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

NCT ID: NCT04465032

Last Updated: 2020-07-09

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-12-10
• Study Completion Date: 2021-12-31

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.

Conditions

NAFLD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Autologous gut microbiome transplantation

Three autologous (own) fecal transplantations (at baseline, 3 and 6 weeks)

Group Type: ACTIVE_COMPARATOR

Gut microbiome transplantation

Intervention Type: OTHER

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.

Allogenic gut microbiome transplantation

Three allogenic (lean donor) fecal transplantations (at baseline, 3 and 6 weeks)

Group Type: EXPERIMENTAL

Gut microbiome transplantation

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: OTHER

Other Intervention Names

Fecal transplantation

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

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dutch Donor Feces Bank

UNKNOWN

Sponsor Role: collaborator

Vedanta Biosciences

UNKNOWN

Sponsor Role: collaborator

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

metushuizen

Principle investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Leiden University Medical Center

Leiden, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Maarten Tushuizen, MD PhD

Role: CONTACT

m.e.tushuizen@lumc.nl

+31 71 5263541

Facility Contacts

Maarten Tushuizen, MD, PhD

Role: primary

m.e.tushuizen@lumc.nl

Merel Ruissen, MD

Role: backup

m.m.ruissen@lumc.nl

References

Groenewegen B, Ruissen MM, Crossette E, Menon R, Prince AL, Norman JM, Ballieux BEPB, Lamb HJ, Terveer EM, Keller JJ, Tushuizen ME. Consecutive fecal microbiota transplantation for metabolic dysfunction-associated steatotic liver disease: a randomized controlled trial. Gut Microbes. 2025 Dec;17(1):2541035. doi: 10.1080/19490976.2025.2541035. Epub 2025 Aug 4.

Reference Type: DERIVED

PMID: 40755230 (View on PubMed)

Other Identifiers

GE17-05

Identifier Type: -

Identifier Source: org_study_id