The Effect of Fecal Microbiota Transplantation in Ankylosing Spondylitis (AS) Patients.

Study Overview
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Brief Summary
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Ankylosing spondylitis (AS) patients often have subclinical gut wall inflammation. Gut dysbiosis has been associated with both AS and Crohn disease, both of which have several features in common. Gut dysbiosis is associated with specific microbial profile in AS patients. Fecal microbiota transplantation (FMT) has been proved to be safe and effective treatment for recurrent Clostridium difficile infection, and the change in gut microbiota is shown to be long lasting. It has led to interest to study its effect on different inflammatory conditions associated with gut dysbiosis. We hypothesize that dysbiosis in AS leads to inflammasome overactivation on gut mucosa. We aim to study the role of gut inflammation, gut microbiota and inflammasome activation in pathogenesis of AS, and the effect of FMT on these factors, as well as clinical activity, in AS patients.

Detailed Description
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This is a double-blind placebo- controlled randomized pilot study with 20 patients with active AS from 2 Finnish outpatient clinics. An ileocolonoscopy will be performed to all patients. 10 patients will receive FMT with feces of one of two healthy donors, and 10 patients with their own feces during ileocolonoscopy. Ileal and colonic biopsies will be taken to assess gut wall inflammation and mucosal microbiota composition. Ileocolonoscopy will be controlled in 6 months in patients with macroscopic inflammatory lesions in the first colonoscopy. From mucosal biopsies we will assess intestinal mucosal structure, inflammasome activity, cytokine expression, and the mucin layer thickness and the amount of bacterial LPS (lipopolysaccharide), which are associated with mucosal integrity. Blood levels of zonulin and LPS as indicators of mucosal permeability and bacterial penetrance will be assessed. Fecal samples will be collected repeatedly to measure fecal calprotectin, and to assess the bacterial profile changes. From mucosal biopsies and fecal samples microbial DNA will be segregated and bacterial species sorted by rRNA- based sequence technique. Clinical activity of AS will be assessed in follow-up visits as well as repeated BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), BASFI (Bath Ankylosing Spondylitis Functional Index) and MASES (Maastricht Ankylosing Spondylitis Enthesitis Score) evaluations, and measurement of CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate). Follow-up time is 12 months.

Official Title
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The Role of Gut Microbiota in the Pathogenesis of Ankylosing Spondylitis (AS), and the Effect of Fecal Microbiota Transplantation on Gut Microbiota, Gut Wall Inflammation and Clinical Activity of AS

Conditions
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Ankylosing Spondylitis

