Dietary Modulation of Intestinal Microbiota as Trigger of Liver Health: Role of Bile Acids - A Diet for Liver Health

Study Overview
=================
Brief Summary
-----------------
Studies in recent years have demonstrated that the commensal intestinal flora (microbiome) plays a key role in the development of nonalcoholic steatohepatitis (NASH). An unfavourable microbiom can trigger disease development and progression. On the other hand, recent data show that modulation of the microbiom by a diet can prevent the developement of a NASH. Mechanisms of interaction between nutrition, microbiome, intestine and liver are largely unknown. In this research project, the effect of a fibre-rich oat bran on NASH will therefore be investigated. A better understanding of the interaction between diet, microbiome, intestine and liver could form the basis for new preventive therapies of NASH.

Detailed Description
-----------------
In recent years, the results of animal experiments and some human intervention studies indicate that the commensal intestinal flora (microbiome) plays a key role in the development of nonalcoholic steatohepatitis (NASH). An unfavourable composition of the microbiome can trigger disease development and progression. On the other hand, recent data show that modulation of the microbiome through diet, such as a high-fibre diet, can prevent the developement of a NASH. It has been shown that the uptake of fibre-rich oats reduces LDL and total cholesterol without altering the HDL cholesterol level. Indeed, the results of several human intervention studies suggest that a regular intake of oat flakes with prebiotic food supplements is sufficient to lower LDL and total cholesterol levels. In a small clinical trial it was also shown that an intake of oat bran with prebiotic food supplements in two servings per day was associated with a significant reduction in ALT and AST activity in the serum of overweight individuals with signs of altered liver function. In addition, the use of oat bran to influence postprandial glucose and insulin response and satiety was discussed. However, the mechanisms underlying the positive effects of treatments with pro-, pre- or synbiotics are not yet fully understood and generally accepted therapeutic strategies are still lacking. The exact influence of a fibre-rich diet on intestinal microbiom and bile acid composition is not yet known. In the research project described, the effect of oat bran with prebiotic food supplements on NASH will be investigated and mechanisms of interaction between diet, microbiome, bile acids and liver will be uncovered. A better understanding of this interaction could form the basis for new preventive therapies of NASH.

Official Title
-----------------
Dietary Modulation of Intestinal Microbiota as Trigger of Liver Health: Role of Bile Acids - A Diet for Liver Health (ADLH)

Conditions
-----------------
NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
-----------------
* Dietary Supplement: oatmeal flakes with prebiotic food supplements
* Dietary Supplement: millet flakes


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Fatty liver disease diagnosed by sonography (steatosis hepatis grade II and III) and CAP measurement (> 280dB) compliance Exclusion Criteria: Allergy to oats Alcohol intake of more than 30 g/d (men) or 20 g/d (women) Treatment with ursodeoxycholic acid (UDCA), vitamin E or other NASH drugs 3 months prior to randomization Hepatocellular carcinoma or non-hepatic malignancy within the last 5 years Evidence of cirrhosis of the liver (Child A, B, C) or a history of decompensation Liver diseases not related to NASH, including chronic viral hepatitis B/D or C, autoimmune hepatitis, Wilson's disease or clinically manifest iron overload (heterozygous HFE is permitted), cholestatic liver disease (PBC/PSC) Adiposity surgery in the last 5 years BMI <18.5 kg / m2 Liver transplantation Fibroscan> 12 kPa (patients with liver cirrhosis) Lack of CAP and ultrasound evaluation Age > 75 years HIV infection Heart Failure (New York Heart Association Class III - IV) Myocardial infarction, unstable coronary artery disease, coronary artery intervention or stroke in the last 6 months Unstable COPD, chronic inflammatory bowel disease or rheumatoid arthritis Unstable renal failure (changes in serum creatinine > 50% in the last 3 months) or terminal renal failure requiring dialysis Uncontrolled hypertension (SBP / DBP> 180/90 despite therapy) Uncontrolled metabolic conditions (poorly controlled or decompensated diabetes mellitus, HbA1c >7.5%) Food allergies or intolerances that require strict adherence to a diet, such as lactose intolerance or celiac disease. Pregnancy or breastfeeding women (anamnesis) Treatment with drugs or substances that can induce secondary NASH (e.g., tamoxifen, corticosteroids, amiodarone, methotrexate) or alleviate NASH (TNF antagonists) (e.g. metformin) Use of herbal food supplements Any participant who has taken antibiotics 6 weeks prior to the study

