Sudarshan Paramsothy

Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial

BACKGROUND The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis. METHODS We conducted a multicentre, double-blind, randomised, placebo-controlled trial at three hospitals in Australia. We randomly allocated patients with active ulcerative colitis (Mayo score 4-10) in a 1:1 ratio, using a pre-established randomisation list, to either faecal microbiota transplantation or placebo colonoscopic infusion, followed by enemas 5 days per week for 8 weeks. Patients, treating clinicians, and other study staff were unaware of the assigned treatment. Faecal microbiota transplantation enemas were each derived from between three and seven unrelated donors. The primary outcome was steroid-free clinical remission with endoscopic remission or response (Mayo score ≤2, all subscores ≤1, and ≥1 point reduction in endoscopy subscore) at week 8. Analysis was by modified intention-to-treat and included all patients receiving one study dose. We performed 16S rRNA stool analysis to assess associated microbial changes. This trial is registered with ClinicalTrials.gov, number NCT01896635. The trial has ended; this report presents the final analysis. FINDINGS From November, 2013, to May, 2015, 85 patients were enrolled to our trial, of whom 42 were randomly assigned faecal microbiota transplantation and 43 were allocated placebo. One patient assigned faecal microbiota transplantation and three allocated placebo did not receive study treatment and were excluded from the analysis. The primary outcome was achieved in 11 (27%) of 41 patients allocated faecal microbiota transplantation versus three (8%) of 40 who were assigned placebo (risk ratio 3·6, 95% CI 1·1-11·9; p=0·021). Adverse events were reported by 32 (78%) of 41 patients allocated faecal microbiota transplantation and 33 (83%) of 40 who were assigned placebo; most were self-limiting gastrointestinal complaints, with no significant difference in number or type of adverse events between treatment groups. Serious adverse events occurred in two patients assigned faecal microbiota transplantation and in one allocated placebo. Microbial diversity increased with and persisted after faecal microbiota transplantation. Several bacterial taxa were associated with clinical outcome; in particular, the presence of Fusobacterium spp was associated with lack of remission. INTERPRETATION Intensive-dosing, multidonor, faecal microbiota transplantation induces clinical remission and endoscopic improvement in active ulcerative colitis and is associated with distinct microbial changes that relate to outcome. Faecal microbiota transplantation is, thus, a promising new therapeutic option for ulcerative colitis. Future work should focus on precisely defining the optimum treatment intensity and the role of donor-recipient matching based on microbial profiles. FUNDING Broad Medical Research Program, Gastroenterological Society of Australia, Mount Sinai (New York) SUCCESS fund, University of New South Wales.

Fecal Microbiota Transplantation: Indications, Methods, Evidence, and Future Directions

Fecal microbiota transplantation (FMT) has attracted great interest in recent years, largely due to the global Clostridium difficile infection (CDI) epidemic and major advances in metagenomic sequencing of the gastrointestinal (GI) microbiota, with growing understanding of its structure and function. FMT is now recommended as the most effective therapy for relapsing CDI and, with further refinement, may even be used in “first-time” CDI. There is interest also in other conditions related to GI dysbiosis—for example, inflammatory bowel disease, irritable bowel syndrome, obesity, and diabetes mellitus—although quality evidence is at present lacking. A few trials are now underway in FMT for ulcerative colitis. Many unanswered questions remain, including FMT methodology—for example, optimal route of administration, what makes a “good donor,” safety issues, and long-term effects of FMT.

Therapeutic faecal microbiota transplantation: current status and future developments.

Purpose of review Faecal microbiota transplantation (FMT) has undergone dramatic progression over the past year and continues to evolve as knowledge of the gastrointestinal microbiota (GiMb) develops. This review summarizes therapeutic advances in FMT, latest FMT therapies and presents the potential of FMT therapeutics in other gastrointestinal and extra-intestinal conditions. Recent findings The GiMb is now known to have a central role in the pathogenesis of many diseases. The success of FMT in curing Clostridium difficile infection (CDI) is well established and preliminary findings in other gastrointestinal conditions are promising. Published data from over 500 CDI cases suggest that FMT is generally well tolerated with minimal side effects. The commercial potential of FMT is being explored with several products under development, including frozen GiMb extract, which has been shown highly effective in treating relapsing CDI. Such products will likely become more available in coming years and revolutionize the availability and method of delivery of GiMb. Summary Recent literature unequivocally supports the use of FMT in treating relapsing CDI. Trials are underway to determine the therapeutic potential of FMT in other conditions, particularly inflammatory bowel disease. Therapeutic FMT is a dynamic field with new and emerging indications along with ongoing developments in optimal mode of administration.

