Post Faecal Microbiota Transplantation Research Articles

P-Cresol Sulfate Is a Sensitive Urinary Marker of Fecal Microbiota Transplantation and Antibiotics Treatments in Human Patients and Mouse Models.

Fecal microbiota transplantation (FMT) has emerged as a highly effective therapy for recurrent Clostridioides difficile infection (rCDI) and also a potential therapy for other diseases associated with dysbiotic gut microbiota. Monitoring metabolic changes in biofluids and excreta is a noninvasive approach to identify the biomarkers of microbial recolonization and to understand the metabolic influences of FMT on the host. In this study, the pre-FMT and post FMT urine samples from 11 rCDI patients were compared through metabolomic analyses for FMT-induced metabolic changes. The results showed that p-cresol sulfate in urine, a microbial metabolite of tyrosine, was rapidly elevated by FMT and much more responsive than other microbial metabolites of aromatic amino acids (AAAs). Because patients were treated with vancomycin prior to FMT, the influence of vancomycin on the microbial metabolism of AAAs was examined in a mouse feeding trial, in which the decreases in p-cresol sulfate, phenylacetylglycine, and indoxyl sulfate in urine were accompanied with significant increases in their AAA precursors in feces. The inhibitory effects of antibiotics and the recovering effects of FMT on the microbial metabolism of AAAs were further validated in a mouse model of FMT. Overall, urinary p-cresol sulfate may function as a sensitive and convenient therapeutic indicator on the effectiveness of antibiotics and FMT for the desired manipulation of gut microbiota in human patients.

S2458 Rosacea Improved Following Treatment With Combination Antibiotics and Fecal Microbiota Transplantation: Two Case Reports

Introduction: Rosacea is a chronic skin condition affecting nearly 18% of the population worldwide. It is characterised by flushing or redness of the cheeks, nose, chin and/or forehead. In severe cases visible blood vessels, inflammatory acne or skin thickening may be present. The cause of rosacea remains unknown and treatments are limited. Emerging evidence suggests a link between gastrointestinal (GI) microbiome dysbiosis and rosacea. Here, we report 2 cases who received fecal microbiota transplantation (FMT) for irritable bowel syndrome (IBS) and reported an improvement in concomitant rosacea. Case Description/Methods: Case 1: A female (65yrs) presented with known IBS characterised by bloating, abdominal pain and diarrhoea. Medical history included subtotal hysterectomy and optical rosacea, treated with hourly eye drops and cyclosporine eye gel. The patient was subsequently treated with vancomycin and rifaximin, with reduction in abdominal pain, bloating and bowel frequency. The patient also reported reduced eye irritation from optical rosacea. The patient then underwent FMT for 10 days (1 colonoscopic infusion, 9 rectal enemas). At 6 months, the patient reported a 75% improvement in GI symptoms and reported ongoing improvement in optical rosacea although still reliant on cyclosporine eye gel. Follow up at one year post FMT demonstrated recurrence of GI symptoms and optical rosacea. Case 2: A female (45yrs) presented with abdominal cramps, bloating, flatulence and alternating diarrhoea and constipation. Concomitant medical history was endometriosis and severe acne rosacea treated with twice daily application of topical mupirocin ointment. Investigations excluded organic pathology and IBS was diagnosed. The patient was subsequently treated with vancomycin and rifaximin followed by FMT for 10 days (1 colonoscopic infusion, 9 rectal enemas). At 6 months, the patient had no ongoing GI symptoms and continued to report ongoing improvement in acne rosacea with some flushing persisting. Follow up at 6 years post FMT demonstrated ongoing clinical improvement with occasional abdominal pain and diarrhoea. The patient no longer experienced acne rosacea and had ceased all medications. Discussion: To our knowledge this is the first report of antibiotics followed by FMT to treat rosacea, with improvements reported in both the short and long term. Future prospective trials are required to confirm FMT as a treatment for rosacea.

S156 Microbiome Alteration via Fecal Microbiota Transplantation (FMT) Is Effective for Immune Checkpoint Inhibitor (ICI) Induced-Colitis (IMC) Refractory to Immunosuppressive Therapy