Ages Eligible for Study
-----------------
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1<br>Patients consuming placebo (millet flakes) each day | Dietary Supplement: millet flakes<br>* The study participants should consume the prescribed amount of the study product every day. The intake should be divided into 1-2 meals. It is not necessary to limit or change normal eating habits.<br>|
| Experimental: Group 2<br>Patients consuming oatmeal flakes with a low dosage of prebiotic food supplements | Dietary Supplement: oatmeal flakes with prebiotic food supplements<br>* The study participants should consume the prescribed amount of the study product every day. The intake should be divided into 1-2 meals. It is not necessary to limit or change normal eating habits.<br>|
| Experimental: Group 3<br>Patients consuming oatmeal flakes with a high dosage of prebiotic food supplements | Dietary Supplement: oatmeal flakes with prebiotic food supplements<br>* The study participants should consume the prescribed amount of the study product every day. The intake should be divided into 1-2 meals. It is not necessary to limit or change normal eating habits.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the influence of a dietary supplement in oat bran on the course of disease in the early stages of NASH by CAP (Controlled Attenuation Parameter) measurement to determine liver steatosis. | CAP measurement (dB/m) | 20 weeks | 
| Evaluation of the influence of a dietary supplement in oat bran on the course of disease in the early stages of NASH by determination ALT-concentration in blood samples. | Determination of ALT concentration (U/l) in blood samples | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Influence of dietary supplement in oat bran on concentration of AST | Determination of AST concentration (U/l) in blood samples | 20 weeks | 
| Influence of dietary supplement in oat bran on the concentration of gamma-GT | Determination of gamma-GT concentration (U/l) in blood samples | 20 weeks | 
| Influence of dietary supplement in oat bran on liver steatosis | Sonography - Performing an abdominal ultrasound examination to detect liver steatosis | 20 weeks | 
| Influence of dietary supplement in oat bran on bile acid metabolism | Determination of bile acid composition in stool samples | 20 weeks | 
| Influence of dietary supplement in oat bran on the composition of the intestinal microbiome | Determination of microbiom in stool samples (bacterial DNA and RNA are isolated from the stool to determine the microbial composition) | 20 weeks | 
| Influence of dietary supplement in oat bran on intestinal permeability marker like citrullin | Determination of intestinal permeability marker like citrullin (µmol/l) | 20 weeks | 
| Influence of dietary supplement in oat bran on metabolic markers | Determination of concentration of diffenrent, previously not defined metabolic markers in blood samples by untargeted metabolomics analysis | 20 weeks | 
| Influence of dietary supplement in oat bran on inflammatory markers of NASH | Determination of concentration of previously not defined inflammatory markers of NASH in blood samples by multiplex assays | 20 weeks | 
| Influence of dietary supplement in oat bran on blood pressure | Measurement of blood pressure (mmHg) | 20 weeks | 
| Assessment of quality of life | Questionnaires to evaluate quality of life: EQ-5D-5L EQ-5D questionnaires with 5-point Likert scale: having no problems, having slight problems, having moderate problems, having severe problems & being unable to do/having extreme problems (the answers euquals 1-5 points, with 5 points beeing the worst outcome) | 20 weeks | 
| Assessment of the feeling of satiety/gastrointestinal symptoms | Questionnaire Structured Assessment of Gastrointestinal Symptoms (SAGIS): 5-point Likert scale from no problem, mild, moderate, severe and very severe problem (0-4 points; 4 points equals very severe problem | 20 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liver health, Diet, Microbiom