Fecal Microbiota Transplantation in Irritable Bowel Syndrome With Bloating

Fecal Microbiota Transplantation in Irritable Bowel Syndrome With Bloating: a Double Blind, Placebo Controlled Randomised Clinical Trial

Intestinal microbiota dysbiosis is thought to play an important role in the complex pathophysiology of irritable bowel syndrome (IBS), especially in diarrhoea-predominant IBS and possibly in IBS with severe bloating. Fecal microbiota transplantation or FMT has been shown to be an effective means of correcting this imbalance in the gut microbiota, especially in patients with recurrent Clostridium difficile infections where it has become a preferred treatment strategy.

In a preliminary pilot study in 12 patients we found that FMT was a safe and accepted therapy in IBS patients. In 75% of patients an amelioration of IBS symptoms in general and abdominal bloating was seen three months after transplantation.

In this study the effects of FMT on patients with IBS without constipation and bloating will be investigated in a double blind, placebo controlled RCT.

Study Overview

• Status: Completed
• Conditions: Irritable Bowel Syndrome
• Intervention / Treatment: Procedure: FMT with own stool; Procedure: FMT with donor stool

Detailed Description

Intestinal microbiota dysbiosis is thought to play an important role in the complex pathophysiology of irritable bowel syndrome (IBS), especially in diarrhoea-predominant IBS and possibly in IBS with severe bloating. Fecal microbiota transplantation or FMT has been shown to be an effective means of correcting this imbalance in the gut microbiota, especially in patients with recurrent Clostridium difficile infections where it has become a preferred treatment strategy.

In a preliminary pilot study in 12 patients we found that FMT was a safe and accepted therapy in IBS patients. In 75% of patients an amelioration of IBS symptoms in general and abdominal bloating was seen three months after transplantation.

In this study the effects of FMT on patients with IBS without constipation and bloating will be investigated in a double blind, placebo controlled RCT. Donors for this study will be recruited from a healthy donor pool who will donate stool after clearance of a strict inclusion protocol which will assess the presence of any infectious diseases. Stool will be frozen following the protocol described in Hamilton et al 2012. Patients will deliver a stool portion that will be frozen as well.

At time of FMT, patients will be randomised in a double blinded fashion to the treatment arm (healthy donor stool) or placebo arm (own stool). Transplantation will be preformed by means of a colonoscopy with deliverance in the right colon and ileum.

Following FMT patients will be followed clinically with questionnaires and regular visits to the clinic. Stool samples will be collected on a regular basis for microbiome analysis.

At the end of the study, patients from the placebo-group will be given the opportunity to be transplanted with healthy donor stool if necessary. Follow-up will continu for a total duration of one year.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Ghent University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

1. Inclusion Criteria for patients:

   • signed informed consent
   • Irritable bowel syndrome with predominant diarrhoea as defined by the ROME III criteria and with symptoms of abdominal bloating
   • IBS symptom score > 3 on at least 2 subscores (abdominal discomfort, abdominal bloating, abdominal pain, urgency, stool frequency, stool consistency)

2. Exclusion Criteria for patients:

   • predominant constipation as defined by Rome III criteria
   • pregnancy or inadequate anti conception for the duration of the trial
   • celiac disease
   • any contra-indications for colonoscopy
   • structural abnormalities of the colon (e.g. ileocecal resection, gastric bypass)
   • severe gastro-intestinal comorbidities (e.g. IBD, coloncarcinoma)
   • non gastro-intestinal malignancy
   • severe psychiatric comorbidity which had important effects on the quality of life
   • antimicrobial treatment 4 weeks prior to screening visit
   • treatment with probiotics 2 weeks prior to screening visit
   • recent diagnosis of lactose intolerance (< 3 months before screening visit)
   • any severe comorbidity that might interfere with the study course as determined by the treating physician

3. Inclusion criteria for donors

   • age 18 - 75 years
   • signed informed consent
   • normal screening protocol which includes screening for infectious diseases (eg. blood HIV, Syphilis, Hepatitis B or C; stool: enteropathogens, clostridium, ESBL, CPE)