Introduction: Immune checkpoint inhibitors (ICI) target advanced malignancies with high efficacy, but also predispose to immune related adverse events such as immune-mediated colitis (IMC). While evidence-based management is lacking, medical therapy is limited to immunosuppressant therapy which may compromise cancer outcome. The composition of gut commensal bacteria is associated with response to ICI therapy and IMC severity, but optimal strategies to target the microbiome have yet to be identified. Fecal microbiota transplantation (FMT) represents a feasible way to restore microbial diversity and composition in patients for clinical benefit. Methods: We present a case series of 12 patients with IMC who received FMT following unsuccessful treatment to immunosuppression with a detailed stool microbiome analysis. Of note, donor stool had successfully been employed previously in treatment of recurrent C.difficile diarrhea. Results: All patients had advanced cancer with grade 3-4 diarrhea that failed immunosuppression. 3 patients received FMT twice. 83% had symptom improvement at a median duration of 14 days (IQR 9-16). Seven (58.3%) patients had complete clinical response, while five (41.7%) had either partial or no response. 42% of patients achieved both endoscopic and histologic remission at the last follow up. 4 (33%) resumed cancer therapy post FMT. 4 (33%) patients required immunosuppression for GI irAE after failing FMT. There were no FMT related complications at 7 and 30 days respectively. At the end of the study period, 92% achieved clinical remission. 3 patients in the cohort succumbed to underlying malignancy. The clinical characteristics are summarized in Table. 16S rRNA sequencing of patient stools before and following FMT revealed that complete response to FMT was significantly associated with greater gut dysbiosis before FMT, higher alpha diversity and an increased abundance in bacterial families Coriobacteriaceae and Bifidobacteriaceae from the phylum Actinobacteria post FMT. (Figure 1). Conclusion: FMT for refractory IMC represents a novel approach wherein the gut microbial diversity and composition may be targeted to confer therapeutic benefit for IMC. The data from this study gives greater insight into the unique microbial signatures that may play a role in FMT response to IMC. We speculate that routine use of FMT may have value in enhancing effectiveness of immunotherapy in some cancers while preventing gastrointestinal drug side effects.Figure 1.: A)Paired analysis depicting changes in alpha diversity B) Coriobacteriaceae and Bifidobacteriaceae comparing pre-FMT and post-FMT. C) beta diversity of donors, Complete responders (CR) and Partial/Non-responders (PR/NR) at baseline (pre-FMT). Significance was assessed by comparing donor to CR (P= 0.012) and donor to PR/NR (P=0.4).Table 1.: Demographic, Oncologic, IMC and FMT-related characteristics of patients.

Fecal microbiota transplantation and Clostridioides difficile infection among privately insured patients in the United States.

Clostridioides difficile infection (CDI) may be rising in severity in the US over the past decade and its treatment landscape is changing given the recent adoption of fecal microbiota transplantation (FMT) METHODS: We built a retrospective observational cohort using a database of a national care-plan containing medical claims of over 50 million individuals between 2008 and 2019. We used International Classification of Disease (ICD) and prescription data to identify patients with CDI. We estimated trends in disease burden and FMT use, and evaluated complications post FMT using a phenome-wide association approach. We identified 38,396 patients with CDI; the median age was 60years (IQR 45-74) and 60% were female (n = 23,374). The rate of CDI increased from 33.4 to 69.46 cases per 100,000 person-years between 2008 and 2015, and stabilized from 2015 to 2019 (increase of 4.77 cases per 100,000 person-years per year, 95% CI 3.55-5.98 prior to 2015 vs. 2.01 95% CI - 10.16 to 14.18 after 2015). Of the 7715 patients with recurrent CDI, 407 patients (5%) underwent FMT. Gastrointestinal complications were increased within 1 month post FMT (OR 99.60, p < 0.001). Sepsis was identified in two individuals (0.49% 95% CI 0.05-1.7%) within the first month post FMT. The risk of CDI recurrence significantly decreased post FMT compared with anti-CDI antibiotics in the multivariable model (raw-recurrence rate 9.8% vs 36%, aOR = 0.21, 95% CI 0.12-0.53, p < 0.001). We show that FMT is strongly associated with a decrease in CDI recurrence compared with the usual care with generally mild complications for up to 2years.

Abstract 5730: A new polyphenol prebiotic isolated from Myrciaria dubia improves gut microbiota composition and increases anti-PD-1 efficacy in murine cancer models

