Fecal Microbiota Transplantation and ACHIM for Manipulating Gut Microbiota in IBS Patients
Condition: Irritable Bowel Syndrome; Dysbiosis
MeSH terms: Irritable Bowel Syndrome; Syndrome; Dysbiosis
Study type: Interventional

Summary: 
      The double-blinded placebo-controlled study compares the effect of fecal microbiota
      transplantation vs. Anaerobically Cultivated Human Intestinal Microbiota (ACHIM) or placebo
      (own feces) on manipulating the gut microbiota in patients with diarrhea-predominant
      irritable bowel syndrome (IBS).
    

Detailed description: 
      Fecal transplantation (FMT), the infusion of a fecal preparation from a healthy donor into
      the gastrointestinal tract of another human being is capable of altering the gut microbiome
      of the new host. There is speculation that human faeces from a healthy donor may constitute
      the ideal "probiotic", thus suggesting FMT as a treatment option for conditions where an
      altered microbiota has been detected, including irritable bowel syndrome (IBS) .
      Anaerobically Cultivated Human Intestinal Microbiota (ACHIM) is an alternative way to
      manipulate gut microbiota instead of FMT. ACHIM suspension is a natural ecosystem of normal
      intestinal bacteria cultivated and propagated regularly in the laboratory (in vitro). After
      20 years of cultivation ACHIM has retained the same rich biodiversity as the original stool
      sample, originating from a healthy donor in 1995. ACHIM can restore the ecological balance of
      the gut when it has been disturbed (dysbiosis) e.g. after antibiotic treatment. ACHIM has
      until now been given to over 400 patients (most of them suffering from recurrent Clostridium
      difficile infection) without any serious side effects being observed. Microbiological tests
      have shown that ACHIM is a well-balanced functional microbiota, and contains the major
      bacterial phyla Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria .

      Thus, in the present study aims at comparing these methods safety and efficacy in relieving
      symptoms in patients with IBS. Given the ethical concerns of unknown and long-term adverse
      effects of FMT therapy, only patients with moderate to severe symptoms will be included.

      Aim:

      The primary aim of this open pilot study was to compare these two gut manipulating methods
      (FMT and ACHIM) in IBS patients.

      The secondary aims were as follows;

        1. To evaluate and to compare the safety and efficacy of FMT and ACHIM suspension in
           relieving symptoms in patients with IBS.

        2. To evaluate and to compare the FMT and ACHIM on quality of life.

        3. To compare the detailed characterisation of microbial community composition (by means of
           16S rRNA profiling) and determination of the kinetics of changes following FMT and ACHIM
           vs. placebo.

      Study design Participants and sample size In a blind study, patients who meet the Rome III
      criteria for IBS with moderate to severe abdominal symptoms will be included. The patients
      will be randomised in three groups for receiving either FMT, ACHIM suspension or placebo (own
      feces), and they will be followed for 12 weeks with regard to efficacy and safety parameters,
      as well as analysis of faecal samples.

      Donor screening:

      Donors of fecal flora are healthy individuals living in the same household as the patients.
      All donors are screened before donation for previous exposure to contagious infectious
      agents. Screening of blood included serologic testing for hepatitis A, hepatitis B, hepatitis
      C, HIV, Epstein-Barr virus and cytomegalovirus. All donor stool samples are cultured for
      enteric bacterial pathogens and screened for viruses and parasites.

      Study procedures Suspension of fresh feces from a close family member for FMT or ACHIM will
      be instilled into the duodenum via an endoscope. This route of administration has been safe
      in all studies.

        -  Faeces transplantation protocol: Fresh stool samples are obtained immediately before
           FMT. 60 ml of sterile 0.9% N-saline are added to a stool specimen with a weight of ~30 g
           and homogenized manually. Screened from the patients' view, 40 ml of faeces-suspension
           are instilled through the work channel of a gastroscope into the lower part of the
           duodenum, and thereafter flushed with 60 ml of sterile 0.9% N-saline.

        -  ACHIM transplantation protocol: The ACHIM suspension (ACHIM Biotherapeutics, Sweden) is
           given through the work channel of a gastroscope into the lower part of duodenum, and
           thereafter flushed with 60 ml of sterile 0.9% N-saline.

        -  Stool samples will be collected twice before study (week - 4 and -0-1), then after week
           1, 4 and 12 and after 6 months. Donor feces for FMT will also be collected. Fresh frozen
           dry stool is sampled at all time points, aliquoted and stored at -80 degrees (<24 hours
           from production to delivery).

