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Fecal microbiota transplantation (FMT) is highly effective in recurrent Clostridioides difficile infection (CDI), increasing evidence supports FMT in severe or fulminant Clostridioides difficile infection (SFCDI). However, the multifactorial mechanisms that underpin the efficacy of FMT are not fully understood. Systems biology approaches using high-throughput technologies may help with mechanistic dissection of host-microbial interactions. Here, we have undertaken a deep phenomics study on four adults receiving sequential FMT for SFCDI, in which we performed a longitudinal, integrative analysis of multiple host factors and intestinal microbiome changes. Stool samples were profiled for changes in gut microbiota and metabolites and blood samples for alterations in targeted epigenomic, metabonomic, glycomic, immune proteomic, immunophenotyping, immune functional assays, and T-cell receptor (TCR) repertoires, respectively. We characterised temporal trajectories in gut microbial and host immunometabolic data sets in three responders and one non-responder to sequential FMT. A total of 562 features were used for analysis, of which 78 features were identified, which differed between the responders and the non-responder. The observed dynamic phenotypic changes may potentially suggest immunosenescent signals in the non-responder and may help to underpin the mechanisms accompanying successful FMT, although our study is limited by a small sample size and significant heterogeneity in patient baseline characteristics. Our multi-omics integrative longitudinal analytical approach extends the knowledge regarding mechanisms of efficacy of FMT and highlights preliminary novel signatures, which should be validated in larger studies.

Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridioides difficile infection. Stool donors are essential, but difficult to recruit and retain. We aimed to identify factors influencing willingness to donate stool. This multi-center study with a 32-item questionnaire targeted young adults and health care workers via social media and university email lists in Edmonton and Kingston, Canada; London and Nottingham, England; and Indianapolis and Boston, USA. Items included baseline demographics and FMT knowledge and perception. Investigated motivators and deterrents included economic compensation, screening process, time commitment, and stool donation logistics. Logistic regression and linear regression models estimated associations of study variables with self-assessed willingness to donate stool. 802 respondents completed our questionnaire: 387 (48.3%) age 21-30 years, 573 (71.4%) female, 323 (40%) health care workers. Country of residence, age and occupation were not associated with willingness to donate stool. Factors increasing willingness to donate were: already a blood donor (OR 1.64), male, altruism, economic benefit, knowledge of how FMT can help patients (OR 1.32), and positive attitudes towards FMT (OR 1.39). Factors decreasing willingness to donate were: stool collection unpleasant (OR 0.92), screening process invasive (OR 0.92), higher stool donation frequency, negative social perception of stool, and logistics of collection/transporting feces. We conclude that 1) blood donors and males are more willing to consider stool donation; 2) altruism, economic compensation, and positive feedback are motivators; and 3) screening process, high donation frequency, logistics of collection/transporting feces, lack of public awareness, and negative social perception are deterrents. Considering these variables could maximize donor recruitment and retention.

Background and aims The molecular mechanisms underlying successful fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (rCDI) remain poorly understood. The primary objective of this study was to characterize alterations in microRNAs (miRs) following FMT for rCDI. Methods Sera from 2 prospective multicenter randomized controlled trials were analyzed for miRNA levels with the use of the Nanostring nCounter platform and quantitative reverse-transcription (RT) polymerase chain reaction (PCR). In addition, rCDI-FMT and toxin-treated animals and ex vivo human colonoids were used to compare intestinal tissue and circulating miRs. miR inflammatory gene targets in colonic epithelial and peripheral blood mononuclear cells were evaluated by quantitative PCR (qPCR) and 3′UTR reporter assays. Colonic epithelial cells were used for mechanistic, cytoskeleton, cell growth, and apoptosis studies. Results miRNA profiling revealed up-regulation of 64 circulating miRs 4 and 12 weeks after FMT compared with screening, of which the top 6 were validated in the discovery cohort by means of RT-qPCR. In a murine model of relapsing-CDI, RT-qPCR analyses of sera and cecal RNA extracts demonstrated suppression of these miRs, an effect reversed by FMT. In mouse colon and human colonoids, C difficile toxin B (TcdB) mediated the suppressive effects of CDI on miRs. CDI dysregulated DROSHA, an effect reversed by FMT. Correlation analyses, qPCR ,and 3′UTR reporter assays revealed that miR-23a, miR-150, miR-26b, and miR-28 target directly the 3′UTRs of IL12B, IL18, FGF21, and TNFRSF9, respectively. miR-23a and miR-150 demonstrated cytoprotective effects against TcdB. Conclusions These results provide novel and provocative evidence that modulation of the gut microbiome via FMT induces alterations in circulating and intestinal tissue miRs. These findings contribute to a greater understanding of the molecular mechanisms underlying FMT and identify new potential targets for therapeutic intervention in rCDI.