Abstract Introduction The gut microbiota influences immune checkpoint inhibitors (ICI) efficacy, and immunogenic commensals bacteria such as Akkermansia muciniphila (AM) and Ruminoccocus are enriched in ICI responder patients. Therefore, strategies to beneficially shift microbiota composition represent a novel therapeutic avenue. Myrciaria dubia (MD) is a polyphenol-rich berry prebiotic that has been recently shown to improve the gut microbiota composition and dampen inflammation in metabolic diseases. Methods Daily oral administration of MD or water was performed in MCA-205 (PD-1 sensitive) and E0071 (PD-1 resistant) murine tumor models treated with iso-control or anti-PD-1. 16s rRNA gene sequencing and qPCR were used to profile the murine fecal microbiota. Tumor immune infiltration was analyzed by flow cytometry and RNA sequencing. Bile acid levels were measured using liquid chromatography coupled to tandem mass spectrometry in mouse feces and plasma at sacrifice. MD supplementation was also tested in antibiotic-treated mice that had undergone a fecal microbiota transplantation (FMT) using feces from non-responder (NR) and responder (R) non-small cell lung cancer (NSCLC) patients. Finally, to determine the bioactive compound, reverse-phase high performance liquid chromatography was used to isolate fractions that were tested in the MCA-205 tumor model. Results In MCA-205, MD gavage alone significantly reduced tumor size and in both tumor models MD increased the efficacy of anti-PD-1 compared to water + anti-PD-1. The activity of MD was inhibited upon antibiotics administration. FMT using mouse feces previously treated with MD recreated the effect in MD-naïve mice. Increases in alpha diversity, and AM and Ruminococcaceae were observed in the feces of MD supplemented mice. Serum and fecal CA, αMCA primary and HDCA and DCA secondary bile acids were upregulated in mice treated with MD. The combination of MD + anti-PD-1 increased the frequency of CD8+/CD4+ Treg and ICOS+ expression on CD8+ T cells, while the depletion of the CD8+ cells inhibited the anti-cancer activity. Next, we validated that FMT from NSCLC ICI patients recreated the patients' phenotypes in the MCA-205 tumor model (R vs NR). Treatment with MD resorted anti-PD-1 anti-tumor efficacy post FMT from NR patients. Lastly, we isolated the bioactive polyphenol molecule from MD and confirmed its anti-cancer effect in vivo. Supplementation of AM and ruminococcus further increased anti-PD1 activity. Conclusion We isolated the bioactive polyphenol molecule from the MD berry and demonstrated that its potent adjuvant effect on anti-PD-1 was associated with a beneficial shift in microbiome and bile acid composition in a CD8+ T cell dependent manner. The modification of the gut microbiota with polyphenol supplementation provides a new therapeutic approach in immuno-oncology. Citation Format: Meriem Messaoudene, Florent Cauchois, Reilly Piedgeon, Khoudia Diop, Corentin Richard, Thibault Varin, Jocelyn Trottier, Olivier Barbier, Geneviève Pilon, Simon Turcotte, André Marette, Bastien Castagner, Bertrand Routy. A new polyphenol prebiotic isolated from Myrciaria dubia improves gut microbiota composition and increases anti-PD-1 efficacy in murine cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5730.

Antibiotic-induced alterations and repopulation dynamics of yellowtail kingfish microbiota

BackgroundThe use of antibiotics in aquaculture is a common infection treatment and is increasing in some sectors and jurisdictions. While antibiotic treatment can negatively shift gut bacterial communities, recovery and examination of these communities in fish of commercial importance is not well documented. Examining the impacts of antibiotics on farmed fish microbiota is fundamental for improving our understanding and management of healthy farmed fish. This work assessed yellowtail kingfish (Seriola lalandi) skin and gut bacterial communities after an oral antibiotic combination therapy in poor performing fish that displayed signs of enteritis over an 18-day period. In an attempt to promote improved bacterial re-establishment after antibiotic treatment, faecal microbiota transplantation (FMT) was also administered via gavage or in the surrounding seawater, and its affect was evaluated over 15 days post-delivery.ResultsAntibiotic treatment greatly perturbed the global gut bacterial communities of poor-performing fish – an effect that lasted for up to 18 days post treatment. This perturbation was marked by a significant decrease in species diversity and evenness, as well as a concomitant increase in particular taxa like an uncultured Mycoplasmataceae sp., which persisted and dominated antibiotic-treated fish for the entire 18-day period. The skin-associated bacterial communities were also perturbed by the antibiotic treatment, notably within the first 3 days; however, this was unlike the gut, as skin microbiota appeared to shift towards a more ‘normal’ (though disparate) state after 5 days post antibiotic treatment. FMT was only able to modulate the impacts of antibiotics in some individuals for a short time period, as the magnitude of change varied substantially between individuals. Some fish maintained certain transplanted gut taxa (i.e. present in the FMT inoculum; namely various Aliivibrio related ASVs) at Day 2 post FMT, although these were lost by Day 8 post FMT.ConclusionAs we observed notable, prolonged perturbations induced by antibiotics on the gut bacterial assemblages, further work is required to better understand the processes/dynamics of their re-establishment following antibiotic exposure. In this regard, procedures like FMT represent a novel approach for promoting improved microbial recovery, although their efficacy and the factors that support their success requires further investigation.