4. Exclusion criteria for donors

   • presence of gastrointestinal symptoms
   • gastro-intestinal or other important comorbidity
   • obesity or metabolic syndrome
   • history of malignancy both gastrointestinal or systemic
   • presence of known colon polyps
   • recent placing of piercings/tattoos
   • sexual risk behaviour
   • antimicrobial therapy 3 months prior to donation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo group (FMT with own stool); Fecal microbiota transplantation with patient's own stool	Procedure: FMT with own stool; fecal microbiota transplantation by means of colonoscopy with deliverance of the transplant in the right colon and terminal ileum. Transplants will be collected prior to the start of the study from the patients and will be frozen at -80 degrees celsius after thorough screening for infectious diseases. At the time of transplantation samples will be frozen and administrated to the patients in the control group; Other Names: Fecal microbiota transplantation with own stool
EXPERIMENTAL: Treatment group (FMT with donor stool); Fecal microbiota transplantation with healthy donor stool	Procedure: FMT with donor stool; fecal microbiota transplantation by means of colonoscopy with deliverance of the transplant in the right colon and terminal ileum. Transplants will be collected prior to the start of the study from a healthy pool of donors and will be frozen at -80 degrees celsius after thorough screening for infectious diseases. At the time of transplantation samples will be frozen and administrated to the patients in the treatment group; Other Names: Fecal microbiota transplantation with healthy donor stool

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of overall IBS symptoms (Key question 1)	On a weekly basis patients will assess their overall IBS symptoms by answering a key question (Are your overall symptoms improved as compared to before the treatment?)	3 months after FMT
Reduction of abdominal bloating (Key question 2)	On a weekly basis patients will assess their sensation of abdominal bloating by answering a key question (Is your overall sensation of bloating improved by FMT as compared to before treatment?)	3 months after FMT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in fecal microbiome composition (Illumina sequencing)	Before and after FMT stool samples will be collected on a regular basis to assess the changes in microbiome changes (Illumina sequencing).	3 months after FMT
Changes in IBS symptom scores at three months after FMT	IBS symptoms will be assessed by use of a daily symptom diary which will measure abdominal discomfort, pain, bloating, flatulence, stool frequency, stool consistency and urgency	3 months after FMT
Changes in IBS symptom scores at six months post FMT	Key questions and symptom diary scores will be repeated 6 months after FMT to assess the duration of effects	6 months
Changes in IBS symtom scores at 9 months post FMT	Key questions and symptom diary scores will be repeated 9 months after FMT to assess the duration of effects	9 months
Changes in IBS symptom scores at 1 year post FMT	Key questions and symptom diary scores will be repeated 1 year after FMT to assess the duration of effects	1 year
Composition of mucosal-adherent microbiota (Illumina sequencing)	Composition of mucosal-adherent microbiota will be assessed by Illumina sequencing. Biopsies will be taken at time of FMT and snap frozen for further analysis.	3 months
Changes of IBS symptom scores in patients who undergo an off-trial FMT	After unblinding patients who were included in the placebo group, will be offered the possibility of FMT. Effects in these patients will be followed by IBS symptoms scores and answers to key questions at 3 months post FMT	3 months

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Investigators: Principal Investigator: Danny De Looze, MD, PhD, University Hospital, Ghent

Publications and helpful links

General Publications

• Dupont HL. Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets. Aliment Pharmacol Ther. 2014 May;39(10):1033-42. doi: 10.1111/apt.12728. Epub 2014 Mar 25.
• Kassinen A, Krogius-Kurikka L, Makivuokko H, Rinttila T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007 Jul;133(1):24-33. doi: 10.1053/j.gastro.2007.04.005. Epub 2007 Apr 14.
• van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037. Epub 2013 Jan 16.
• Borody TJ, Paramsothy S, Agrawal G. Fecal microbiota transplantation: indications, methods, evidence, and future directions. Curr Gastroenterol Rep. 2013 Aug;15(8):337. doi: 10.1007/s11894-013-0337-1.
• Holvoet T, Joossens M, Vazquez-Castellanos JF, Christiaens E, Heyerick L, Boelens J, Verhasselt B, van Vlierberghe H, De Vos M, Raes J, De Looze D. Fecal Microbiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial. Gastroenterology. 2021 Jan;160(1):145-157.e8. doi: 10.1053/j.gastro.2020.07.013. Epub 2020 Jul 15.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2014
• Primary Completion (ACTUAL): December 1, 2017
• Study Completion (ACTUAL): December 1, 2017

Study Registration Dates

• First Submitted: November 11, 2014
• First Submitted That Met QC Criteria: November 20, 2014
• First Posted (ESTIMATE): November 24, 2014

Study Record Updates

• Last Update Posted (ACTUAL): December 8, 2017
• Last Update Submitted That Met QC Criteria: December 7, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: fecal microbiota transplantation; bloating; irritable bowel syndrome
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Intestinal Diseases; Syndrome; Irritable Bowel Syndrome
• Other Study ID Numbers: UGent_Gastro_001