Faecal microbiota transplantation (FMT) in Norwegian outpatients with mild to severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): protocol for a 12-month randomised double-blind placebo-controlled trial.

INTRODUCTION: The observed alteration of the intestinal microbiota in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the effect of transferring a healthy gut flora from a faecal donor using a faecal microbiota transplantation (FMT) will be explored in this trial. METHODS AND ANALYSIS: This is a protocol for a randomised, double-blind, placebo-controlled, parallel-group, single-centre trial, with 12 months follow-up. 80 participants will be included and randomised (1:1:2) to either donor FMT (from two different donors) or placebo (autologous FMT). Participants will be included by the International Clinical Criteria for ME/CFS. The clinical measures of ME/CFS and disease activity include Modified DePaul Questionnaire, Fatigue Severity Scale (FSS), Hospital Anxiety and Depression Scale (HADS), 36-Item Short Form Health Survey (SF-36), ROMA IV criteria, Food Frequency Questionnaire, Repeatable Battery for the Assessment of Neuropsychological Status, heart rate variability testing and reports on the use of antibiotics and food supplements, as well as biobanking of blood, urine and faeces.The primary endpoint is proportion with treatment success in FSS score in donor versus autologous FMT group 3 months after treatment. Treatment success is defined as an FSS improvement of more than 1.2 points from baseline at 3 months after treatment. Adverse events will be registered throughout the study. ETHICS AND DISSEMINATION: The Regional Committee for Medical Research Ethics Northern Norway has approved the study. The study has commenced in May 2019. Findings will be disseminated in international peer-reviewed journal(s), submitted to relevant conferences, and trial participants will be informed via phone calls. TRIAL REGISTRATION NUMBER: NCT03691987.

Randomised, placebo-controlled, double-blinded trial of fecal microbiota transplantation in severe obesity: a study protocol.

INTRODUCTION: Obesity is one of the main threats to public health in western countries and increases the risk of several diseases, overall morbidity and mortality. Sustained weight loss will reduce risk factors and improve several obesity comorbidities. Options are conservative treatment such as lifestyle changes, bariatric surgery or medications. Conservative treatment has a low success rate, and bariatric surgery is typically not reversible, with the risk of complications and recurrences. Treatment of obesity with medications has in recent years shown great promise, but the side effects are many, and the long-term effect is unknown. There is also a need for an option for patients where surgery has contraindications and conservative follow-up does not succeed.The research on obesity and gut microbiota has yielded promising results regarding weight reduction and metabolic health, but more research is needed to better understand the relationship between gut microbiota and severe obesity. This study could show proof of concept that gut microbiota from a lean donor could, in addition to lifestyle intervention, contribute to weight reduction in people suffering from severe obesity. METHOD AND ANALYSIS: This study aims to investigate if a fecal microbiota transplantation (FMT) from a lean donor leads to weight reduction in participants suffering from severe obesity. The study is a single-centre, double-blinded, placebo-controlled, parallel-group study with 60 participants. Participants will be randomised 1:1 for FMT from a lean donor or placebo. FMT or placebo will be delivered once by enema.We will include participants from the outpatient clinic for severe obesity, at the Medical Department, University Hospital of North Norway, Harstad, by invitation only. The study has a follow-up period of 12 months, with study visits of 3, 6 and 12 months post FMT. The primary endpoint is a weight reduction of ≥10%, 12 months after intervention.The results of the study will be published in open access journals. At the end of the study, the participants will receive information on which treatment group they belong to. ETHICS AND DISSEMINATION: The Regional Ethical Committee in North Norway (REK) approved the study protocol (2017/1655/REK Nord). We plan to present the results from the study at (inter)national conferences and publish in open-access general peer-reviewed journals. The enema method for FMT administration used in this study was developed by our study team. TRIAL REGISTRATION NUMBER: NCT03273855.

Colonic distribution of FMT by different enema procedures compared to colonoscopy - proof of concept study using contrast fluid.

BACKGROUND: Fecal microbiota transplantation (FMT) has become an important treatment method in recurrent Clostridioides difficile infections and is under investigation as a treatment for several other diseases. FMT's mechanism of action is assumed to be through alterations of the colon microbiota. FMT can be delivered by several methods, but few studies have directly compared how FMT is distributed in the colon by different methods. Specifically, the proximal distribution of FMT delivered by enema is unknown. METHODS: In eight participants, we administered contrast fluid (CF) with viscosity similar to an FMT in a crossover study design. First, CF was administered by colonoscopy, followed by an abdominal X-ray to visualize the CF distribution. Next, after four to eight weeks, participants were given CF, but as an enema, followed by a positioning procedure. X-rays were obtained before (enema ÷) and after (enema +) the positioning procedure. CONCLUSION: Proportion of participants with CF in cecum were 100% after colonoscopy, 50% after enema + and 38% after enema ÷. In the transverse colon, proportions were 100% (colonoscopy), 88% (enema +) and 63% (enema ÷). There were no adverse events. INTERPRETATION: This study shows proof of concept for the distribution of FMT to proximal colon when delivered by enema. A positioning procedure after the enema slightly improves the proximal distribution. However, colonoscopy is the only method that ensures delivery to the cecum. Studies are needed to see if FMT colon distribution correlates with treatment effectiveness. TRIAL REGISTRATION: The study was retrospectively registered at ClinicalTrials.gov (NCT05121285) (16/11/2021).

