The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD) (NAFTx)

The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD) - a Randomized-controlled Trial -

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.

Study Overview

• Status: Unknown
• Conditions: NAFLD
• Intervention / Treatment: Other: Gut microbiome transplantation

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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Maarten Tushuizen, MD PhD; Phone Number: +31 71 5263541; Email: m.e.tushuizen@lumc.nl

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Recruiting
    • Leiden University Medical Center
    • Contact: Maarten Tushuizen, MD, PhD; Email: m.e.tushuizen@lumc.nl
    • Contact: Merel Ruissen, MD; Email: m.m.ruissen@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Autologous gut microbiome transplantation; Three autologous (own) fecal transplantations (at baseline, 3 and 6 weeks)	Other: Gut microbiome transplantation; Fecal transplantation will be performed at baseline and at week 3 and 6. At the Department of Clinical Bacteriology either the autologous or allogenic feces is prepared for donation by an experienced lab co-worker. The fecal transplantation will be performed via gastroduodenal endoscopy at the Department of Gastroenterology by an experienced endoscopist. To alleviate the procedure, midazolam is offered to the participants. Following placement of the endoscope in the horizontal duodenum, 150 mL feces solution is inserted via the endoscope.; Other Names: Fecal transplantation
Experimental: Allogenic gut microbiome transplantation; Three allogenic (lean donor) fecal transplantations (at baseline, 3 and 6 weeks)	Other: Gut microbiome transplantation; Fecal transplantation will be performed at baseline and at week 3 and 6. At the Department of Clinical Bacteriology either the autologous or allogenic feces is prepared for donation by an experienced lab co-worker. The fecal transplantation will be performed via gastroduodenal endoscopy at the Department of Gastroenterology by an experienced endoscopist. To alleviate the procedure, midazolam is offered to the participants. Following placement of the endoscope in the horizontal duodenum, 150 mL feces solution is inserted via the endoscope.; Other Names: Fecal transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the effect on consecutive FMT on liver fat accumulation	measured by MRI Livermultiscan	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
alterations in anthropometric data	differences in weight in kilograms	3, 6 and 12 weeks
alterations in anthropometric data	differences in systolic and diastolic blood pressure in mmHg	3, 6 and 12 weeks
alterations in anthropometric data	differences in waist in centimeters	3, 6 and 12 weeks
alterations in pancreatic beta-cell function and insulin resistance	measured by plasma C-peptide in nmol/L derived during OGTT + arginin	3, 6 and 12 weeks
alterations in pancreatic beta-cell function and insulin resistance	measured by glucose in mmol/L derived during OGTT + arginin	3, 6 and 12 weeks
alterations in pancreatic beta-cell function and insulin resistance	measured by insulin in mU/L derived during OGTT + arginin	3, 6 and 12 weeks
alterations in liver enzymes	Aspartaat aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma glutamyl transpeptidase (GGT), alkalic phosphatase (AF), bilirubin	3, 6 and 12 weeks
change in bile composition	measured using endoscopic bile samples (qualitative measurements)	3 and 6 weeks
change in bacterial species in small intestine and feces	measured by endoscopic duodenal biopsies and fecal samples	3 and 6 weeks
changes in lipid homeostasis	cholesterol, HDL, LDL, triglycerides	3, 6 and 12 weeks
alterations in psychological stress	by measuring cortisol levels in hair samples	0 and 12 weeks
alterations in psychological stress	by reporting psychological stress daily using stress diaries on a scale from 1-10 (non-validated scale)	week 1, week 4, week 7, week 9 during 7 days
alterations in psychological stress	by Perceived Stres Scale (PSS) questionnaires, scores on a scale from 0-40	0 and 12 weeks
changes in physical activity	measuring physical activity by steps with FitBit activity tracker	during 14 weeks
changes in physical activity	measuring physical activity by active minutes with FitBit activity tracker	during 14 weeks
changes in physical activity	measuring physical activity by heart rate with FitBit activity tracker	during 14 weeks

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Dutch Donor Feces Bank; Vedanta Biosciences

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2019
• Primary Completion (Anticipated): March 31, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: January 8, 2020
• First Submitted That Met QC Criteria: July 7, 2020
• First Posted (Actual): July 9, 2020

Study Record Updates

• Last Update Posted (Actual): July 9, 2020
• Last Update Submitted That Met QC Criteria: July 7, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: GE17-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No