P: 12 PROFIT: PROspective, Randomised Placebo-controlled Feasibility Trial of Faecal Microbiota Transplantation in Cirrhosis Interim Analysis

BACKGROUND: Patients with cirrhosis have intestinal dysbiosis and small bowel bacterial overgrowth, with enhanced gut permeability, allowing translocation of pathogen-associated molecules and viable bacteria into the systemic circulation. Faecal Microbiota Transplantation (FMT) seeks to replace the dysbiotic flora with healthy microbes, to reduce systemic inflammation and improve transplant-free outcomes. PROFIT is a single-blinded randomised placebo-controlled trial of FMT in 32 patients with advanced stable cirrhosis. The primary outcome of the study was to assess the safety and feasibility of a single naso-jejunally administered FMT or placebo (3:1 allocation) in patients with a MELD score between 10 and 16. METHODS: To date eighteen patients have been treated (FMT n = 13; placebo n = 5). 71% of those treated were male [mean age 54.4 years (range 38–75) and mean MELD 12.88 (range 10–16)]. Patients continued lactulose, but were required to discontinue all antibiotics, including rifaximin, two weeks prior to treatment. Following bowel preparation with Moviprep®, 200 mL FMT/placebo was delivered via naso-jejunal tube in to the proximal jejunum at gastroscopy. Patients were assessed for adverse events and underwent clinical review at day 7, 30 and 90 with biobanking of stool, saliva, urine, whole blood and plasma for quantitative metagenomics, metabonomics, bacterial DNA quantification, bile acids, whole blood culture in response to endotoxin and plasma cytokines and leucocyte function testing at a later date. RESULTS: The FMT has been well tolerated and the five serious adverse events (SAEs) reported requiring hospital admission (placebo n = 1; FMT n = 4) were not treatment-related. Biochemistry, leucocyte count and MELD score did not change. Mean venous ammonia reduced at day 30 in the FMT cohort [71.67 μmol/L (95% CI 54.43–88.9) day 0 versus 51.22 μmol/L (CI 35.18–67.26) day 30] whereas it increased in the placebo group [54.4 μmol/L (95% CI 38.17–70.63) day 0 versus 73.25 μmol/L (95% CI 22.54–124) at day 30]. Figure 1 shows a reduction in delta ammonia at day 7 [mean −1.15 (−16.23 to 13.73 95% CI)] versus day 30 [−15.11 (−2.82 to −27.4) post FMT. CONCLUSIONS: The interim analysis shows that nasojejunally administered FMT appears safe and well tolerated in patients with advanced cirrhosis and reduces venous ammonia at day 30.

Faecal microbiota transplantation shortens the colonisation period and allows re-entry of patients carrying carbapenamase-producing bacteria into medical care facilities

BackgroundColonisation with carbapenemase-producing Enterobacteriaceae or Acinetobacter (CPE/A) is associated with complex medical care requiring implementation of specific isolation policies and limitation of patient discharge to other medical facilities. Faecal microbiota transplantation (FMT) has been proposed in order to reduce the duration of gut colonisation. ObjectivesThis study investigated whether a dedicated protocol of FMT could reduce the negativation time of CPE/A intestinal carriage in patients whose medical care has been delayed due to such colonisation. MethodA matched case-control retrospective study between patients who received FMT treatment and those who did not among CPE/A-colonised patients addressed for initial clustering at the current institute. The study adjusted two controls per case based on sex, age, bacterial species, and carbapenemase type. The primary outcome was delay in negativation of rectal-swab cultures. ResultsAt day 14 post FMT, 8/10 (80%) treated patients were cleared for intestinal CPE/A carriage. In the control group, 2/20 (10%) had spontaneous clearance at day 14 after CPE/A diagnosis. Faecal microbiota transplantation led patients to reduce the delay in decolonisation (median 3 days post FMT for treated patients vs. 50.5 days after the first documentation of digestive carriage for control patients) and discharge from hospital (median 19.5 days post FMT for treated patients vs. 41 for control patients). ConclusionFaecal microbiota transplantation is a safe and time-saving procedure to discharge CPE/A-colonised patients from the hospital. A standardised protocol, including 5 days of antibiotic treatment, bowel cleansing and systematic indwelling devices removal, should improve protocol effectiveness.

Fearing the Unknown - The Fate of Inflammatory Bowel Disease After Fecal Microbiota Transplantation for Clostridium difficile Infection