The use of Faecal Microbiota Transplantation (FMT) in Europe: A Europe-wide survey.

BACKGROUND: Faecal microbiota transplantation (FMT) is an emerging treatment modality, but its current clinical use and organisation are unknown. We aimed to describe the clinical use, conduct, and potential for FMT in Europe. METHODS: We invited all hospital-based FMT centres within the European Council member states to answer a web-based questionnaire covering their clinical activities, organisation, and regulation of FMT in 2019. Responders were identified from trials registered at clinicaltrials.gov and from the United European Gastroenterology (UEG) working group for stool banking and FMT. FINDINGS: In 2019, 31 FMT centres from 17 countries reported a total of 1,874 (median 25, quartile 10-64) FMT procedures; 1,077 (57%) with Clostridioides difficile infection (CDI) as indication, 791 (42%) with experimental indications, and 6 (0•3%) unaccounted for. Adjusted to population size, 0•257 per 100,000 population received FMT for CDI and 0•189 per 100,000 population for experimental indications. With estimated 12,400 (6,100-28,500) annual cases of multiple, recurrent CDI and indication for FMT in Europe, the current European FMT activity covers approximately 10% of the patients with indication. The participating centres demonstrated high safety standards and adherence to international consensus guidelines. Formal or informal regulation from health authorities was present at 21 (68%) centres. INTERPRETATION: FMT is a widespread routine treatment for multiple, recurrent CDI and an experimental treatment. Embedded within hospital settings, FMT centres operate with high standards across Europe to provide safe FMT. A significant gap in FMT coverage suggests the need to raise clinical awareness and increase the FMT activity in Europe by at least 10-fold to meet the true, indicated need. FUNDING: NordForsk under the Nordic Council and Innovation Fund Denmark (j.no. 8056-00006B).

Effects of fecal microbiota transplantation in subjects with irritable bowel syndrome are mirrored by changes in gut microbiome.

Irritable bowel syndrome (IBS) is a common disorder of the lower gastrointestinal tract. The pathophysiology is far from settled, but a gut microbial dysbiosis is hypothesized to be a contributing factor. We earlier published a randomized double-blind placebo-controlled clinical trial on fecal microbiota transplantation (FMT) for IBS - the REFIT trial. The present data set describes the engraftment and includes participants from the study who received active FMT; 14 participants with effect of FMT (Effect) and 8 without (No effect). Samples were collected at baseline, after 6 and 12 months. Samples from the transplants (Donor) served as a comparator. In total 66 recipient samples and 17 donor samples were subjected to deep metagenomic sequencing, and taxonomic and functional analyses were performed. Alpha diversity measures showed a significantly increased diversity and evenness in the IBS groups compared to the donors. Taxonomic profiles showed higher relative abundance of phylum Firmicutes, and lower relative abundance of phylum Bacteroidetes, compared to donors at baseline. This profile was shifted toward the donor profile following FMT. Imputed growth rates showed that the resulting growth pattern was a conglomerate of donor and recipient activity. Thirty-four functional subclasses showed distinct differences between baseline samples and donors, most of which were shifted toward a donor-like profile after FMT. All of these changes were less pronounced in the No effect group. We conclude that FMT induces long-term changes in gut microbiota, and these changes mirror the clinical effect of the treatment. The study was registered in ClinicalTrials.gov (NCT02154867).

The effect of fecal microbiota transplantation on IBS related quality of life and fatigue in moderate to severe non-constipated irritable bowel: Secondary endpoints of a double blind, randomized, placebo-controlled trial.

BACKGROUND: Severity in irritable bowel syndrome (IBS) is associated to impaired quality of life and fatigue. Fecal microbiota transplantation (FMT) induces significant relief in gastro-intestinal related complaints. The objective was to evaluate the effect of FMT on the secondary endpoints: IBS-related quality of life and fatigue in patients with non-constipated IBS. METHOD: In this double-blind randomized placebo-controlled, parallel-group, single-center study, we enrolled patients with non-constipated IBS, defined by the ROME 3 criteria. We randomly assigned participants (2:1) in blocks of six to active or placebo FMT. Responder in fatigue and quality of life were defined as a decrease of 20 points in total Fatigue Impact Scale score, and improvement of 14 points in the IBS-quality of life questionnaire, respectively. In a modified-intention-to-treat population, we excluded participants who did not undergo treatment or who were diagnosed with any other disease by pinch biopsies during the treatment procedure. FINDINGS: Between Jan1, and Oct 30, 2015, we recruited 90 participants and randomly assigned them to active treatment (n = 60) or placebo (n = 30). Three participants did not undergo FMT and four were excluded after diagnosis of microscopic colitis, leaving 83 for final modified intention-to-treat analysis (55 in the active treatment group and 28 in the placebo group). Significant improvement in QoL (Odds ratio (OR) 3,801; confidence interval (CI) = 1,309-11,042 p = 0.011) and fatigue (OR = 4,398; CI = 1,175-16,468 and p = 0,020) was found at six months. Absence of other self reported functional disorders and presence of depression at baseline is suggested to predict a lasting effect of FMT in QoL and fatigue, respectively. INTERPRETATION: FMT induced significant relief in quality of life and fatigue. Results suggest a lasting effect of FMT in subgroups that should be further investigated in future studies. Funding Helse Nord, Norway and the Norwegian Centre of Rural Medicine, University of Tromsø, Norway.

Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a common condition characterised by abdominal pain, bloating, and poor quality of life. IBS might be caused by a gut dysbiosis. We aimed to compare faecal microbiota transplantation (FMT) with placebo in patients with IBS. METHODS: In this double-blind, randomised, placebo-controlled, parallel-group, single-centre study, we enrolled patients with IBS with diarrhoea or with diarrhoea and constipation (excluding dominating constipation) defined by the ROME III criteria, scored as moderate to severe according to the IBS severity scoring system (IBS-SSS; a score of ≥175). Eligible participants were aged 18-75 years and were recruited locally by general practitioners in northern Norway. We randomly assigned participants (2:1) in blocks of six to active or placebo FMT. Personnel not involved in the clinical performance of the trial generated the randomisation sequence using a randomisation website. Non-study personnel performed the final allocation and standardised the active and placebo transplants to make them identical in appearance and temperature. The faeces were freshly processed, and were used the same day (fresh transplant) or were stored in a freezer for later use (frozen transplant); participants' own faeces served as placebo. A dose of 8 mg loperamide was administered orally 2 h before endoscopy to retain the transplant. The transplant (50-80 g of faeces mixed with 200 mL of isotonic saline and 50 mL of 85% glycerol) was administered by a colonoscope to the caecum. The primary endpoint was symptom relief of more than 75 points assessed by IBS-SSS, 3 months after FMT. The primary analysis was done in the modified intention-to-treat population, excluding participants who did not undergo treatment or who were diagnosed with any other disease by pinch biopsies obtained during the treatment procedure. For the safety analysis, only participants who did not undergo treatment were excluded. The study is registered with ClinicalTrials.gov, number NCT02154867. The trial has been extended with an open-labelled study treating the placebo group with frozen FMT for further exploratory studies. FINDINGS: Between Jan 1, and Oct 30, 2015, we recruited 90 participants and randomly assigned them to active treatment (n=60) or placebo (n=30). Three participants did not undergo FMT and four were excluded after diagnosis of microscopic colitis, leaving 83 for final modified intention-to-treat analysis (55 in the active treatment group and 28 in the placebo group). 36 (65%) of 55 participants receiving active treatment versus 12 (43%) of 28 receiving the placebo showed response at 3 months (p=0·049). One participant had transient nausea and vertigo (active group) and was observed at the hospital for a few hours after the procedure. Two participants had soiling of transplant on their way home from treatment (one in each group) and three experienced self-limiting intermittent abdominal pain (one in the active group and two in the placebo group). No serious adverse events could be attributed to FMT. INTERPRETATION: FMT induced significant symptom relief in patients with IBS. However, larger multicentre studies are needed to confirm the results. FUNDING: HelseNord and the Norwegian Centre of Rural Medicine, University of Tromsø.

Microscopic colitis: a missed diagnosis among patients with moderate to severe irritable bowel syndrome.

OBJECTIVE: Irritable bowel syndrome (IBS) is a very common condition in general practise, affecting 10-20% of the population in the Western world. The clinical picture of diarrhoea-predominant IBS (IBS-D) resembles other chronic diarrhoeic conditions, such as microscopic colitis (MC). It is impossible to separate these by clinical examinations or lab-tests that can be done in general practise. The aim of this study was to detect any missed diagnoses when only using a symptom-based approach for the diagnosis of IBS. MATERIAL AND METHODOLOGY: We examined 87 participants diagnosed with IBS by the Rome III criteria. All the participants underwent full clinical examination, lab-tests and colonoscopy including mucosa biopsies for histological examination. RESULTS: The histological analysis revealed four cases of MC in participants who for years had been diagnosed with IBS. We found no biochemical or clinical markers that made it possible to differentiate between IBS and MC. MC was only found in the participants diagnosed with IBS-D. CONCLUSION: When long-lasting, unresolved diarrhoeic conditions are present in patients over 45-50 years of age, colonoscopy with biopsy should be performed to rule out MC and other pathologies before diagnosing IBS. In younger patients with pronounced watery diarrhoea, one should consider colonoscopy individually if there is no response to IBS-treatment.