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Gut Microbiota and Modulation of Liver Damage in NAFLD

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ClinicalTrials.gov Identifier: NCT02158351
Recruitment Status : Unknown
Verified June 2014 by STEFANO GINANNI CORRADINI, University of Roma La Sapienza.
Recruitment status was:  Recruiting
First Posted : June 6, 2014
Last Update Posted : June 9, 2014
Sponsor:
Collaborator:
Göteborg University
Information provided by (Responsible Party):
STEFANO GINANNI CORRADINI, University of Roma La Sapienza

Brief Summary:
Several experimental data suggest that gut-derived endotoxin and GM composition can act as a "second hit" or insult to convert hepatic SS to NASH and cause both local hepatic and systemic inflammation.This study's aim is to analyze microbiota diversity, providing information both on intestinal microbial composition and on the metabolic processes linked to them. In addition, we will correlate, for the first time, GM composition to hepatic and white adipose tissue gene expression patterns of interest and serum and fecal markers possibly related to impaired fat storage and inflammation. We aim to provide preliminary data to design future intervention studies with pre- or probiotics or bile acid derivatives to prevent/treat inflammation and fibrosis in NAFLD patients.

Condition or disease Intervention/treatment
Simple Steatosis (SS) Non-alcoholic Steatohepatitis (NASH) Obesity Procedure: liver and white adipose tissue biopsies

  Show Detailed Description

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Study Type : Observational
Estimated Enrollment : 55 participants
Observational Model: Case Control
Time Perspective: Cross-Sectional
Official Title: Role and Pathogenetic Mechanisms of Intestinal Microbiota in Non-alcoholic Fatty Liver Disease Severity in Obese and Non-obese Subjects
Study Start Date : November 2013
Estimated Primary Completion Date : July 2014
Estimated Study Completion Date : October 2014


Group/Cohort Intervention/treatment
Simple steatosis
We will run a cross-sectional observational study including two groups of human subjects: patients with simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). Grouping in patients SS or NASH will be performed based on the histological diagnosis of the type of NAFLD obtained at operation (sleeve gastrectomy or cholecystectomy). BMI will be considered as a confounding variable to be statistically analyzed. Main hypothesis: GM can lead to liver inflammation in patients with liver fat accumulation.
Procedure: liver and white adipose tissue biopsies
Non-alcoholic steato-hepatitis
We will run a cross-sectional observational study including two groups of human subjects: patients with simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). Grouping in patients SS or NASH will be performed based on the histological diagnosis of the type of NAFLD obtained at operation (sleeve gastrectomy or cholecystectomy). BMI will be considered as a confounding variable to be statistically analyzed. Main hypothesis: GM can lead to liver inflammation in patients with liver fat accumulation.
Procedure: liver and white adipose tissue biopsies



Primary Outcome Measures :
  1. gut microbiota composition [ Time Frame: 12 months ]
    In patients with simple steatosis SS vs those with NASH the gut microbiota composition is different even after BMI normalization


Secondary Outcome Measures :
  1. In each patient group overall gut microbiota composition, and hepatic and (only in the obese patients submitted to bariatric surgery) adipose tissue mRNA expression of relevant lipid and inflammatory response pathways [ Time Frame: 12 months ]
    In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition, and hepatic and (only in patients submitted to bariatric surgery) adipose tissue messenger ribonucleic acid (mRNA) expression of relevant lipid and inflammatory response pathways: Acetyl-coenzyme A-carboxylase (ACC1), Fatty acid Synthase (FAS), Sterol regulatory element-binding protein (SREBP1c), apolipoprotein B (ApoB), farnesoid X receptor (FXR), Carbohydrate-responsive element-binding protein (ChREBP), TGR5, Sterol regulatory element-binding protein (SREBP2a), liver X receptor (LXR), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), low density lipoprotein receptor (LDLR) , Proprotein-convertase-subtilisin/kexin type 9 (PCSK9), tumor necrosis factor α (TNF-α), toll-like receptor 4 (TLR-4), NLRP3 (NOD-like receptor 3), c-Jun N-terminal kinase (JUN-K)

  2. In each patient group overall gut microbiota composition, and hepatic and (only in the obese patients submitted to bariatric surgery) adipose tissue mRNA expression of relevant lipid and inflammatory response pathways [ Time Frame: 12 months ]
    In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition, and hepatic and (only in patients submitted to bariatric surgery) adipose tissue mRNA expression of relevant lipid and inflammatory response pathways: ACC1 (Acetyl-CoA carboxylase), FAS (Fatty acid Synthase), SREBP1c (Sterol regulatory element-binding protein), ApoB (apolipoprotein B), FXR (farnesoid X receptor), ChREBP (Carbohydrate-responsive element-binding protein), TGR5, SREBP2a (Sterol regulatory element-binding protein), LXR (liver X receptor), HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), LDLR (low density lipoprotein receptor) , PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9), TNF-α (tumor necrosis factor α), TLR-4 toll-like receptor 4), NLRP3 (NOD-like receptor 3), JUN-K (c-Jun N-terminal kinase)


