Clinical trial NCT04465032: The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD)
Official title: The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD) - a Randomized-controlled Trial -
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: NAFLD
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Dutch Donor Feces Bank
name: Vedanta Biosciences
First posted: 2020-07-09
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blinded randomized controlled trial, randomization 1:1 to allogenic and autologous gut microbiome transplantation
Primary purpose: TREATMENT

Brief summary: Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence, linked to metabolic, cardiovascular and malignant morbidity and without any officially approved treatment. It is increasingly recognized that the gut microbiome is implicated in the pathogenesis and progression of numerous chronic diseases, including NAFLD. Through the so-called gut-liver axis, the liver is exposed to gut-bacterial-derived products, including toxins (lipopolysaccharides), enzymes (methylamines), alcohol, and short-chain fatty acids (mainly acetate, propionate, and butyrate), that may lead to accumulation of triglycerides, inflammatory responses, oxidative stress and accompanying damage to the hepatocytes. The primary objective is to study the effect of consecutive FMT on liver fat accumulation measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12 weeks. Secondary objectives are weight, waist, blood pressure, metabolic parameters (including glucose, cholesterol, pancreatic beta-cell function, HOMA-IR), objective and subjective stress indicators, gut-microbiota and bile composition and liver enzymes. Stool samples will be collected for microbiota analysis at time point 0, 3, 6 and 12 weeks.

Detailed description: Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence, linked to metabolic, cardiovascular and malignant morbidity and without any officially approved treatment. It is increasingly recognized that the gut microbiome is implicated in the pathogenesis and progression of numerous chronic diseases, including NAFLD. Through the so-called gut-liver axis, the liver is exposed to gut-bacterial-derived products, including toxins (lipopolysaccharides), enzymes (methylamines), alcohol, and short-chain fatty acids (mainly acetate, propionate, and butyrate), that may lead to accumulation of triglycerides, inflammatory responses, oxidative stress and accompanying damage to the hepatocytes. The investigators hypothesize that altered gut microbiota underlie (hepatic) insulin resistance and liver fat accumulation in NAFLD patients. Fecal microbiota transplantation, through amelioration of gut-microbiota released products like lipopolysaccharides, short-chain fatty acids, alcohol and enzymes, and changes in bile acids, may positively affect NAFLD.

During the study 20 patients will be randomized for infusion of allogenic (lean donor) or autologous (own) feces by gastroscopy at time points 0, 3 and 6 weeks on a 1:1 basis. Prior to randomization, and at 12 weeks, all patients will undergo LiverMultiscan to non-invasively quantify liver fat accumulation and other features of NAFLD. In addition, various metabolic parameters (lipids, HOMA-IR), objective and subjective stress indicators, gut-microbiota and bile composition, and liver enzymes will be measured.

The primary objective is to study the effect on consecutive FMT on liver fat accumulation measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12 weeks. Secondary objectives are alterations in anthropometrical data (weight, waist, blood pressure), changes in fecal microbiota, liver enzymes, bile composition and metabolic parameters including glucose, lipids, pancreatic beta-cell function and insulin resistance measured as HOMA-IR and objective and subjective stress indicators.

Eligibility criteria: Inclusion Criteria:

* Obese (BMI \> 27 kg/m2)
* Males and postmenopausal females
* Aged 18 to 70 years
* Hepatic steatosis defined as increased hyperechogenicity of the liver on abdominal ultrasound and/or histological signs of steatosis
* Written informed consent

Exclusion Criteria:

* Exclusion criteria for MRI (claustrophobia, pacemaker, metal implants, etc)
* Any other liver disease than NAFLD/NASH
* Present excessive alcohol use defined as \> 2 units/day
* Recent use (\< 3 months) of antibiotics
* use of possible drugs interfering microbiota or recent (\< 3 months) changes in dosages
* use of GLP-1 RA or SU-derivatives
* Recent (\< 3 months) weight change (\>5%)
* Cardiovascular co-morbidity defined as heart failure, coronary insufficiency and hypertension in past history
* Previous use of glucocorticosteroids, hormonal substitution, pagitaxel, theofyllin, amiodarone, myelosuppresive agents.
* A psychiatric, addictive or any other disorder that compromises the subjects ability to understand the study content and to give written informed consent for participation in the study

Primary outcomes:
measure: the effect on consecutive FMT on liver fat accumulation
timeFrame: 12 weeks
Secondary outcomes:
measure: alterations in anthropometric data
timeFrame: 3, 6 and 12 weeks
measure: alterations in anthropometric data
timeFrame: 3, 6 and 12 weeks
measure: alterations in anthropometric data
timeFrame: 3, 6 and 12 weeks
measure: alterations in pancreatic beta-cell function and insulin resistance
timeFrame: 3, 6 and 12 weeks
measure: alterations in pancreatic beta-cell function and insulin resistance
timeFrame: 3, 6 and 12 weeks
measure: alterations in pancreatic beta-cell function and insulin resistance
timeFrame: 3, 6 and 12 weeks
measure: alterations in liver enzymes
timeFrame: 3, 6 and 12 weeks
measure: change in bile composition
timeFrame: 3 and 6 weeks
measure: change in bacterial species in small intestine and feces
timeFrame: 3 and 6 weeks
measure: changes in lipid homeostasis
timeFrame: 3, 6 and 12 weeks
measure: alterations in psychological stress
timeFrame: 0 and 12 weeks
measure: alterations in psychological stress
timeFrame: week 1, week 4, week 7, week 9 during 7 days
measure: alterations in psychological stress
timeFrame: 0 and 12 weeks
measure: changes in physical activity
timeFrame: during 14 weeks
measure: changes in physical activity
timeFrame: during 14 weeks
measure: changes in physical activity
timeFrame: during 14 weeks
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
Study officials:
References: