-time PCR. Sub-hypotheses: In NASH compared to SS, there will be: a) lower fecal butyrate concentration; b) higher endotoxin and other inflammatory markers (TNF-α, IL-6) in plasma. Potential covariates assessed: small intestinal bacterial overgrowth (SIBO), measured by glucose hydrogen breath test (GHBT), which can contribute to endotoxemia and inflammation; IR, diabetes status, lipid profile, plasma vitamin E, liver enzymes, anthropometry, food intake, physical activity and environmental factors.

B. Prospective cohort study: Patients undergoing bariatric surgery with either SS or NASH (up to 60 of them recruited from Part A) will be followed prospectively over 12 months to assess changes in the IM and liver histology. Goal is to have 60 subjects who complete the study with a 2nd liver biopsy. Main Hypothesis: In morbidly obese patients with NAFLD (SS or NASH), changes in IM post bariatric surgery will be associated with changes in liver histology. Specifically, an increased number of F. prausnitzii in feces with be associated with improvement in liver histology while a reduction will be associated with deterioration of liver histology. Objective: To correlate changes in liver histology (NAFLD activity score [NAS], inflammation, fibrosis, steatosis) between 0 and 12 months with changes in F. prausnitzii. Other changes of the fecal IM community structure, fecal short chain fatty acids (including butyrate), plasma endotoxin, inflammatory markers (TNF-α, IL-6) and SIBO will also be assessed, in addition to diet, activity, weight change, improvement of diabetes and plasma vitamin E. Secondary hypotheses: Increased number of F. prausnitzii in feces will be associated with increased fecal butyrate, lower serum endotoxin and lower inflammatory markers (TNF-α, IL-6) in plasma.

Significance: In humans with morbid obesity and NAFLD undergoing bariatric surgery, very little data are available on IM and its metabolic effect and contribution to NAFLD. These studies will add more information regarding the role of IM and its effect on potential mechanisms contributing to NAFLD. It will also provide us with pilot data for future intervention studies assessing the potential use of pre- or probiotics for NAFLD in morbidly obese subjects in the setting of bariatric surgery.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

NAFLD is the hepatic manifestation of the metabolic syndrome, and the prevalence is 74-98% in morbidly obese individuals. The aim of this study is to examine the role of intestinal microbiota (IM) in non-alcoholic fatty liver disease (NAFLD) in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. Alterations of the human gut flora (intestinal microbiota) will be determined before and after surgery in realtion with the change of liver histology.

Criteria

Inclusion Criteria:

  • BMI>40 kg/m2 or BMI>35-40 kg/m2 with severe weight loss comorbidities
  • Male or female, equal or over 18 years of age
  • Alcohol consumption is leass than 20 g/d

Exclusion Criteria:

  • No diagnosis of NAFLD
  • Having liver disease of other etiology
  • Having advance liver disease
  • Having abnormal coagulation or other reason contraindicating a Liver Biopsy
  • On medication known to precipitate steatohepatitis 6 months prior to entry
  • On regular intake of non-steroidal anti-inflammatory drugs, prebiotics, probiotics and antibiotics, ursodeoxycholic or any experimental drug in the 3 months prior to study entry
  • Having type-1 diabetes, chronic gastrointestinal diseases, previous gastrointestinal surgery modifying the anatomy (prior to bariatric surgery)
  • Smoking
  • Pregnancy or Breastfeeding
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01856465

Contacts
Contact: Johane Allard, MD, FRCP 416-340-5159 Dr.Johane.Allard@uhn.ca
Contact: Nita Prayitno, Ph.D. 416-340-4104 nprayitn@uhnresearch.ca

Locations
Canada, Ontario
University Health Network Recruiting
Toronto, Ontario, Canada, M5G 2C4
Contact: Bianca M Arendt, PhD, CCRP    416-340-4104    barendt@uhnresearch.ca   
Contact: Johane P Allard, MD    416-340-5159    johane.allard@uhn.on.ca   
Principal Investigator: Johane P Allard, MD         
Sponsors and Collaborators
Johane Allard
Canadian Institutes of Health Research (CIHR)
Investigators
Principal Investigator: Johane Allard, MD. FRCPC University Health Network, Toronto
  More Information

Publications:

Responsible Party: Johane Allard, Professor of Medicine, Gastroenterologist, University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT01856465     History of Changes
Other Study ID Numbers: 13-6115-A
Study First Received: May 14, 2013
Last Updated: January 10, 2014
Health Authority: Canada: Canadian Institutes of Health Research
Canada: Ethics Review Committee

Keywords provided by University Health Network, Toronto:
Bariatric surgery
NAFLD
Steatohepatitis
Simple Steatosis
Intestinal Microbiota

Additional relevant MeSH terms:
Fatty Liver
Liver Diseases
Obesity, Morbid
Body Weight
Digestive System Diseases
Nutrition Disorders
Obesity
Overnutrition
Overweight
Signs and Symptoms

ClinicalTrials.gov processed this record on October 23, 2014