Other Outcome Measures:
  1. In each group, overall gut microbiota composition, and serum fasting and (only in the obese patients) post-prandial bile acid levels, serum markers of inflammation and liver damage and white adipose tissue mRNA expression of relevant genes [ Time Frame: 18 months ]
    In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition, and serum fasting and (only in patients submitted to bariatric surgery) post-prandial bile acid levels.In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition, and serum markers of inflammation and liver damage (endotoxin, TNF-alfa, IL-6, aspartate aminotransferase (AST), alanine aminotransferase (ALT), cytokeratin 18.In each patient group [simple steatosis (SS) and NASH], overall gut microbiota composition and white adipose tissue mRNA expression of relevant genes chosen on the base of the mRNA expression results on liver specimens.


Biospecimen Retention:   Samples With DNA
Stool samples, serum, plasma, liver and (only in the obese patients) adipose tissue


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
two groups of patients with morbid obesity undergoing sleeve gastrectomy will be enrolled. Grouping in patients with simple steatosis (SS) or non-alcoholic steatohepatitis (NASH) will be performed based on the histological diagnosis of the type of NAFLD obtained at operation. Two groups of non-obese patients undergoing cholecystectomy for gallstone disease will be enrolled. Grouping in patients with simple steatosis (SS) or non-alcoholic steatohepatitis (NASH) will be performed based on the histological diagnosis of the type of NAFLD obtained at operation.
Criteria

Inclusion Criteria:

  1. Male or female, equal or over 18 years old
  2. Eligible for Sleeve Gastrectomy for obesity with BMI 35-50 kg/m2
  3. Eligible for Cholecystectomy for symptomatic gallstones and bright liver at ultrasounds
  4. Alcohol consumption is less than 20 g/d

Exclusion Criteria:

  1. Having liver disease of other etiology
  2. Having advanced liver disease
  3. Having abnormal coagulation or other reason contraindicating a Liver Biopsy
  4. On regular intake of medications known to cause or exacerbate steatohepatitis or antibiotic, pre- or probiotics in the previous 3 months
  5. Use of vitamin E or fish oil supplements in the previous 2 months
  6. Alcohol consumption of more than 20 g/dl
  7. Inflammatory bowel diseases
  8. previous gastrointestinal surgery modifying the anatomy (prior to bariatric surgery)
  9. Pregnancy or lactating state

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02158351


Contacts
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Contact: Stefano Ginanni Corradini, MD, PhD +39 0649972086 stefano.corradini@uniroma1.it
Contact: Fredrik Bäckhed, MD, PhD

Locations
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Italy
Stefano Ginanni Corradini Recruiting
Rome, Italy, 00161
Contact: Stefano Ginanni Corradini, MD, PhD    +39 0649972086    stefano.corradini@uniroma1.it   
Sponsors and Collaborators
University of Roma La Sapienza
Göteborg University
Investigators
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Study Director: Stefano Ginnani Corradini, MD, PhD Sapienza University of Rome
Study Director: Fredrik Backhed, MD Wallenberg laboratoriet, Gotebörg, Sweden
Principal Investigator: Frida Leonetti, MD, PhD Sapienza University of Rome
Principal Investigator: Gianfranco Silecchia, MD Sapienza University of Rome
Principal Investigator: Francesco Gossetti, MD Sapienza University of Rome
Principal Investigator: Adriano De Santis, MD, PhD Sapienza University of Rome
Principal Investigator: Claudio Di Cristofano Sapienza University of Rome

Publications:

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Responsible Party: STEFANO GINANNI CORRADINI, MD, PhD, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT02158351     History of Changes
Other Study ID Numbers: 2943/14.11.2013
First Posted: June 6, 2014    Key Record Dates
Last Update Posted: June 9, 2014
Last Verified: June 2014

Keywords provided by STEFANO GINANNI CORRADINI, University of Roma La Sapienza:
Simple steatosis (SS)
Non-alcoholic steatohepatitis (NASH)
Gut microbiota (GM)
Non alcoholic fatty liver disease (NAFLD)

Additional relevant MeSH terms:
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Non-alcoholic Fatty Liver Disease
Fatty Liver
Liver Diseases
Digestive System Diseases
Liver Extracts
Hematinics