Donor Recruitment for Fecal Microbiota Transplantation.

Background:Increasing demand for fecal microbiota transplantation (FMT) has created a need for stool banks sourced from long-term healthy donors. Here, we describe our experience in recruiting and screening fecal donors. Methods:Mailbox, newspaper, and online advertisements were used. Potential donors were required to satisfy a prescreen telephone conversation, pass blood and stool investigations, then undertake a screening interview including medical history, physical examination, and evaluation of donor selection criteria. Results:One hundred sixteen potential donors were prescreened of whom 74 failed—47 declined based on study donation requirements (primarily related to frequency and duration of donations), 13 had medical comorbidities, 6 variant Creutzfeldt–Jakob disease risk factors, 8 for other reasons. Thirty-eight completed stool and blood testing—1 failed blood testing (indeterminate hepatitis C serology), whereas 15 failed stool investigations (5 Dientamoeba fragilis, 5 Blastocystis hominis, 1 B. hominis and D. fragilis, 1 Giardia intestinalis plus D. fragilis, 1 Norovirus plus Clostridium difficile toxin positive, and 2 leucocytes or erythrocytes on stool microscopy). Of the 18 potential donors proceeding to screening interview, 6 were excluded (3 body mass index >30, 1 illicit drug use, 1 uncontrolled anxiety and concerns regarding compliance, 1 irregular bowel movements after new medication commencement). In total, only 12 of 116 (10%) potential donors were enrolled as study donors. Conclusions:Recruitment of fecal donors for FMT is challenging with only a small percentage ultimately serving as donors. Many were unable or unwilling to meet the donor commitment requirements. A surprisingly large proportion of healthy asymptomatic donors failed stool testing, primarily due to gastrointestinal parasites.

Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis

Background Faecal microbiota transplantation [FMT] has been investigated as a potential treatment for inflammatory bowel disease [IBD]. We thus performed a systematic review and meta-analysis assessing the effectiveness and safety of FMT in IBD. Methods A systematic review was conducted until January 2017. Studies were excluded if patients had co-infection or data were pooled across disease subtypes (ulcerative colitis [UC], Crohns disease [CD], pouchitis). Clinical remission was established as the primary outcome. Pooled effect sizes and 95% confidence intervals were obtained using the random effects model. Results In all, 53 studies were included [41 in UC, 11 in CD, 4 in pouchitis]. Overall, 36% [201/555] of UC, 50.5% [42/83] of CD, and 21.5% [5/23] of pouchitis patients achieved clinical remission. Among cohort studies, the pooled proportion achieving clinical remission was 33% (95% confidence interval [CI] = 23%-43%] for UC and 52% [95% CI = 31%-72%] for CD, both with moderate risk of heterogeneity. For four RCTs in UC, significant benefit in clinical remission (pooled odds ratios [[P-OR] = 2.89, 95% CI = 1.36-6.13, p = 0.006) with moderate heterogeneity [Cochrans Q, p = 0.188; I2 = 37%] was noted. Sub-analyses suggest remission in UC improved with increased number of FMT infusions and lower gastrointestinal tract administration. Most adverse events were transient gastrointestinal complaints. Microbiota analysis was performed in 24 studies, with many identifying increased diversity and a shift in recipient microbiota profile towards the donor post-FMT. Conclusions FMT appears effective in UC remission induction, but long-term durability and safety remain unclear. Additional well-designed controlled studies of FMT in IBD are needed, especially in CD and pouchitis.

Fecal microbiota transplantation: a new standard treatment option for Clostridium difficile infection

The last 20 years have seen a progressive increase in the global incidence and severity of Clostridium difficile infection (CDI), particularly in North America and Europe. This increase has been accompanied by the identification and increased prevalence of new, hypervirulent toxigenic strains such as NAP1/BI/027 [1], which in the USA alone is responsible for worsened outcomes and a mortality reaching some 300 deaths per day from 3 million new cases annually [2]. It is within the context of the CDI epidemic that fecal microbiota transplantation (FMT) has gained acceptance as the most effective therapy for CDI [3]. This editorial makes the case that the

Is Crohn's disease ready for fecal microbiota transplantation?