Introduction: Fecal microbiota transplantation (FMT) has been approved to treat severe, refractory and recurrent clostridium difficile infection (CDI). Patients with inflammatory bowel disease (IBD) are at increased risk of CDI. Additionally, a flare up of IBD is clinically similar to CDI. However, data on IBD flares after FMT is limited to case series. We conducted a systematic review of the literature to document the fate of IBD after FMT for CDI. Methods: A comprehensive search encompassing Medline, Embase, Scopus, and Cochrane Library for studies from January 2010 to May 2018 was performed using controlled vocabulary as well as natural language terms for FMT and CDI. Studies reporting the clinical outcome of CDI and IBD after FMT were included. We excluded studies without follow-up data. Results: of the 749 studies initially screened, 10 case series enrolling 445 patients suffering from IBD and underwent FMT treatment for CDI were included (Table 1); 51% were females. Ulcerative colitis was diagnosed in about half of the patients (228; 51%). All patients had failed at least one course of antibiotic therapy for CDI prior to FMT. Of the studies that documented IBD status and immunosuppressive therapy at time of FMT (n = 381 patients), 46% had active IBD that required immunosuppression (Table 2). After single FMT, 319 (71.7%) patients achieved CDI cure (Table 3). The overall clinical remission rate of CDI after FMT was 79% (n = 353). FMT failure, defined as persistent or recurrent CDI was observed in 84 (19%) patients. In regards to the underlying IBD, 21% (93/445) of patients experienced an IBD flare up after FMT. Additionally, 29% (130/445) of patients required escalation in the treatment regimen of IBD, and 3.8% (17) required surgical intervention for the underlying IBD. No serious adverse events attributed to FMT were reported, except for transient hypotension in one patient post FMT. No mortalities related to FMT were reported. Conclusion: FMT is safe and efficacious for eradicating CDI in patients with underlying IBD. However, a significant proportion of patients may suffer from IBD exacerbation or need IBD treatment modification after FMT, underscoring the need for appropriate selection and risk stratification of FMT candidates. The current body of evidence consists of uncontrolled case series, highlighting the need of prospective randomized controlled trials to assess the fate of IBD after FMT for CDI.732_A Figure 1 No Caption available.732_B Figure 2 No Caption available.732_C Figure 3 No Caption available.

Risk Factors for Symptoms of Post-Infectious Irritable Bowel Syndrome Following Fecal Microbiota Transplantation

Introduction: Fecal microbiota transplantation (FMT) by colonoscopy and capsules is effective for recurrent Clostridium difficile infection (CDI), regardless of donor source. Many patients report altered bowel habits and abdominal symptoms post-FMT despite CDI resolution. However, it is uncertain if functional illness post-FMT is directly related to FMT or to pre-existing factors. Currently, pre-screening of patients for IBS pre-FMT is not routinely conducted. We aimed to assess the relationship between post-FMT symptoms and (1) FMT delivery modality (2) donor source (patient selected/universal stool bank) and (3) recipient clinical features. Methods: We conducted a prospective cohort study at an academic center of adults with recurrent CDI treated with FMT by (1) colonoscopy with patient selected donor stool (2) colonoscopy from a universal stool bank or (3) capsules from a universal stool bank. In addition to pre-FMT screening for infections and detailed history, patients were evaluated using Rome III criteria and pre-CDI Bristol Stool Scale. Post-FMT assessment occurred at 8-weeks. Clinical cure was defined as absence of diarrhea or a negative CDI test. Clinically cured patients were assessed for gastrointestinal symptoms using modified Rome III criteria and stool consistency was assessed by the Bristol stool scale. Fisher's exact test for binary and student's t-test for continuous variables were performed for statistical analyses. Multivariate logistic regression was performed to identify predictors for post-FMT, postinfectious IBS symptoms. Results: 107 subjects underwent FMT: 42 by colonoscopy with a patient selected donor, 35 by colonoscopy with stool bank donors and 30 by FMT capsules. Among this cohort, 72.2% were female and had a mean age of 61.1+/-18.1 years. Importantly, 22 patients (20%) had pre-existing IBS by Rome III criteria. Fifteen (13.8%) did not achieve CDI cure with a single FMT. Among the clinically cured, 26 (27.9%) had symptoms of post-infectious IBS at 8-week follow-up: 9 with constipation and 17 with loose stools. In addition, 13 patients reported bloating or increased gas. Neither donor stool type nor delivery modality was associated with post-FMT IBS (p=0.39 and p=0.51, respectively). On univariate analyses, risk factors associated with post-FMT IBS included both pre-existing IBS and inflammatory bowel disease (IBD) (p=0.001 and 0.02, respectively) (Table 1). These remained significant in the multivariable model adjusting for age, sex, and FMT donor type (OR 5.9, 95%CI 1.8-19.1, p=0.002 and OR 4.5, 95%CI 1.2-17.9, p=0.03, respectively).Table: Table. Predictors of Post-Infectious IBS post FMTConclusion: Post-infectious IBS is common after CDI and many will experience these symptoms after an FMT; however, the only significant predictive factors were pre-existing IBS and IBD. Thus, all FMT patients should be screened for IBS and IBD at baseline to optimize post FMT expectation.