        -  Microbial DNA analyses: Microbiota analysis was performed using the Genetic Analysis
           (GA) map™ DysbiosisTest (Genetic Analysis AS, Oslo, Norway). The GA-test is based on
           regular molecular biology techniques, comprising fecal sample homogenization and
           mechanical bacterial cell disruption; combined with chemical cell lysis; automated total
           bacterial genomic DNA extraction using magnetic beads; 16S ribosomal ribonucleic acid
           (rRNA) polymerase chain reaction (PCR) DNA amplification covering the variable regions
           V3-V9; probe labelling by single nucleotide extension; hybridisation to complementary
           probes coupled to magnetic beads; and signal detection using BioCode 1000A 128-Plex
           Analyzer (Applied BioCode, Santa Fe Springs, California, USA). A Dysbiosis Index (DI)
           above 2 (maximum 5) indicate a microbiota that differs from the reference group (DI 1-2:
           non-dysbiosis, DI 3: moderate, DI 4-5: severe dysbiosis).

        -  Blood samples (Complete blood count, kidney and liver function tests) and urine
           analysis.

        -  Symptom and quality of life assessment: Gastrointestinal symptoms, bowel habits and
           quality of life will be recorded during a 12 week follow up period, at day 0, weeks 1,
           4, 12 and 28 for symptom and quality of life assessment. The patients are asked to
           report the severity of global IBS symptoms and each of the symptoms (diarrhoea,
           bloating, flatulence and pain) during the preceding week, using a four-point scale (0 =
           none, 1 = mild, 2 = moderate, 3 = severe). IBS Symptom Severity Scale (IBS-SSS) contains
           5 questions that are rated on a 100-point visual analogue scale (VAS) (the severity of
           abdominal pain, the frequency of abdominal pain, the severity of abdominal distension,
           dissatisfaction with bowel habits, and interference with quality of life). The score
           ranging is from 0 to 500, with a higher score indicating the worse condition (scores <
           175 represent mild IBS symptoms, 175 - 300 represents moderate severity, > 300 represent
           severe IBS). A decrease of 50 points on the IBS-SSS has been shown to correlate with
           improvement in clinical symptoms.

      Short form of Nepean Dyspepsia Index (SF-NDI) will be used to evaluate quality of life.

      Statistical analyses:

      Longitudinal analysis of microbiota composition will be performed with repeated measures
      ANOVA (for alpha diversity and bacterial abundances). If non-normal data, arcsine square root
      transformation or a nonparametric test will be used. Original donor and recipient stool
      microbiota will be compared (measures of alpha diversity and abundances of taxa) at baseline
      and at each recipient stool sampling time point using nonparametric or parametric methods.

      Safety considerations:

      Long experience has been gained during the past years at Haukeland University Hospital in
      performing FMT for treatment-resistant Cl. difficile enterocolitis and have developed an
      extensive program for identifying safe donors of faeces for FMT. Over the years, no serious
      side effects have occurred. The subset of IBS patients who are eligible for the study are
      typically patients with a heavy symptom burden, with few treatment alternatives. Therefore,
      the balance of safety concerns versus possibility of symptom improvement is considered to be
      positive, and will stress the importance of collecting safety data on FMT and ACHIM before
      this treatment is becoming more widely used.
    

Intervention name(s): Anaerobically Cultivated Human Intestinal Microbiota (ACHIM); Donor fecal microbiota transplantation; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): One vial of ACHIM suspension (ACHIM Biotherapeutics AB, Vallingby, Sweden), containing 30 x 109 CFU of bacteria, was given through the work channel of a gastroscope into the lower part of duodenum.; Only 60 ml of sterile 0.9% normal saline were added to a stool specimen, collected from the respective donor, with a weight of ~30 g and homogenized manually. Then 60 ml of feces-suspension (screened from the patients view) were instilled through the work channel of a gastroscope into the lower part of the duodenum.; Only 60 ml of sterile 0.9% normal saline were added to the patient's own stool specimen with a weight of ~30 g and homogenized manually. Then 60 ml of feces-suspension (screened from the patients view) were instilled through the work channel of a gastroscope into the lower part of the duodenum.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Double-blinded placebo-controlled study
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: IBS; Fecal microbiota transplantation; ACHIM; Placebo; Gut microbiota