Specific Bacteria and Metabolites Associated With Response to Fecal Microbiota Transplantation in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) can induce remission in patients with ulcerative colitis (UC). In a randomized controlled trial of FMT in patients with active UC, we aimed to identify bacterial taxonomic and functional factors associated with response to therapy. METHODS: We performed a double-blind trial of 81 patients with active UC randomly assigned to groups that received an initial colonoscopic infusion and then intensive multidonor FMT or placebo enemas, 5 d/wk for 8 weeks. Patients in the FMT group received blended homogenized stool from 3-7 unrelated donors. Patients in the placebo group were eligible to receive open-label FMT after the double-blind study period. We collected 314 fecal samples from the patients at screening, every 4 weeks during treatment, and 8 weeks after the blinded or open-label FMT therapy. We also collected 160 large-bowel biopsy samples from the patients at study entry, at completion of 8 weeks of blinded therapy, and at the end of open-label FMT, if applicable. We analyzed 105 fecal samples from the 14 individual donors (n = 55), who in turn contributed to 21 multidonor batches (n = 50). Bacteria in colonic and fecal samples were analyzed by both 16S ribosomal RNA gene and transcript amplicon sequencing; 285 fecal samples were analyzed by shotgun metagenomics, and 60 fecal samples were analyzed for metabolome features. RESULTS: FMT increased microbial diversity and altered composition, based on analyses of colon and fecal samples collected before vs after FMT. Diversity was greater in fecal and colon samples collected before and after FMT treatment from patients who achieved remission compared with patients who did not. Patients in remission after FMT had enrichment of Eubacterium hallii and Roseburia inulivorans compared with patients who did not achieve remission after FMT and had increased levels of short-chain fatty acid biosynthesis and secondary bile acids. Patients who did not achieve remission had enrichment of Fusobacterium gonidiaformans, Sutterella wadsworthensis, and Escherichia species and increased levels of heme and lipopolysaccharide biosynthesis. Bacteroides in donor stool were associated with remission in patients receiving FMT, and Streptococcus species in donor stool was associated with no response to FMT. CONCLUSIONS: In an analysis of fecal and colonic mucosa samples from patients receiving FMT for active UC and stool samples from donors, we associated specific bacteria and metabolic pathways with induction of remission. These findings may be of value in the design of microbe-based therapies for UC. ClinicalTrials.gov, Number NCT01896635.

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.

The gut microbiota: cause and cure of gut diseases.

The gastrointestinal microbiota is emerging as a central factor in the pathogenesis of a range of gastrointestinal and hepatic disorders. Epidemiological studies, and experimental studies in animals and humans, have highlighted a likely causative role of this microbial community in the modern global epidemics of inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steato-hepatitis, obesity and metabolic syndrome. New techniques for microbial culture and gene sequencing are enabling the identification of specific pathogens and protective organisms in these conditions. Factors that change the microbiota are being defined: dietary pattern, specific foods, food additives in processed food and drinks, such as emulsifiers and non-sugar sweeteners, and antibiotics. Microbiota changes in early life appear critical to the later development of a range of inflammatory disorders. For many of these conditions, the treatment paradigm will change, at least in part, from immune suppression and drug therapy to treatments that reshape the microbiota or restore its integrity. These treatments include dietary changes, specific microbial manipulation and faecal microbiota transplantation. A dialogue is needed regarding population strategies that target disease prevention. This will include how food is produced, what additives it contains, and how it is processed. Widespread use of antibiotics, from agricultural and veterinary to medicinal settings, needs more attention. At the individual level, microbial profiles may be able to predict who is at risk of disease when subjected to particular environmental influences, and what microbial restoration is needed to minimise risk.

Gastroenterologist perceptions of faecal microbiota transplantation.

AIM: To explore gastroenterologist perceptions towards and experience with faecal microbiota transplantation (FMT). METHODS: A questionnaire survey consisting of 17 questions was created to assess gastroenterologists' attitude towards and experience with FMT. This was anonymously distributed in hard copy format amongst attendees at gastroenterology meetings in Australia between October 2013 and April 2014. Basic descriptive statistical analyses were performed. RESULTS: Fifty-two clinicians participated. Twenty one percent had previously referred patients for FMT, 8% more than once. Ninety percent would refer patients with Clostridium difficile infection (CDI) for FMT if easily available, 37% for ulcerative colitis, 13% for Crohn's disease and 6% for irritable bowel syndrome. Six percent would not refer any indication, including recurrent CDI. Eighty-six percent would enroll patients in FMT clinical trials. Thirty-seven percent considered the optimal mode of FMT administration transcolonoscopic, 17% nasoduodenal, 13% enema and 8% oral capsule. The greatest concerns regarding FMT were: 42% lack of evidence, 12% infection risk, 10% non infectious adverse effects/lack of safety data, 10% aesthetic, 10% lack of efficacy, 4% disease exacerbation, and 2% inappropriate use; 6% had no concerns. Seventy seven percent believed there is a lack of accessibility while 52% had an interest in learning how to provide FMT. Only 6% offered FMT at their institution. CONCLUSION: Despite general enthusiasm, most gastroenterologists have limited experience with, or access to, FMT. The greatest concerns were lack of supportive evidence and safety issues. However a significant proportion would refer indications other than CDI for FMT despite insufficient evidence. These data provide guidance on where education and training are required.

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.

Translational research and efficacy of biologics in Crohn's disease: a cautionary tale.

In the last several years many biologic agents for Crohn's disease have been developed. Due to their unique molecular specificity biologics are de facto indicators of the ultimate significance of the molecule targeted by the biologic itself. Here, we have reviewed many clinical studies that have used biologics for Crohn's disease. Their results show that despite potentially sound theoretical mechanisms of action and some initially promising data, most biologics - with few notable exceptions - have failed. Pharmacologic, study design or patient-related issues might explain these findings in some studies. However in many cases clinical failure of biologics might highlight the complexity of in vivo events and the potential deficiencies of current experimental settings. Hence, these observations call for new and efficient ways of predicting drug efficacy in clinical trials based on bench research. Conceivably, computer-based pathogenetic models could be used to simulate and predict clinical studies results in vivo.

Surgery for Crohn's disease and anti-TNF agents: the changing scenario.

Surgery has been a mainstay of therapy for Crohn's disease for a long time, essentially as a consequence of the fairly modest efficacy of traditional medications such as immunomodulators, antibiotics and 5-ASA, especially in severe cases. However, in the past decade and half, the advent of anti-TNF agents has greatly changed the medical approach to this disease and may modify its general management as well. Here, we have reviewed the current literature on incidence of surgery, timing of surgery and postoperative recurrence of Crohn's disease before and after the advent of anti-TNF agents. In addition, we have reviewed the risk of perioperative complications in patients on anti-TNF agents before surgery. The data show that the use of these medications is changing or expecting to change shortly a number of surgical aspects of Crohn's disease management.