Background Severe and fulminant Clostridioides Difficile infection(CDI) is associated with increased mortality and morbidity. Current guidelines recommend high dose vancomycin with metronidazole for treatment. Surgery is a high risk for patients failing medical therapy partly due to multiple comorbidities. Emerging evidence suggests efficacy of sequential fecal microbiota transplantation(FMT) by colonoscopy combined with vancomycin in patients failing maximal medical therapy. Fidaxomicin is non-inferior to vancomycin in treating CDI; however, it has not been studied in severe/fulminant cases. It is not known if FMT by enema combined with fidaxomicin is efficacious and safe in this patient population. Aims This single center, prospective, open-label pilot study aimed to determine the efficacy and safety of combined sequential FMT by enema plus fidaxomicin in severe or fulminant CDI not responding to maximal medical therapy. Primary outcome was resolution of diarrhea 2 weeks following final FMT. Secondary outcomes were resolution of diarrhea 8 weeks following final FMT, safety of proposed treatment protocol and colectomy rate. Methods Consecutive patients with severe or fulminant CDI, who fulfilled study inclusion criteria were recruited. Sequential cycles of FMT, administered by enema daily over three days(720cc followed by 360cc and 180cc), plus fidaxomicin 200mg PO BID were given. Clinical symptoms and inflammatory markers were monitored during the study and subsequent cycles of FMT were administered when clinical or biochemical improvement plateaued. A final FMT was administered with CDI resolution. Results A total of three patients were enrolled between Jan 22 to Aug 8, 2019, shown in Table 1. One patient had fulminant CDI due to shock, and the others had severe CDI. All had severe pseudomembranous colitis seen on endoscopy at enrollment. Two of three patients reached both primary and secondary outcomes with 2 FMT cycles. The only patient who did not reach the primary was successfully managed with long term vancomycin suppression. This patient had failed multiple FMTs prior to enrollment. There were no adverse events noted and no colectomy was required during this study. Conclusions This pilot study is the first to demonstrate efficacy and safety of combined sequential FMT by enema and fidaxomicin in treating severe or fulminant CDI patients. An adequately powered study is required to validate these findings. Funding Agencies CIHRAlberta Health Services, University of Alberta Hospital Foundation

BACKGROUND: FMT is highly effective in the treatment of RCDI. Delivery of FMT by upper route and lower routes has been utilized, achieving cure rate of at least 80%. However, the ideal route of delivering FMT has not been determined. AIMS: To compare 1) the cure rate of RCDI; 2) safety; 3) patient satisfaction, preference and changes in quality of life between capsule vs colonoscopy delivered FMT. METHODS: Adult patients who had at least 3 documented episodes of CDI were randomized to FMT administered by either capsule or colonoscopy at 1:1 ratio. Key exclusion criteria included severe and complicated CDI; inflammatory bowel disease (IBD), unless stable symptoms for ≥ 3 months; dysphagia. Seven volunteer stool donors provided stool for FMT. RESULTS: 116 patients (57 in capsule and 59 in colonoscopy arm) were randomized between Oct 2014 - Aug 2016 in Edmonton and Calgary. Participant baseline characteristics were shown in Table 1. The cure rate of RCDI was 96.2% in the capsule arm and 95.9% in the colonoscopy arm after a single FMT (non-inferiority p value 0.5). The proportion of patients rating treatment “not at all unpleasant” was higher in the capsule arm (67%; 95% CI:56–78%) than the colonoscopy arm (44%; 95% CI: 31–59%). CONCLUSIONS: FMT administered by capsules was as efficacious as colonoscopy. No serious AE attributable to FMT was identified with either delivery modality. Fewer minor AEs were seen with capsule. Both FMT delivery methods improved quality of life, but fewer patients found capsule to be an unpleasant treatment modality. FUNDING AGENCIES: Alberta Health Services

