Investigation on the Role of Gut-liver Axis for Non-alcoholic Steatohepatitis Through Bariatric Surgery

Recruiting

• Conditions: Non-Alcoholic Steatohepatitis; Non-Alcoholic Fatty Liver Disease; Bariatric Surgery
• Interventions: Procedure: Bariatric surgery

• Registration Number: NCT04501042
• Lead Sponsor: National Taiwan University Hospital

Brief Summary

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Non-alcoholic steatohepatitis (NASH) is an aggressive form of NAFLD with remarkable inflammatory features which may cause advanced fibrosis and liver cancer. So far there is no FDA-approved drug for treating NASH. A 10% weight loss by life style modification is a standard recommendation to treat NASH which achieves only 10-20% success rate in clinical practice. Thus, the development of therapeutics to prevent and treat NASH is certainly an unmet need. For now, the mechanism of how simple steatosis progresses to NASH remains unclear and accumulating evidences suggest the role of gut microbiota may be essential. Studies have also noted the bariatric surgery effectively improve diabetes and NASH with significant alterations in the composition and function of gut microbiome. In this study, the investigators aim to investigate the role of gut microbiota in the pathophysiology of NASH by comparing NAFLD severity, gut microbiome, metabolomics, immune profiles among patients before and after the bariatric surgery. With these efforts, the investigators wish to decipher the mechanism of how bariatric surgery may improve NASH through changing the gut microbiota and find out microbe-associated molecular signatures between NASH and NAFLD through this study.

Detailed Description

The investigators anticipate to recruit 140 morbidly obese patients who will receive bariatric surgery including 100 patients receiving sleeve gastrectomy (SG) and 40 receiving gastric bypass surgery (GB). Liver biopsy will be performed during the operation to confirm the histological scores of NAFLD severity. The investigators expect to have 50% NASH and 50% NAFL patients from these morbidly obese patients based on previous domestic data. (i.e. 50 patients receiving SG to have NASH and 50 patients receiving SG to have NAFL; 20 patients receiving GB to have NASH and 20 patients receiving GB to have NAFL.) In this study, the investigators have two study objectives which are as follows.

1. The first objective is to discover potential mechanisms among gut-liver axis for preventing or promoting NAFL to NASH by comparing (1) fecal microbiome composition and metabolomics, (2) peripheral blood biochemistry, metabolomics, immune cell phenotypes, and cytokines (3) portal vein biochemistry, metabolomics, immune cell phenotypes, and cytokines (4) Liver metabolomics and RNA-seq (5) gut permeability test (lactulose/mannitol challenge) (6) host genetic susceptibility for NAFLD (PNPLA3 and TM6SF2) between the tissue-proved NASH and NAFL patients in this study with a cross-sectional comparison.

2. The second objective is to longitudinally investigate the potential mechanisms of bariatric surgery for improving NASH via a gut-microbiota dependent pathway. Clinical and experimental data before (baseline) and after (1st, 3rd, 6th months) bariatric surgery will be collected which include (1) non-invasive evaluation of NAFLD severity (Fibroscan, MRI-PDFF (proton density fat fraction) and MRE), (2) blood biochemistry, metabolomics, immune cell phenotypes, and cytokines (3) fecal microbiome and metabolomics (4) gut permeability test (5) liver biopsy histology (if available)

Study Timeline

• Study Start: 2019-05-16
• Study First Submitted: 2020-07-22
• Study First Submitted QC: 2020-08-02
• Study First Posted: 2020-08-06
• Status Verified: 2021-09
• Last Update Submitted: 2022-09-25
• Last Update Posted: 2022-09-27
• Primary Completion: 2024-04-01
• Study Completion: 2024-09-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 140

Inclusion Criteria

Age >20，morbidly obese patients who will receive bariatric surgery.

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Exclusion Criteria

• Average daily alcohol intake >20 grams,
• Hepatitis B carriers, Hepatitis C carriers,
• people with liver disease caused by other causes
• liver cirrhosis,
• diseases related to abnormal blood coagulation,
• inflammatory bowel disease,
• routine use of steroids or immunity Inhibitors and other immunomodulatory drugs
• ursodeoxycholic and other drugs that affect bile acid metabolism
• those who have used antibiotics or probiotics within one month

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
NASH (before bariatric surgery)	Bariatric surgery	age \>20，morbid obesity receiving bariatric surgery and was proved NASH histologically. Data collected before bariatric surgery.
NASH (after bariatric surgery)	Bariatric surgery	age \>20，morbid obesity receiving bariatric surgery and was proved NASH histologically. Data collected after bariatric surgery.

Primary Outcome Measures

Name	Time	Method
Change of NAFLD severity score (histology) from baseline to the 6th month	Baseline and 6 months after bariatric surgery	Liver biopsy will be performed before and after surgery (if available) to acquire histology evaluation
Change of NAFLD severity measured by Fibroscan from baseline to the 6th month	Baseline and 6 months after bariatric surgery	Fibroscan (CAP and kPa)
Change of NAFLD severity measured by MRI proton density fat fraction from baseline to the	Baseline and 6 months after bariatric surgery	MRI proton density fat fraction (%)
Change of NAFLD severity measured by magnetic resonance elastography from baseline to the	Baseline and 6 months after bariatric surgery	magnetic resonance elastography (kPa)

Secondary Outcome Measures

Name	Time	Method
Change of gene expression profiles of liver tissue	Baseline and 6 months after bariatric surgery (if available)	gene expression measured by RNA-seq
Change of gut microbiome profiles	Baseline, 1st month, 3rd month and 6th month after surgery	fecal 16S ribosomal RNA sequencing and shotgun metagenome sequencing
Change of metabolomic profiles of liver tissue	Baseline and 6 months after bariatric surgery (if available)	Metabolites in liver tissue measured by liquid chromatography mass
Change of body fluid metabolomic profiles	Baseline, 1st month, 3rd month and 6th month after surgery	Metabolites in blood fluids measured by liquid chromatography mass spectrometry
Change of Immune profiles	Baseline, 1st month, 3rd month and 6th month after surgery	Immune cell phenotype patterns in body fluids measured by flow cytometry
Change of gut permeability test	Baseline and 6 months after bariatric surgery	Lactulose/Mannitol challenge test

Trial Locations

Locations (1)

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan