Dietary Intervention and Intestinal Microbiota in Non-alcoholic Fatty Liver

Study Overview
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Brief Summary
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In patients with NAFLD/NASH, changes in liver lipid composition and function tests following a short dietary intervention are associated with changes in gut microbiota

Detailed Description
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Study Hypothesis: In patients with NAFLD/NASH, changes in liver lipid composition and function tests following a short dietary intervention are associated with changes in gut microbiota Study period: Study duration for the participant: 7-10 weeks (1-4 weeks screening period, 3 weeks of intervention + 3 weeks of follow-up) Expected study completion date: 30.04.2012 Study type: Single arm before-after study Number of patients: 20 subjects with obesity and NAFLD / NASH Main criteria for inclusion: Obesity defined as BMI>30 Abnormal liver function tests defined as ALT > 1.5 times the upper limit of normal NAFLD present at liver biopsy Age > 18 years, < 60 years Main exclusion criteria: Inability or unwillingness to give consent Parenteral nutrition or other ongoing dietary intervention Bulimia Other known cause of chronic liver disease, including hepatitis B or C, iron overload, Use of substances known to alter intestinal permeability, including alcohol and NSAIDs Intervention: The phase 2 Eurodiet® program will be used as standardized hypo-caloric diet during a 3-weeks intervention period. The products are commercially available and prescribed to reach 1000 kcal/day. These products will be offered free of charge. Primary Objective: To assess the impact of dietary intervention on the relative abundance of fecal Bacteroidetes (expressed as the bacteroidetes to firmicutes ratio) in patients with obesity, abnormal liver function tests and NAFLD Secondary Objectives: To compare fecal microbiota from patients with NAFLD or NASH at baseline To assess fecal microbiota changes in patients with NAFLD or NASH after dietary intervention To measure liver fat content at baseline and after dietary intervention To assess changes in liver function tests and ultrasensitive CRP, cytokines and serum LPS in relation to changes in microbiota and liver lipid composition To measure orocecal transit time, an index of intestinal pullulation, at baseline and after dietary intervention in patients with NAFLD or NASH To measure intestinal permeability at baseline and after dietary intervention in patients with NAFLD or NASH To assess body composition changes in relation to changes in microbiota and liver lipid composition Statistical methods: Baseline and end-of-treatment changes for both bacterial genders and subspecies will be compared using paired-sample Wilcoxon signed-rank test. ANOVA and paired t-test for comparison of other changes within groups. Pearson or Spearman tests will be used to assess correlations between changes in microbiota and changes in liver fat content, liver function tests, CRP, cytokines and intestinal pullulation and permeability. Sample size: 20 patients with NAFLD/NASH will be studied before and after dietary intervention. Assessment of end-points: Fecal microbiota will be analysed with 454-Flex metagenomics Ultrasensitive CRP and serum LPS changes as compared with baseline Serum cytokines as measured with ELISA Liver fat content and composition will be measured using MR spectroscopy Small intestinal overgrowth and intestinal permeability will be assessed using standard 13C breath tests and polyethyleneglycol absorption test Body mass composition changes will be assessed using bioelectrical impedance analysis Safety : All adverse events will be recorded throughout the study, in compliance with GCP ICH E6 and national regulations.

Official Title
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Effect of Dietary Intervention on Intestinal Microbiota in Patients With Non-alcoholic Fatty Liver Disease

Conditions
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Obesity, Non-alcoholic Fatty Liver Disease (NAFLD)

Intervention / Treatment
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* Other: Hypocaloric diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obesity defined as BMI>30 Abnormal liver function tests defined as ALT > 1.5 times the upper limit of normal NAFLD present at liver biopsy Age > 18 years, < 60 years Exclusion Criteria: Inability or unwillingness to give consent Bulimia Other known cause of chronic liver disease, including hepatitis B or C, iron overload, Use of substances known to alter intestinal permeability, including alcohol and NSAIDs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| hypocaloric diet<br>The included patients are assigned to a hypocaloric standardized diet for 3 weeks. | Other: Hypocaloric diet<br>* Eurodiet,standardized hypo-caloric diet, during 3 weeks<br>* Other names: eurodiet 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| abundance of fecal abundance of fecal Bacteroidetes | Bacterial cells/g caecal content | thrice, at inclusion, day 21 and day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| liver fat content | picsel/uni MRI | twice, at inclusion and day 21 | 
| liver function tests | mmol/l | four times, at screening, inclusion, day 21 and day 42 | 
| CRP | mg/l | thrice, at screening, inclusion and day 21 | 
| serum cytokines | ng/ml | twice, at inclusion and day 21 | 
| serum LPS | pg/ml | twice, at inclusion and day 21 | 
| Breath test pullulation |  | twice, at inclusion and day 21 | 
| intestinal permeability | Polyethylene glycol 3350/Polyethylene glycol 400 ratio | twice, at inclusion and day 21 | 
| body composition | body composition in kg and % of body weight | thrice, at inclusion, day 21 and day 42 | 
| liver lipid composition (biopsy) |  | once, at screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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obesity, non-alcoholic fatty liver disease