Identification of donor microbe species that colonize and persist long term in the recipient after fecal transplant for recurrent Clostridium difficile

Fecal microbiota transplantation has been shown to be an effective treatment for patients with recurrent C. difficile colitis. Although fecal microbiota transplantation helps to re-establish a normal gut function in patients, the extent of the repopulation of the recipient microbial community varies. To further understand this variation, it is important to determine the fate of donor microbes in the patients following fecal microbiota transplantation. We have developed a new method that utilizes the unique single nucleotide variants of gut microbes to accurately identify microbes in paired fecal samples from the same individual taken at different times. Using this method, we identified transplant donor microbes in seven recipients 3–6 months after fecal microbiota transplantation; in two of these fecal microbiota transplantation, we were able to identify donor microbes that persist in recipients up to 2 years post-fecal microbiota transplantation. Our study provides new insights into the dynamics of the reconstitution of the gastrointestinal microbe community structure following fecal microbiota transplantation.

Sa1772 - Prevalence of Early Antibiotic Use Post-Fecal Microbiotatransplantation and Corresponding Risk of FMT Failure

Sa1772 - Prevalence of Early Antibiotic Use Post-Fecal Microbiotatransplantation and Corresponding Risk of FMT Failure

P589 Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis

Background: Given the importance of the enteric microbiota in the pathogenesis of the inflammatory bowel diseases, faecal microbiota transplantation (FMT) has been advocated as a potential therapeutic strategy, and has been the recent subject of increasing research. We thus performed a systematic review and meta-analysis to assess the effectiveness and safety of FMT in the treatment of inflammatory bowel diseases. Methods: A systematic review of the literature was conducted up until the end of March 2016 in accordance with PRISMA and Cochrane recommendations. Electronic databases were searched, along with hand searching of major conference proceedings. Studies were excluded if patients had co-infection or if data was pooled across disease subtypes (ulcerative colitis (UC), Crohn's disease (CD), pouchitis) and could not be individually extracted. Clinical remission was established as the primary outcome; clinical response, endoscopic remission and safety were secondary outcomes. Pooled effect sizes and 95% confidence intervals were obtained using the random effects model. Heterogeneity, sensitivity and subgroup analyses were also performed. Results: 5940 records were identified of which 82 articles were reviewed. Thirty eight studies were included (29 in UC [including 3 randomised controlled trials], 11 in CD, 3 in pouchitis) reporting on 371 UC, 73 CD and 22 pouchitis patients. Overall, 37.5% (139/371) of UC patients, 49.5% (36/73) of CD patients and 18% (4/22) of pouchitis patients achieved clinical remission during follow-up. Among the cohort studies, the pooled proportion of patients that achieved clinical remission was 33% (95% CI 24%– 44%) for UC with a moderate risk of heterogeneity (Cochran's Q, p=0.121; I2 =31%) and 53% (95% CI 30%– 75%) for CD with a moderate risk of heterogeneity (Cochran's Q, p=0.081; I2 =49%). For the 3 RCTs of FMT in UC, there was borderline benefit in clinical remission (P-OR =2.37, 95% CI =0.91–6.19, p=0.078) with moderate heterogeneity (Cochran's Q, p=0.168; I2 =44%). The controlled trial and cohort data suggest remission in UC is improved with increased number of FMT infusions and administration via the lower gastrointestinal tract. Most adverse events were transient minor gastrointestinal complaints. Microbiota analysis was performed in 16 studies, with many identifying a shift in recipient microbiota profile towards that of the donor post FMT. Conclusions: There is a need for additional well designed controlled studies of FMT in IBD, especially in CD and pouchitis. FMT appears to be effective in the induction treatment of UC, particularly with increasing number of infusions. Long term durability and safety remain unclear.

All-Cause Hospital Admissions Decreased After Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection

Introduction:Clostridium difficileinfection (CDI) is currently the most frequent health-care acquired infection. It is associated with debilitating diarrhea, sepsis, shock, renal failure, and intestinal perforation and has an initial recurrence rate of 20% rising to 65% with subsequent recurrences. Costs in the US are estimated at 4.8 billion annually. Fecal Microbiota Transplantation (FMT) is used to correct the dysbiosis associated with recurrent CDI (rCDI) and prevent future recurrence. We hypothesized a decrease in hospital admissions after successful FMT for rCDI. Methods: A retrospective chart review was conducted of all recipients of FMT for rCDI at our institution from September 2013 to April 2016 to compare the frequency of CDI-associated hospital admissions in the six months before FMT to frequency six months after FMT. A similar comparison was done for all-cause admissions except CDI. One patient was excluded from analysis due to incomplete preparation for FMT. Results: 105 patients with rCDI underwent FMT with a median age of 69 and 74.7% were female. There were 130 hospitalizations for CDI documented in the six months prior to FMT. In the six months post FMT there were 11 admissions for CDI (mean 1.25 compared to 0.10). The cohort was admitted an additional 34 times in the six months prior to FMT for causes other than CDI which included diabetic ketoacidosis, sepsis, hypokalemia, dementia, hypertension, fall with subdural hematoma, altered mental status, alcohol withdrawal, and alcoholic ketoacidosis. In the six months after FMT there 27 admissions for causes other than CDI including feeding tube malfunction, sepsis, pneumonia, diabetes, altered mental status, urosepsis, urinary tract infection, dehydration, fall, subdural hematoma, epilepsy, lactic acidosis, cocaine abuse, and gastroparesis. The mean hospitalization rate decreased from 0.33 to 0.26. Conclusion: This retrospective study suggests that the number of hospital admissions for CDI may be dramatically reduced by FMT for rCDI in the six months post FMT. Our results also revealed a decreased number of admissions post FMT for other comorbidities, thus suggesting that FMT improves the overall health the overall health of patients with rCDI. Our results call for a multicenter study of 30-day and 6-month hospital admission rates pre- and post-FMT for rCDI as there may be a role for early intervention with FMT to decrease the deleterious effect of rCDI on all-cause illnesses.

