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Intestinal Microbiota and NAFLD Pre and Post Bariatric Surgery

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ClinicalTrials.gov Identifier: NCT01856465
Recruitment Status : Recruiting
First Posted : May 17, 2013
Last Update Posted : March 24, 2020
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Johane Allard, University Health Network, Toronto

Tracking Information
First Submitted Date May 14, 2013
First Posted Date May 17, 2013
Last Update Posted Date March 24, 2020
Actual Study Start Date June 2013
Estimated Primary Completion Date May 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: January 10, 2014)
Firmicutes/Bacteroides ratio in feces [ Time Frame: Baseline, 6, 12 months ]
16S rRNA sequencing will be performed on the Ion Torrent platform
Original Primary Outcome Measures
 (submitted: May 14, 2013)
  • In morbidly obese patients with Steatohepatitis (NASH) compared to Simple Steatosis (SS), the overall bacterial dynamics in the intestine are different [ Time Frame: 8 months ]
    The ratio of Firmicutes/Bacteroidetes in fecal sample is higher in NASH patients compared to SS patients
  • Change in NAFLD activity score (NAS) [ Time Frame: 12 months ]
    Changes in intestinal microbiota post bariatric (RYGB) surgery assocciated with changes in liver histology
Change History
Current Secondary Outcome Measures
 (submitted: January 10, 2014)
  • Overall microbiota composition, amount of selected groups of microorganisms and concentration of Short Chain Fatty Acid (SCFA) in stool sample [ Time Frame: 8 months ]
    Lower fecal butyrate concentration in NASH vs SS
  • The amount of endotoxin, TNF-alfa and IL-6 in plasma/serum [ Time Frame: 8 months ]
    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 ]
    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 ]
    NAFLD Activity score (Kleiner) on liver histology
Original Secondary Outcome Measures
 (submitted: May 14, 2013)
  • Overall microbiota composition, amount of selected groups of microorganisms and concentration of Short Chain Fatty Acid (SCFA) in stool sample [ Time Frame: 8 months ]
    Lower fecal butyrate concentration in NASH vs SS
  • The amount of endotoxin, TNF-alfa and IL-6 in plasma/serum [ Time Frame: 8 months ]
    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 ]
    Change in the number of F. prausnitzii in stool between baseline and 12 months related with the change in liver histology
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Intestinal Microbiota and NAFLD Pre and Post Bariatric Surgery
Official Title Role of Intestinal Microbiota in Non-alcoholic Fatty Liver Disease Pre and Post bAriatric Surgery
Brief Summary 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.
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.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Liver biopsy and stool samples
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.
Condition
  • Morbid Obesity
  • Non-alcoholic Fatty Liver Disease
Intervention Not Provided
Study Groups/Cohorts Bariatric surgery of morbid obese
Morbid obese patient who undergo Bariatric surgery with NAFLD (NASH or SS) status
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: May 14, 2013)
120
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 2020
Estimated Primary Completion Date May 2020   (Final data collection date for primary outcome measure)
Eligibility 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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Johane Allard, MD, FRCP 416-340-5159 Dr.Johane.Allard@uhn.ca
Contact: Katherine JP Schwenger, BASc, MAN, RD, PhD 416-340-4413 kschweng@uhnresearch.ca
Listed Location Countries Canada
Removed Location Countries  
 
Administrative Information
NCT Number NCT01856465
Other Study ID Numbers 13-6115-A
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Johane Allard, University Health Network, Toronto
Study Sponsor Johane Allard
Collaborators Canadian Institutes of Health Research (CIHR)
Investigators
Principal Investigator: Johane Allard, MD. FRCPC University Health Network, Toronto
PRS Account University Health Network, Toronto
Verification Date March 2020