Intervention / Treatment
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* Other: Fecal microbiota transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AS by either the 1984 New York criteria or the ASAS (Assessment of SpondyloArthritis International Society) criteria for axial spondyloarthritis. Active disease measured by BASDAI > 4. Availability of consecutive fecal samples over 1 year period. Compliance to attend ileocolonoscopy and FMT procedure. Exclusion Criteria: Diagnosis of inflammatory bowel disease. Antibiotic therapy within the last 3 months. Use of any probiotics within the last 3 months. Pregnancy. Unability to provide a written consent. Other reason which by the opinion of the investigator makes patient ineligible for the study.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study group<br>Allogeneic fecal microbiota transplantation (from donor) | Other: Fecal microbiota transplantation<br>* Fecal microbiota transplantation<br>|
| Placebo Comparator: Control group<br>Autologous fecal microbiota transplantation (own stool) | Other: Fecal microbiota transplantation<br>* Fecal microbiota transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of FMT (fecal microbiota transplantation) on the clinical activity of ankylosing spondylitis (AS) as assessed by change in BASDAI (Bath Ankylosing Spondylitis Disease Activity Index). | BASDAI scale 0-10 (the higher the score the more severe the symptoms). Decrease in BASDAI indicates positive outcome. | 5 measurements within 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of FMT on the clinical activity of AS as assessed by change in BASFI (Bath Ankylosing Spondylitis Functional Index). | BASFI scale 0-10 (the higher the score the more severe the symptoms). Decrease in BASFI indicates positive outcome. | 5 measurements within 12 months. | 
| The effect of FMT on the clinical activity of AS as assessed by change in MASES (Maastricht Ankylosing Spondylitis Enthesitis Score). | MASES scale 0-13 (the higher the score the more severe the symptoms). Decrease in MASES indicates positive outcome. | 5 measurements within 12 months. | 
| The effect of FMT on C-reactive protein (CRP) concentration. | Change in inflammatory parameter CRP concentration indicates positive outcome. | 7 measurements within 12 months. | 
| The effect of FMT on erythrocyte sedimentation rate (ESR) level. | Change in inflammatory parameter ESR level indicates positive outcome. | 7 measurements within 12 months. | 
| The effect of FMT on gut wall inflammation as assessed by change in fecal calprotectin (F-calpro) level. | Change in fecal calprotectin level indicates positive outcome. | 7 measurements within 12 months. | 
| The effect of FMT on gut microbiota composition in AS patients. | Change in gut microbiota composition evaluated by stool microbial analysis indicates positive outcome. | 7 stool microbial analysis within 12 months. | 
| Association between specific intestinal pathogens and disease activity as assessed by BASDAI score. | BASDAI scale 0-10 (the higher the score the more severe the symptoms). Association between specific microbial profile and higher or lower disease activity assessed by BASDAI indicates a positive outcome. | 7 stool microbial samples and 5 BASDAI measurements within 12 months. | 
| Association between specific intestinal pathogens and disease activity as assessed by CRP concentration. | Association between specific intestinal pathogens and (higher or lower) CRP concentration compared to patients with different microbial profile indicates a positive outcome. | 7 stool microbial samples and 7 CRP measurements within 12 months. | 
| Association between gut wall cytokine expression and disease activity as assessed by BASDAI score. | BASDAI scale 0-10 (the higher the score the more severe the symptoms). Association between the level of cytokine expression and BASDAI score indicates a positive outcome. | Intestinal biopsies at baseline. | 
| Association between gut wall inflammasome activity and disease activity as assessed by BASDAI score. | BASDAI scale 0-10 (the higher the score the more severe the symptoms). Association between gut wall inflammation as assessed by inflammasome activity and disease activity as assessed by BASDAI score indicates a positive outcome. | Intestinal biopsies at baseline. | 
| Association between gut wall cytokine expression and disease activity as assessed by CRP concentration. | Association between gut wall inflammation as assessed by the level of cytokine expression and the disease activity as assessed by CRP concentration indicates a positive outcome. | Intestinal biopsies at baseline. | 
| Association between gut wall inflammasome activity and disease activity as assessed by CRP concentration. | Association between gut wall inflammation as assessed by inflammasome activity and disease activity as assessed by CRP concentration indicates a positive outcome. | Intestinal biopsies at baseline. | 
| Association between F-Calpro level and disease activity as assessed by BASDAI score. | Calprotectin- level < 100 ug/l is considered as normal. BASDAI scale 0-10 (the higher the score the more severe the symptoms). Association between gut wall inflammation as assessed by F-Calpro level and disease activity as assessed by BASDAI score indicates a positive outcome. | 7 F-Calpro- measurements and 5 BASDAI measurements within 12 months. | 
| Association between F-Calpro level and disease activity as assessed by CRP concentration. | Calprotectin- level < 100 ug/l is considered as normal. Association between gut wall inflammation as assessed by F-Calpro and disease activity as assessed by CRP concentration indicates a positive outcome. | 7 F-Calpro and CRP measurements within 12 months. | 
| The effect of FMT on gut wall permeability as assessed by blood zonulin concentration. | Change in zonulin concentration indicates a positive outcome. | 5 measurements within 12 months. | 
| The effect of FMT on gut wall bacterial penetrance as assessed by lipopolysaccharide (LPS) concentration. | Change in LPS concentration indicates a positive outcome. | 5 measurements within 12 months. | 
| The effect of FMT on gastrointestinal symptoms as assessed by GSRS (The Gastrointestinal Symptom Rating Scale). | GSRS score scale 15-105. The higher the score the more severe the symptoms. Decrease in GSRS indicates a positive outcome. | 5 GSRS evaluations within 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ankylosing spondylitis, fecal microbiota transplantation, intestinal mucosal immunity, dysbiosis, microbiome