Post-Fecal Microbiota Transplantation (FMT) Constipation and Abdominal Distention Due to Methane-Predominant Bacterial Overgrowth Contracted from the Donor

FMT is becoming increasingly used in patients with severe, recurrent and/or relapsing Clostridium difficile infections (CDI). Despite durable benefits associated complications are poorly defined. Up to 10% of patients develop bloating and constipation after FMT (Lee CH 2014); however, causality is not established as most patients undergoing FMT are ill and suffer from significant gastrointestinal (GI) symptoms. Excessive methane production (>10 ppm) is present in up to 25% of the general population and can lead to constipation and bloating. (Chang 2015) Here we report a 21 year-old female with history of recurrent sinusitis due to IgA deficiency requiring multiple courses of antibiotics and no prior GI-related complaints. She contracted CDI in Jan 2014, which persisted despite treatment with vancomycin and metronidazole. In July 2014, she underwent FMT via colonoscopy from her stepbrother. Despite eradication of CDI, she developed significant post-prandial bloating, distention, fatigue and constipation without rectal bleeding or constitutional symptoms. Her physical exam was without focal abnormalities. Laboratory evaluation showed normal IgG and IgM levels, but undetectable IgA and IgE titres. ANA was slightly elevated at 1:80, however CRP, anti-CCP, anti-tTG, C3, C4, LFTs, lipase CBC, and electrolytes were normal. Anti-vinculin and anti-CdtB antibodies were negative, as were stool for C. difficile, elastase, calprotectin and O&P. EGD and ileocolonoscopy were normal with normal gastric and duodenal biopsies. Capsule endoscopy and CT of the abdomen were normal. Antidepressants, low FODMAPs diet, peppermint, over-the-counter laxatives, linaclotide, lubiprostone and prucalopride proved to be minimally effective. Breath testing performed in Oct 2014 showed normal hydrogen levels, but significantly elevated methane peaking at 51 ppm (Figure 1). On further testing, FMT donor was also found to be an excessive methane producer, with a methane level of 35 ppm. The patient was treated with 14 days of rifaximin 550 mg TID and neomycin 500 mg BID leading to eradication of excessive methane production to 0 ppm and resolution of her GI symptoms. CDI has not recurred as of June 2016. This is the first report of methane-predominant bacterial overgrowth contracted from the FMT donor as a potential cause of post-FMT IBS-like symptoms such as bloating and constipation. Screening of FMT donors for excessive methane production may prevent such complications.Figure 1

Treatment of First-Time Clostridium difficile Infection With Fecal Microbiota Transplantation

Introduction:Clostridium difficile infection (CDI) is treated with Fecal Microbiota Transplantation (FMT) after two failed treatments with antibiotics, e.g. vancomycin(V) or metronidazole(M). To date, however, there have been no reports of FMT in CDI as a first line treatment. Success rate of FMT in relapsing CDI is close to 90%. Given CDI often follows antibiotic use which may result in depleted bacterial classes; it is irrational to use further antibiotics then await relapse to access FMT. It makes sense to treat with FMT to eradicate CDI and replace missing flora components simultaneously. Hence, we offered FMT to patients with initial diagnosis of CDI. To maintain uniform approach we used pre-FMT antibiotics. No patients with inflammatory bowel disease were included in this study. Methods: Consecutive patients were recruited with toxin-positive CDI (toxin assay or PCR) upon stool test analysis for transcolonoscopic FMT as an initial infusion, followed next day by rectal enema. Patients reported general irritable bowel syndrome (IBS) symptoms including; bloating, abdominal pain, excessive flatulence and nausea. Symptom data was recorded at initial presentation on a scale of mild, moderate or severe. Symptom data recorded again at 8/52 and 6/12 post FMT. For pre-treatment 15 had V 500mg BD, 6 had V 500mg BD + Rifaximin(R) 1000mg BD, 4 had V 500mg BD + M 200mg BD, 2 had V 250mg mane 500 nocte, 1 had 500mg R daily and the final patient had no pre-treatment (consultant driven choice). Stool cultures and toxin assays were repeated after 4 weeks. Patients were seen in clinic approximately 8 weeks after FMT as part of standard-of-care follow-up. Treatment success defined as negative stool culture and toxin assay. Results: All 29 patients recruited and treated achieved eradication of CDI. 26% reported transient bloating and flatulence immediately after FMT. 34% reported a decline in bowel motions from an average of 5.9 BM to 1.6 BM per day. 17% of patients reported constipation initially. Globally initial symptoms lessened in severity with 55%. Hence the majority of these patients had co-existing (IBS) for many months or years and most continued to have some components of their IBS after their FMT-eradication of CDI. Conclusion: - In these patients with initial diagnosis of CDI, FMT was a safe and 100% effective treatment of CDI. - Transient adverse effects of bloating / flatulence were noted. - Accompanying IBS can persist after CDI cure in this cohort albeit moderate improvement occurs in some.

