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

Ankylosing Spondylitis Clinical Trial

— ASGUT  

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT03726645
• Other study ID #: HospitalDHU/Rheumatology
• Status: Enrolling by invitation
• Phase: Early Phase 1
• Start date: October 24, 2018
• Est. completion date: April 2020

Study information

• Verified date: May 2019
• Source: Hospital District of Helsinki and Uusimaa
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 20
• Est. completion date: April 2020
• Est. primary completion date: April 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Ankylosing Spondylitis
• Spondylitis
• Spondylitis, Ankylosing

Intervention

Other:
• Fecal microbiota transplantation
Fecal microbiota transplantation

Locations

Country	Name	City	State
Finland	Hospital District of Helsinki and Uusimaa, Department of Rheumatology	Helsinki	Uusimaa

Sponsors (1)

Lead Sponsor	Collaborator
Hospital District of Helsinki and Uusimaa

Country where clinical trial is conducted

Finland, 

References & Publications (20)

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Breban M, Tap J, Leboime A, Said-Nahal R, Langella P, Chiocchia G, Furet JP, Sokol H. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann Rheum Dis. 2017 Sep;76(9):1614-1622. doi: 10.1136/annrheumdis-2016-211064. Epub 2017 Jun 12. — View Citation

Ciccia F, Bombardieri M, Principato A, Giardina A, Tripodo C, Porcasi R, Peralta S, Franco V, Giardina E, Craxi A, Pitzalis C, Triolo G. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2009 Apr;60(4):955-65. doi: 10.1002/art.24389. — View Citation

Ciccia F, Ferrante A, Triolo G. Intestinal dysbiosis and innate immune responses in axial spondyloarthritis. Curr Opin Rheumatol. 2016 Jul;28(4):352-8. doi: 10.1097/BOR.0000000000000296. Review. — View Citation

Ciccia F, Guggino G, Rizzo A, Alessandro R, Luchetti MM, Milling S, Saieva L, Cypers H, Stampone T, Di Benedetto P, Gabrielli A, Fasano A, Elewaut D, Triolo G. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis. Ann Rheum Dis. 2017 Jun;76(6):1123-1132. doi: 10.1136/annrheumdis-2016-210000. Epub 2017 Jan 9. — View Citation

Costello ME, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, Marshall M, Kenna TJ, Triolo G, Brown MA. Brief Report: Intestinal Dysbiosis in Ankylosing Spondylitis. Arthritis Rheumatol. 2015 Mar;67(3):686-691. doi: 10.1002/art.38967. — View Citation

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Jalanka J, Mattila E, Jouhten H, Hartman J, de Vos WM, Arkkila P, Satokari R. Long-term effects on luminal and mucosal microbiota and commonly acquired taxa in faecal microbiota transplantation for recurrent Clostridium difficile infection. BMC Med. 2016 Oct 11;14(1):155. — View Citation

Knodler LA, Crowley SM, Sham HP, Yang H, Wrande M, Ma C, Ernst RK, Steele-Mortimer O, Celli J, Vallance BA. Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe. 2014 Aug 13;16(2):249-256. doi: 10.1016/j.chom.2014.07.002. — View Citation

Leirisalo-Repo M, Turunen U, Stenman S, Helenius P, Seppälä K. High frequency of silent inflammatory bowel disease in spondylarthropathy. Arthritis Rheum. 1994 Jan;37(1):23-31. — View Citation

Mattila E, Uusitalo-Seppälä R, Wuorela M, Lehtola L, Nurmi H, Ristikankare M, Moilanen V, Salminen K, Seppälä M, Mattila PS, Anttila VJ, Arkkila P. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology. 2012 Mar;142(3):490-6. doi: 10.1053/j.gastro.2011.11.037. Epub 2011 Dec 7. — View Citation

Nurmi K, Kareinen I, Virkanen J, Rajamäki K, Kouri VP, Vaali K, Levonen AL, Fyhrquist N, Matikainen S, Kovanen PT, Eklund KK. Hemin and Cobalt Protoporphyrin Inhibit NLRP3 Inflammasome Activation by Enhancing Autophagy: A Novel Mechanism of Inflammasome Regulation. J Innate Immun. 2017;9(1):65-82. doi: 10.1159/000448894. Epub 2016 Sep 22. — View Citation

Nurmi K, Virkanen J, Rajamäki K, Niemi K, Kovanen PT, Eklund KK. Ethanol inhibits activation of NLRP3 and AIM2 inflammasomes in human macrophages--a novel anti-inflammatory action of alcohol. PLoS One. 2013 Nov 11;8(11):e78537. doi: 10.1371/journal.pone.0078537. eCollection 2013. — View Citation

Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, Kovanen PT, Eklund KK. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010 Jul 23;5(7):e11765. doi: 10.1371/journal.pone.0011765. — View Citation

Rajamäki K, Nordström T, Nurmi K, Åkerman KE, Kovanen PT, Öörni K, Eklund KK. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem. 2013 May 10;288(19):13410-9. doi: 10.1074/jbc.M112.426254. Epub 2013 Mar 25. — View Citation

Tailford LE, Crost EH, Kavanaugh D, Juge N. Mucin glycan foraging in the human gut microbiome. Front Genet. 2015 Mar 19;6:81. doi: 10.3389/fgene.2015.00081. eCollection 2015. Review. — View Citation

Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994 Dec 1;180(6):2359-64. — View Citation

Tito RY, Cypers H, Joossens M, Varkas G, Van Praet L, Glorieus E, Van den Bosch F, De Vos M, Raes J, Elewaut D. Brief Report: Dialister as a Microbial Marker of Disease Activity in Spondyloarthritis. Arthritis Rheumatol. 2017 Jan;69(1):114-121. doi: 10.1002/art.39802. Epub 2016 Dec 1. — View Citation

Van Praet L, Van den Bosch FE, Jacques P, Carron P, Jans L, Colman R, Glorieus E, Peeters H, Mielants H, De Vos M, Cuvelier C, Elewaut D. Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model. Ann Rheum Dis. 2013 Mar;72(3):414-7. doi: 10.1136/annrheumdis-2012-202135. Epub 2012 Nov 8. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	The effect of FMT on C-reactive protein (CRP) concentration.	Change in inflammatory parameter CRP concentration indicates positive outcome.	7 measurements within 12 months.
Secondary	The effect of FMT on erythrocyte sedimentation rate (ESR) level.	Change in inflammatory parameter ESR level indicates positive outcome.	7 measurements within 12 months.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.