BACKGROUND: Fecal microbial transplantation (FMT) has been shown to be a highly effective therapy for rCDI. Success rate is > 90%. A recent study using sterile fecal filtrate successfully prevented CDI recurrence in 5 patients, suggesting live microbes may not be required for efficacy. AIMS: To determine whether live microbes are necesary for the clinical efficacy of FMT by comparing treatment outomces in rCDI patients receiving either lyophilized sterile fecal filtrate (LSFF) or lyophilized FMT (LFMT). Primary outcome: proportion of patients in each group with no CDI recurrence at week 8. Secondary outcomes: mortality rate and infections directly attributable to CDI or treatment at week 8. METHODS: In this single center pilot study, eligible participants with rCDI were randomized to LSFF or LFMT at 1:1. Inclusion criteria: age >18 years; diagnosis of at least 3 episodes of RCDI, each episode defined by presence of diarrhea (≥3 unformed stools/24 h), positive for C. difficile toxin, episodes occurring within 2 months of each other after finishing anti-CDI therapy, and recurring diarrhea after symptom resolution following at least 10 d of anti-CDI therapy; CDI infection under symptomatic control with

Importance Fecal microbiota transplantation (FMT) is effective in preventing recurrentClostridium difficileinfection (RCDI). However, it is not known whether clinical efficacy differs by route of delivery. Objective To determine whether FMT by oral capsule is noninferior to colonoscopy delivery in efficacy. Design, Setting, and Participants Noninferiority, unblinded, randomized trial conducted in 3 academic centers in Alberta, Canada. A total of 116 adult patients with RCDI were enrolled between October 2014 and September 2016, with follow-up to December 2016. The noninferiority margin was 15%. Interventions Participants were randomly assigned to FMT by capsule or by colonoscopy at a 1:1 ratio. Main Outcomes and Measures The primary outcome was the proportion of patients without RCDI 12 weeks after FMT. Secondary outcomes included (1) serious and minor adverse events, (2) changes in quality of life by the 36-Item Short Form Survey on a scale of 0 (worst possible quality of life) to 100 (best quality of life), and (3) patient perception on a scale of 1 (not at all unpleasant) to 10 (extremely unpleasant) and satisfaction on a scale of 1 (best) to 10 (worst). Results Among 116 patients randomized (mean [SD] age, 58 [19] years; 79 women [68%]), 105 (91%) completed the trial, with 57 patients randomized to the capsule group and 59 to the colonoscopy group. In per-protocol analysis, prevention of RCDI after a single treatment was achieved in 96.2% in both the capsule group (51/53) and the colonoscopy group (50/52) (difference, 0%; 1-sided 95% CI, −6.1% to infinity;P Conclusions and Relevance Among adults with RCDI, FMT via oral capsules was not inferior to delivery by colonoscopy for preventing recurrent infection over 12 weeks. Treatment with oral capsules may be an effective approach to treating RCDI. Trial Registration clinicaltrials.gov Identifier:NCT02254811

N-glycosylation is a common and yet complex posttranslational process that covalently links glycans (complex oligosaccharides) to proteins and lipids, affecting cellular structure and function. Glycans have important biological functions in protein maturation and turnover, cell adhesion and trafficking, and receptor binding and activation. 1 In the immune system, glycosylation also modulates the function of immunoglobulin G (IgG).