The role of faecal microbiota transplantation in the treatment of inflammatory bowel disease

Purpose of the review Faecal microbiota transplantation (FMT) has emerged as a potent form of therapeutic microbial manipulation. There is much interest in exploring its potential in conditions such as inflammatory bowel disease (IBD) where disturbances in the gastrointestinal microbiota play a crucial role in disease pathogenesis. Recent findings There are 4 randomized controlled trials of FMT as induction therapy in ulcerative colitis, with meta-analyses suggesting significant benefit over placebo. Allied microbial studies have identified potential microbial and metabolic predictors of therapeutic efficacy and highlighted the importance of optimizing future donor and patient selection. Recent literature has evaluated the use of complementary microbial manipulation through pre-antibiotics to improve treatment efficacy. Studies have also assessed the durability of FMT response and its use in maintenance therapy of UC. While data on FMT are more limited in Crohn’s disease and pouchitis, cohort and pilot randomized controlled data a now also emerging in these areas

Safety of drugs used for the treatment of Crohn’s disease

Introduction: Medications in treating Crohn’s disease (CD) have evolved over the last two decades, particularly with the use of biologic agents. There are, however, concerns about the safety and adverse events associated with these medications. The authors review the safety profile of immunosuppressive medications used in Crohn’s disease in adult patients. Areas covered: The authors performed a literature search until October 2018 to examine safety data on thiopurines, methotrexate, anti-TNFα agents, vedolizumab and ustekinumab. The authors focused on ‘trial’ and ‘real-world’ data for the biologic agents. Safety in pregnancy and the elderly are also presented. Expert opinion: Available data in CD suggest that immunosuppressive medications are relatively safe, although there are concerns about an elevated risk of serious infections, skin cancer and lymphoma particularly with thiopurines and anti-TNFα agents. Data on vedolizumab and ustekinumab suggest these newer biologic agents are well tolerated; however, longer term data in CD are required to identify risks with extended use. Apart from methotrexate, there appear to be no adverse congenital outcomes with exposure of drugs during pregnancy

Lyophilised Oral Faecal Microbiota Transplantation in Ulcerative Colitis - a Randomised Placebo-Controlled Trial

Background: Colonoscopic infusion and enemas of faecal microbiota transplantation (FMT) induce remission in ulcerative colitis (UC) but whether oral FMT achieves induction and maintenance of remission in UC is unknown.Methods: A double-blind, randomised placebo-controlled trial was conducted. Following 2-weeks of amoxicillin, metronidazole and doxycycline, patients with active UC were randomised 1:1 to FMT or placebo capsules for 8-weeks. The primary outcome was steroid-free clinical remission with endoscopic remission or response. At week-8, FMT-responders were re-randomised 1:1 to continue or withdraw FMT for a further 48-weeks. Modified intention-to-treat analysis was performed and included all patients who received at least one study dose. The gastrointestinal microbiota was profiled using 16S rRNA and ITS region amplicon sequencing. This report presents the final analysis.Findings: From May 2019 to March 2020, 35 subjects were randomised (15 FMT/ 20 placebo). Recruitment was terminated early due to the SARS-COV-2 pandemic. The primary outcome was achieved in 8/15(53%) with FMT versus 3/20(15%) with placebo (difference:38·3% [95%CI: 8·6–68·0]; P =0·027; OR:5·0[95%CI: 1·8–14·1]). Ten FMT-responders entered the maintenance phase. By 56-weeks, 6/6 (100%) subjects randomised to withdraw FMT relapsed (median time to treatment escalation 24-weeks); whereas 4/4(100%) subjects on maintenance-FMT had endoscopic and histologic mucosal healing. Adverse events occurred in 10/15(67%) FMT and 18/20(85%) placebo subjects and were generally mild and self-limiting. Serious adverse events included worsening UC (2 FMT, 1 placebo) and PR bleeding (1 placebo). Antibiotics reduced pathobionts and FMT increased species richness relative to placebo (P<0·0001). Therapeutic effectiveness was associated with high donor microbial alpha-diversity and Bacteroides species, and increases in Bacteroides ovatus-like taxa in recipients.Interpretation Antibiotics followed by orally-administered FMT induces remission in subjects with active UC with corresponding microbial changes. Maintenance FMT in responders was safe, well tolerated and appeared to sustain the response achieved during induction therapy. Trial Registration: The study was registered with the Australian New Zealand Clinical Trial Registry ACTRN12619000611123.Funding: The study was supported by: St Vincent’s Clinic Foundation (2019), Gastroenterological Society of Australia (2020) and Gutsy Group (202-2021). CH is supported by a Research Entry Scholarship through the Royal Australasian College of Physicians; SP is supported by an NHMRC Investigator Grant, NOK is supported by a Scientia Fellowship from UNSW.Declaration of Interest: CH reports speaker fees and educational support from Janssen, Pfizer, Takeda, Ferring, Sandoz and Abbvie. SP has served as a consultant for Finch Therapeutics and has received speaker fees from Ferring, Janssen and Takeda. SG reports Speaker fees, educational grants or travel sponsorship from Janssen Cilag, AbbVie, Takeda, Ferring, Shire, Pfizer. Advisory board fees Pfizer and AbbVie. TJB has a pecuniary interest in the Centre for Digestive Diseases, is a medical advisor to Finch therapeutics and holds patents in FMT treatment. RWL reports personal fees from AbbVie, personal fees from Aspen, personal fees from Ferring, grants and personal fees from Hospira/ Pfizer, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from Shire, grants from NHMRC, personal fees from Celgene, personal fees from Dr Falk Pharma, personal fees from Novartis, personal fees from MSD, grants from Gutsy Group, personal fees from Chiesi, personal fees from BMS, personal fees from Glutagen, outside the submitted work. All other authors have no conflicts of interest to declare.Ethical Approval: This investigator-initiated study was approved by the St Vincent’s Hospital Sydney Human Research Ethics Committee (HREC/18/SVH/219) with The University of Sydney serving as study sponsor. All patients provided written informed consent

