Impact of FMT on the Phenome in Patients With NAFLD and Fibrosis

Study Overview
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Brief Summary
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The goal of this pilot experimental medicine interventional study is to explore the degree of transferability of the gut microbiome and associated metabolomic changes in patients with non-alcoholic fatty liver disease (NAFLD) and fibrosis who receive faecal microbiota transplant (FMT). The main questions is aims to answer is: To what extent is the gut microbiome transferable from donor to recipient in patients with NAFLD with fibrosis who receive FMT? What are the dynamics of how the gut microbiome changes over time in these patients? To what degree does the recipient metabolome change in association with this? Participants will receive up to three capsulised FMT preparations prepared from a donor selected rationally based upon their metabolomic characteristics. They will be asked to attend for serial clinical assessments (including FibroScan and MRE/ MRI-PDFF), and will also be asked to provide serial blood, urine and stool samples for assessment of microbiome and metabolome profiling.

Official Title
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Investigating the Impact of Faecal Microbiota Transplant on the Clinical Phenome of Patients With Non-alcoholic Fatty Liver Disease and Fibrosis

Conditions
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Non-Alcoholic Fatty Liver Disease, Fecal Microbiota Transplantation

Intervention / Treatment
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* Other: Faecal microbiota transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-75 years of age. Previously-diagnosed NAFLD, with predicted fibrosis based upon non-invasive assessment with FibroScan (i.e. liver stiffness measurement (LSM) > 8kPa). Raised liver ALT (> 30IU/l for men, > 19IU/l for women) or AST (> 37IU/l for men, > 31IU/l for women) with negative non-invasive liver screen (including negative screen for viral hepatitis, autoimmune liver disease and metabolic liver disease, and normal echocardiogram within two years in the scenario where congestive hepatopathy may be considered). Able to consent for themselves in English. Exclusion Criteria: Severe or life-threatening food allergy. Pregnant or lactating women; or women trying to conceive. Patients with suspected or confirmed cirrhosis (as assessed by clinical, radiological or histological criteria). Use of particular medications, including: Systemic antibiotics within the six weeks prior to study enrolment. Immunosuppression that may influence risks related to FMT (including - but not limited to: use of corticosteroids within eight weeks of intervention; use of cytotoxic chemotherapy; use of azathioprine, tacrolimus, mycophenolate mofetil and/or immunosuppressive biologic therapy, e.g. infliximab). Use of GLP-1 agonists. Patients not expected to survive the duration of the study's follow-up (six months). Swallowing difficulties that may preclude safe use of FMT capsules, including oral-motor dyscoordination. Alcohol consumption > 20g/ day. Any active cancer (including treatment within the past six months). Active infection at the point of recruitment, including COVID-19 infection. Prior receipt of a liver transplant. BMI < 23 in Asian potential participants and BMI < 25 in Caucasians. Advanced chronic kidney disease (eGFR < 30 ml/min). Chronic intestinal disease, including coeliac disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, and chronic diarrhoea. Prior bariatric surgery. Patients unable to undergo MRI scans (e.g. due to the individual having metallic implants).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Human participants with NAFLD and fibrosis
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NAFLD patients<br>Patients receiving capsulised FMT | Other: Faecal microbiota transplant<br>* Capsulised faecal microbiota transplant prepared from rationally selected donor, based upon donor metabolomic charateristics<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in faecal microbiome composition | Using 16S rRNA gene sequencing and shotgun metagenomic sequencing | 24 weeks after initial FMT | 
| Change in gut microbial metabolite composition | Using 1H-NMR and mass spectrometry | 24 weeks after initial FMT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in liver fat on MRI | Using MRI-PDFF | 16 weeks after initial FMT | 
| Changes in liver fat on FibroScan | Using CAP | 16 weeks after initial FMT | 
| Changes in liver stiffness on MRI | Using MRE | 16 weeks after initial FMT | 
| Changes in liver stiffness on FibroScan | Using transient elastography | 16 weeks after initial FMT | 
| Changes in HbA1c |  | 24 weeks after initial FMT | 
| Changes in insulin resistance | Combining fasting glucose and insulin levels to generate HOMA-IR | 24 weeks after initial FMT | 
| Changes in BMI | Through combination of measurement of weight in kilogram and height in metres, reporting BMI in kg/m^2 | 24 weeks after initial FMT | 
| Changes in lipid metabolism | Serum lipid profile | 24 weeks after initial FMT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, Gut microbiome, Metabolomics