Fecal Microbiota Transplant for Treatment of Clostridium difficile Infection in Immunocompromised Patients

Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients. A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT. Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3-46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT. This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.

Fecal microbiome transplantation for recurrent Clostridium difficile infection: Report on a case series

BackgroundClostridium difficile infection (CDI) continues to increase in incidence and severity, and was the most common nosocomial infection in the USA in 2010. Most cases of CDI respond to a standard course of antibiotics, but recurrent C. difficile infection (RCDI) has become increasingly frequent, and alternative treatments are needed. We examined the efficacy of fecal microbiota transplantation (FMT) instilled into the upper gastrointestinal tract for RCDI. Materials and methodsThe medical records for all patients treated with FMT during a 9-year period at a single institution in northern Minnesota were reviewed retrospectively. Eighty-nine FMT courses were provided by nasogastric tube to 87 patients, and demographic and clinical data were abstracted, including details of treatments prior to FMT, rate of FMT treatment success and clinical course during a 60-day post FMT follow up period. Fourteen FMT courses failed to meet criteria for inclusion. ResultsEach patient served as his or her own control, having failed standard treatment. After exclusions, the case series included 75 FMT courses administered to 74 patients. Fifty-nine FMT courses resulted in clinical resolution of diarrhea for a primary cure rate of 79%. Diarrhea relapsed following 16 FMT courses; in 9 of these cases diarrhea subsequently resolved after a single course of vancomycin. No adverse events were noted. ConclusionsOur findings parallel findings from other studies when FMT has been provided via the upper GI tract, and suggest that patients with recurrent CDI may resolve diarrhea by introducing stool from healthy donors into the upper GI tract via nasogastric tube.

Persistent Clostridium difficile Infection in a Patient with Decompensated Liver Disease: “Double Transplant” Saves a Life!

Background: Over the past several years, Clostridium difficile Infection (CDI) has become more frequent and virulent. Patients hospitalized with severe liver disease are at increased risk for CDI. Persistent or recurrent CDI poses a dual threat in the pre-transplant setting- continued CDI leads to further morbidity and perhaps death. Importantly, the presence of any active infection precludes consideration for a potentially life saving liver transplant. Case Report: We report a 39-year-old white male with chronic hepatitis C infection and decompensated cirrhosis with a MELD score of 19- who developed diarrhea and abdominal pain. Stool tested positive for C. difficile toxin. Despite treatment with oral Vancomycin, Rifaximin and Saccharomyces boulardii, he continued to have frequent watery stools and was positive for C. diff toxin on repeat stool examination. He developed increasing jaundice and MELD score increased to 28, but because of his ongoing C. diff. infection he had to be made inactive on the liver transplant list. Because of the high risk of death and the ongoing CDI, a decision was made to perform fecal microbiota transplantation (FMT). His wife consented to be the “donor” and after appropriate fecal and serological testing, the patient underwent polyethylene glycol (PEG) bowel preparation and the following morning had FMT performed via colonoscopy. Colonoscopy revealed mild inflammatory changes, without psudomembranes. Over the next several days, diarrhea resolved and stool for C. diff toxin A&B was negative on day seven post FMT. Diarrhea did not recur, he was re-activated on the transplant list, and underwent successful deceased donor liver transplant six weeks later. He remains well, active as a truck driver, over one year post transplants. Conclusions: FMT should be considered if persistent or recurrent CDI occurs in patients with decompensated liver disease awaiting liver transplantation. FMT is effective (90% cure rate for colonoscopic FMT in most series). Response to FMT is typically rapid, unlike alternative treatment such as pulse-tapered vancomycin. This rapidity of response can be lifesaving, as active CDI precludes liver transplantation.