Fecal microbiota transplantation (FMT), in which homogenized stool from a healthy donor is infused into the gastrointestinal (GI) tract of a patient, has come to the fore in recent years and is being investigated as a treatment method for a number of GI and indeed non-GI disorders. The use of FMT in inflammatory bowel disease (IBD) has attracted increasing attention since the first reports in the late 1980s. Bennet and Brinkman’s1 initial report documented the complete clinical remission of a case of ulcerative colitis (UC) for at least 6 months following FMT through retention enema. Our Sydney group treated its first colitis patient in 1988 and has repeatedly reported cases of prolonged remission in IBD patients following FMT,2–4 with remission persisting up to 13 years in some cases. Unlike its application in recurrent Clostridium difficile infection (CDI), however, the success of FMT in IBD remains variable. In 2012, a systematic review of FMT for IBD5 found that the majority (albeit not an overwhelming majority) of patients experienced symptom improvement, disease remission, and cessation of medication following FMT treatment. This review was limited to the 9 small case series/reports available at the time. A number of randomized controlled trials of FMT for IBD, at least 4 of which are for Crohn’s disease (CD), are now underway to further characterize treatment efficacy and safety. In this issue, Kao et al6 have reported marked clinical and histologic improvement following colonoscopic FMT in a 26-year-old man with Crohn’s colitis. Four weeks after FMT, the patient’s modified Harvey-Bradshaw Index had reduced to 0, fecal calprotectin levels had normalized, and complete mucosal healing was evident upon colonoscopy. This observation provides evidence of the untapped power of the normal luminal flora to inhibit even the most severe inflammation of Crohn’s colitis, in contrast to the previous theory of IBD being the result of “inappropriate and ongoing activation of the mucosal immune system driven by the presence of normal luminal flora.”7 In the case presented by Kao and colleagues, clinical response was not sustained. Indeed, such a marked effect with clinical and endoscopic remission after a single infusion is certainly not the norm, with several other published reports yielding disappointing results.8 In our experience, CD is overall less responsive to FMT compared with UC, and, although a few exceptional cases may demonstrate striking results after a single infusion, in the vast majority of those who do respond, multiple infusions are required. Nonetheless, an additional 2 recent case reports9,10 have described similar responses in 2 patients with CD following a single FMT treatment, while we have reported prolonged CD remission following repeated FMT.11 As such, these case reports raise important questions, none more so than why some patients with IBD respond so impressively after a single or several FMT infusions and others fail to do so. It may be that FMT is more effective in cases of short disease duration, before colonic dysbiosis becomes deeply established. Alternatively, perhaps FMT is more effective in IBD cases in which antibiotic use is potentially associated with disease onset. It may also be that some manifestations of IBD-associated dysbiosis are more susceptible than others to rapid reversal after FMT, as occurs with CDI. Donor characteristics may be equally important in determining interpatient variability in FMT efficacy, in particular the donor’s microbial profile. Anecdotally, we have noticed that FMT response rates are better with certain donors than with others. This is likely because donor selection is at present a very basic and imprecise process that works on the principle of

Resumption of oral intake following percutaneous endoscopic gastrostomy

Background and Aims:  Percutaneous endoscopic gastrostomy (PEG) provides enteral nutrition to patients who cannot swallow. Few studies have prospectively evaluated its long‐term outcomes or eventual resumption of oral intake.

23 EMERGENT COLECTOMY RATES DECREASED WHILE ELECTIVE IPAA RATES WERE STABLE OVER TIME: A NATIONWIDE INPATIENT SAMPLE STUDY

Purpose Despite advances in biologic therapy, approximately 10–15% of ulcerative colitis (UC) patients require surgery. We aimed to (1) examine the rates of emergent colectomy and elective ileal pouch anal anastomosis (IPAA) over time among UC patients in the USA and (2) investigate disparities in surgery rates by patient demographics.

The Biosimilar Revolution: Coming to an IBD Patient Near You?

The emergence of biologic therapies almost 20 years ago revolutionized the treatment of inflammatory bowel diseases (IBD), and these therapies are now widely acknowledged to be the most effective agents currently available for the treatment of these conditions. As the initial biologic agents start to come off patent, biosimilar agents have emerged as alternatives to the originator drugs. Given the unique drug development and manufacturing processes involved in the creation of biologic agents, it poses distinct regulatory challenges compared to generic compounds of conventional medications. Reductions in medication costs have been touted as a major benefit of biosimilar therapies but there are concerns regarding the adequacy of existing regulatory processes and data requirements for biosimilar therapy approval, and the true “bioequivalence” of these agents. Infliximab biosimilars for the treatment of inflammatory bowel disease have been available in Europe and Asia for a few years, and are expected to become available in the USA in 2017–18. In this chapter, we will discuss how biosimilars are approved, the clinical data that have led to the approval of CT-P13 along with available postmarketing data in IBD, and the controversies and unanswered questions that remain.