Intestinal Microbiota and NAFLD Pre and Post Bariatric Surgery

November 1, 2022 updated by: Johane Allard

Role of Intestinal Microbiota in Non-alcoholic Fatty Liver Disease Pre and Post bAriatric Surgery

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
120

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 2C4
        • University Health Network

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Bariatric surgery of morbid obese
Morbid obese patient who undergo Bariatric surgery with NAFLD (NASH or SS) status

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Firmicutes/Bacteroides ratio in feces
Time Frame: Baseline, 6, 12 months
16S rRNA sequencing will be performed on the Ion Torrent platform
Baseline, 6, 12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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
8 months
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.
8 months
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
12 months
NAFLD activity score
Time Frame: baseline, 12 months
NAFLD Activity score (Kleiner) on liver histology
baseline, 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Johane Allard

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Canadian Institutes of Health Research (CIHR)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Johane Allard, MD. FRCPC, University Health Network, Toronto

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 30, 2022

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 30, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 14, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 14, 2013

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 17, 2013

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 2, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 1, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 13-6115-A

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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