The Current Landscape and Lessons from Fecal Microbiota Transplantation for Inflammatory Bowel Disease

Allegretti, Jessica R.; Eysenbach, Lindsay; El-Nachef, Najwa; Fischer, Monika; Kelly, Colleen R.; Kassam, Zain

doi:10.1097/mib.0000000000001247

Cited by 40 publications

(31 citation statements)

References 36 publications

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“…A number of studies, including randomized controlled trials, 4-6 systematic reviews, and meta-analyses, [7][8][9] suggest that FMT is effective in the treatment of patients with active UC. FMT appears to be more effective than other methods of microbial manipulation, including antibiotics, probiotics, and prebiotics.…”

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confidence: 99%

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

et al. 2019

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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 ¼ 55), who in turn contributed to 21 multidonor batches (n ¼ 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. Gastroenterology 2019;156:1440-1454 BASIC AND TRANSLATIONAL ATBacteroides 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

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

et al. 2019

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“…A significant number of patients, who are in need of recurrent antibiotic therapy to control their pouchitis symptoms, develop antibiotic-dependent pouchitis (ADP). Fecal microbiota transplantation (FMT) is an established therapeutic option for patients with recurrent Clostridioides difficile infection, and is also a promising therapeutic modality for patients with active UC with the aim of re-establishing the homeostasis of the intestinal microbiome [5, 6]. Microbial dysbiosis, which can only be controlled with antibiotics, is thought to be a major driver of clinical symptoms in patients with ADP [7].…”

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confidence: 99%

Combined Endoscopic and Oral Fecal Microbiota Transplantation in Patients with Antibiotic-Dependent Pouchitis: Low Clinical Efficacy due to Low Donor Microbial Engraftment

et al. 2019

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Background and Objective: A significant number of pouch patients develop antibiotic-dependent pouchitis (ADP). Microbial dysbiosis is thought to be a major driver of clinical symptoms in ADP. The objective of this proof of concept study was to evaluate safety, efficacy, and donor microbial engraftment of an intensified fecal microbiota transplant (FMT) consisting of a single endoscopic FMT followed by daily oral FMT for 2 weeks in patients with ADP. Methods: We performed a prospective placebo-controlled double-blind FMT trial in patents with established ADP and planned to enroll 20 patients in this proof of concept study. In case of non-response, patients were offered an optional open label active FMT treatment. The endpoints were safety, clinical remission without need for antibiotics during 16 weeks of follow-up, quantitative changes of fecal calprotectin (FCP), and engraftment of donor FMT as determined by metagenomic sequencing of the V4 region of the 16S rRNA gene. Results: Due to a lower than expected clinical remission rate and low FMT engraftment, enrollment in the study was stopped prematurely after 6 patients were included. All 6 patients enrolled in the placebo-controlled portion failed to respond and needed antibiotic rescue therapy shortly after FMT. FCP increased in the majority of patients in the setting of relapse after FMT. In the active open label FMT extension study 1 out of 5 patients achieved antibiotic-free clinical remission. FMT engraftment after active FMT was observed only in this single patient, whereas engraftment of donor FMT occurred in none of the other patients receiving active FMT, paralleling the lack of clinical response. Conclusions: Low donor FMT engraftment resulted in low clinical efficacy of FMT in patients with ADP. Before embarking on larger clinical trials with FMT in patients with ADP or other forms of pouchitis, it is mandatory to explore approaches for superior FMT engraftment.

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“…Nevertheless, thinking about FMT this way obscures the potential challenge of donor stool heterogeneity when treating more complex diseases. 2,5 For complex diseases, 'superstool' might be rare, if it exists at all, and it might not be as remarkably effective as FMT is for CDI. For example, in a trial in 2015 using FMT to treat IBD, 6 stool donors were used.…”

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“…Consideration of all FMT as a single, monolithic 'drug' will hide any heterogeneity and could substantially impair clinical trials. 2,5,7 Instead, FMT must be approached as a fundamentally different therapeutic modality in which each donor produces a unique drug and each condition might respond differently to each drug (Figure 1). Consider a dating analogy in which everyone in your pool of potential dates passes a background check, and then you randomly go on dates from that pool.…”

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“…To generate more sophisticated hypotheses that can move us away from whole stool FMT and toward defined, specialized and specific therapeutics, we need to aggregate information across donors and clinical trials. 2 To minimize the potential pitfalls of FMT research and leverage its unique ability to answer clinical, translational and even basic scientific questions, we make three recommendations. First, researchers should use adaptive trials to overcome the challenge of donor stool heterogeneity and deliver the best possible therapy in the treatment arm, beginning the search for 'superstool'.…”

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Searching for superstool: maximizing the therapeutic potential of FMT

Olesen

Leier

Alm

et al. 2018

Nat Rev Gastroenterol Hepatol

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The Current Landscape and Lessons from Fecal Microbiota Transplantation for Inflammatory Bowel Disease

Cited by 40 publications

References 36 publications

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

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

Combined Endoscopic and Oral Fecal Microbiota Transplantation in Patients with Antibiotic-Dependent Pouchitis: Low Clinical Efficacy due to Low Donor Microbial Engraftment

Searching for superstool: maximizing the therapeutic potential of FMT

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