Vitamin D metabolites are lower with active Crohn’s disease and spontaneously recover with development of remission

Background: Vitamin D deficiency is associated with active Crohn’s disease (CD). However, it remains unclear if lower 25-hydroxyvitamin D [25(OH)D] concentration is the cause, or consequence, of intestinal inflammation. Existing literature has focused on circulating 25(OH) D rather than the active metabolite 1,25(OH)2D, or its breakdown product, 24,25(OH)2D. We aimed to characterise vitamin D metabolism in a cohort of patients with active and inactive CD. Methods: Fifty-four patients with CD and not on corticosteroids or vitamin D supplements, were enrolled in a 6-month prospective cohort study. Sera were collected on enrolment and at 6months and tested for 25(OH)D, 1,25(OH)2D, 24,25(OH)2D using liquid chromatography tandem mass spectroscopy as well as vitamin-D-binding protein. Results: There were no differences in 25(OH)D or 1,25(OH)2D levels between participants with active versus inactive disease. Levels of 24,25(OH)2D were significantly lower in those with active compared with inactive disease (mean 3.9 versus 6.0µmol/l; p=0.007) and therefore the ratio of 25(OH)D:24,25(OH)2D was higher (mean 17.3 versus 11.1; p=0.001). In those patients with active disease who achieved remission, there was a mean increase in 25(OH) D of 32.3nmol/l (i.e. to a level in the sufficient range) and 24,25(OH)2D of 2.1µmol/l. These increases were not seen in patients with persistently active or inactive disease. Conclusion: Levels of 24,25(OH)2D, but not 25(OH)D, were lower in patients with active CD, and spontaneously increased with resolution of underlying inflammation. The utility of 24,25(OH)2D as a biomarker of disease activity and vitamin D status in CD warrants further exploration

Entyvio lengthen dose-interval study: lengthening vedolizumab dose interval and the risk of clinical relapse in inflammatory bowel disease

Vedolizumab (VDZ), an α4β7 anti-integrin antibody, is efficacious in the induction and maintenance of remission in ulcerative colitis (UC) and Crohn's disease (CD). In the GEMINI long-term safety study, enrolled patients received 4-weekly VDZ. Upon completion, patients were switched to 8-weekly VDZ in Australia. The clinical success rate of treatment de-escalation for patients in remission on VDZ has not been described previously.To determine the proportion of patients who relapsed after switching from 4 to 8-weekly VDZ, the mean time to relapse, and the recapture rate when switching back to 8-weekly dosing.This was a retrospective, observational, multicenter study of patients previously recruited into GEMINI long-term safety in Australia. Data on the demographics and biochemical findings were collected.There were 34 patients [23 men, mean age 49.1 (±13.1) years] and their mean disease duration was 17.6 (±8.5) years. The mean 4-weekly VDZ infusion duration was 286.5 (±48.8) weeks. A total of five (15%) patients relapsed on dose-interval increase (4/17 UC, 1/17 CD) at a median duration from dose interval lengthening to flare of 14 weeks (interquartile range=6-25). Eighty percent (4/5) of patients re-entered remission following dose-interval decrease back to 4-weekly. No clinical predictors of relapse could be determined because of the small cohort size.The risk of patients relapsing when switching from 4 to 8-weekly VDZ ∼15% and is similar between CD and UC. Dose-interval decrease recaptures 80% of patients who relapsed. Therapeutic drug monitoring of VDZ may be of clinical relevance

Australian consensus statements for the regulation, production and use of faecal microbiota transplantation in clinical practice

Objective: Faecal microbiota transplantation (FMT) has proved to be an extremely effective treatment for recurrent Clostridioides difficile infection, and there is interest in its potential application in other gastrointestinal and systemic diseases. However, the recent death and episode of septicaemia following FMT highlights the need for further appraisal and guidelines on donor evaluation, production standards, treatment facilities and acceptable clinical indications. Design: For these consensus statements, a 24-member multidisciplinary working group voted online and then convened in-person, using a modified Delphi approach to formulate and refine a series of recommendations based on best evidence and expert opinion. Invitations to participate were directed to Australian experts, with an international delegate assisting the development. The following issues regarding the use of FMT in clinical practice were addressed: donor selection and screening, clinical indications, requirements of FMT centres and future directions. Evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Results: Consensus was reached on 27 statements to provide guidance on best practice in FMT. These include: (1) minimum standards for donor screening with recommended clinical selection criteria, blood and stool testing; (2) accepted routes of administration; (3) clinical indications; (4) minimum standards for FMT production and requirements for treatment facilities acknowledging distinction between single-site centres (eg, hospital-based) and stool banks; and (5) recommendations on future research and product development. Conclusions: These FMT consensus statements provide comprehensive recommendations around the production and use of FMT in clinical practice with relevance to clinicians, researchers and policy makers