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Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation.

ABSTRACT: BACKGROUND: Clostridium difficile is an opportunistic human intestinal pathogen, and C. difficile infection (CDI) is one of the main causes of antibiotic-induced diarrhea and colitis. One successful approach to combat CDI, particularly recurrent form of CDI, is through transplantation of fecal microbiota from a healthy donor to the infected patient. In this study we investigated the distal gut microbial communities of three CDI patients before and after fecal microbiota transplantation, and we compared these communities to the composition of the donor's fecal microbiota. We utilized phylogenetic Microbiota Array, high-throughput Illumina sequencing, and fluorescent in situ hybridization to profile microbiota composition down to the genus and species level resolution. RESULTS: The original patients' microbiota had low diversity, was dominated by members of Gammaproteobacteria and Bacilli, and had low numbers of Clostridia and Bacteroidia. At the genus level, fecal samples of CDI patients were rich in members of the Lactobacillus, Streptococcus, and Enterobacter genera. In comparison, the donor community was dominated by Clostridia and had significantly higher diversity and evenness. The patients' distal gut communities were completely transformed within 3 days following fecal transplantation, and these communities remained stable in each patient for at least 4 months. Despite compositional differences among recipients' pre-treatment gut microbiota, the transplanted gut communities were highly similar among recipients post-transplantation, were indistinguishable from that of the donor, and were rich in members of Blautia, Coprococcus, and Faecalibacterium. In each case, the gut microbiota restoration led to a complete patient recovery and symptom alleviation. CONCLUSION: We conclude that C. difficile infection can be successfully treated by fecal microbiota transplantation and that this leads to stable transformation of the distal gut microbial community from the one abundant in aerotolerant species to that dominated by members of the Clostridia.

SUBMITTER: Shankar V

PROVIDER: S-EPMC4030581 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation.

Shankar Vijay V Hamilton Matthew J MJ Khoruts Alexander A Kilburn Amanda A Unno Tatsuya T Paliy Oleg O Sadowsky Michael J MJ

Microbiome 20140421

<h4>Background</h4>Clostridium difficile is an opportunistic human intestinal pathogen, and C. difficile infection (CDI) is one of the main causes of antibiotic-induced diarrhea and colitis. One successful approach to combat CDI, particularly recurrent form of CDI, is through transplantation of fecal microbiota from a healthy donor to the infected patient. In this study we investigated the distal gut microbial communities of three CDI patients before and after fecal microbiota transplantation, a ...[more]

PMID: 24855561

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Project description:BackgroundFecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (rCDI). The use of freeze-dried, encapsulated donor material for FMT (cap-FMT) allows for an easy route of administration and remains clinically effective in the majority of rCDI patients. We hypothesized that specific shifts in the microbiota in response to cap-FMT could predict clinical outcome. We further evaluated the degree of donor microbiota engraftment to determine the extent that donor transfer contributed to recovery.ResultsIn total, 89 patients were treated with 100 separate cap-FMTs, with a success rate (no rCDI 60 days post cap-FMT) of 80%. Among responders, the lower alpha diversity (ANOVA P < 0.05) observed among patient's pre-FMT samples was restored following cap-FMT. At 1 week post-FMT, community composition varied by clinical outcome (ANOSIM P < 0.001), with similar abundances among families (Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae) in responder and donor samples. Families that showed differential abundances by outcome (response vs. recurrence) from samples collected 7 days following cap-FMT were used to construct a regression tree-based model to predict recurrence. Results showed a training accuracy of 100% to predict recurrence and the model was 97% accurate against a test data set of samples collected 8-20 days following cap-FMT. Evaluation of the extent of engraftment using the Bayesian algorithm SourceTracker revealed that approximately 50% of the post-FMT communities of responders were attributable to donor microbiota, while an additional 20-30% of the communities were similar to a composite healthy microbiota consisting of all donor samples.ConclusionsRegression tree-based analyses of microbial communities identified taxa significantly related to clinical response after 7 days, which can be targeted to improve microbial therapeutics. Furthermore, reinstatement of a healthy assemblage following cap-FMT was only partially attributable to explicit donor engraftment and continued to develop towards an overall healthy assemblage, independent of donor.

Project description:Bacterial communities from subjects treated for recurrent Clostridium difficile infection (rCDI) by fecal microbiota transplantation (FMT), using either heterologous donor stool samples or autologous stool samples, were characterized by Illumina next-generation sequencing. As previously reported, the success of heterologous FMT (90%) was superior to that of autologous FMT (43%) (P = 0.019), and post-FMT intestinal bacterial communities differed significantly between treatment arms (P < 0.001). Subjects cured by autologous FMT typically had greater abundances of the Clostridium XIVa clade and Holdemania bacteria prior to treatment, and the relative abundances of these groups increased significantly after FMT compared to heterologous FMT and pre-FMT samples. The typical shift to post-FMT, donor-like assemblages, featuring high relative abundances of genera within the Bacteroidetes and Firmicutes phyla, was not observed in the autologous FMT subjects. Autologous FMT patient bacterial communities were significantly different in composition than those for heterologous FMT patients and donors (P < 0.001). The SourceTracker program, which employs a Bayesian algorithm to determine source contributions to sink communities, showed that patients initially treated by heterologous FMT had significantly higher percentages of engraftment (i.e., similarity to donor communities, mean value of 74%) compared to those who suffered recurrence following autologous FMT (1%) (P ≤ 0.013). The findings of this study suggest that complete donor engraftment may be not necessary if functionally critical taxa are present in subjects following antibiotic therapy. This study provides a detailed characterization of fecal bacterial communities in subjects who participated in a previously published randomized clinical trial to treat recurrent C. difficile infection (rCDI). Bacterial communities were characterized to determine differences between subjects who received fecal bacteria either from healthy donor stool samples or their own stool samples as "placebo" in order to determine which groups of bacteria were most important in achieving a cure. The results of this study suggested that bacteria associated with secondary bile acid metabolism could potentially provide resistance to infection and that complete transfer of healthy donor microorganisms was not necessary to resolve CDI following unsuccessful antibiotic treatment.

Project description:Fecal microbiota transplantation (FMT) has become a common rescue therapy for recurrent Clostridium difficile infection, and encapsulated delivery (cFMT) of healthy donor microbiota shows similar clinical efficacy as more traditional routes of administration. In this study, we characterized long-term patterns of bacterial engraftment in a cohort of 18 patients, who received capsules from one of three donors, up to 409 days post-FMT. Bacterial communities were characterized using Illumina sequencing of the V5-V6 hypervariable regions of the 16S rRNA gene, and engraftment was determined by using the Bayesian algorithm SourceTracker. All patients recovered clinically and were free of C. difficile infection following cFMT. The majority of patients (61%) showed high levels of engraftment after the first week following FMT, which were sustained throughout the year. A small subset, 22%, experienced a decline in donor engraftment after approximately 1 month, and a few patients (17%), two of whom were taking metformin, showed delayed and low levels of donor engraftment. Members of the genera Bacteroides, Parabacteroides, and Faecalibacterium were significantly and positively correlated with donor similarity (ρ = 0.237 to 0.373, P ≤ 0.017). Furthermore, throughout the year, patient fecal communities showed significant separation based on the donor fecal microbiota that they received (P < 0.001). Results of this study, which characterize long-term engraftment following cFMT, suggest that numerical donor similarity is not strictly related to clinical outcome and identify a persistent donor-specific effect on patient fecal microbial communities. Furthermore, results suggest that members of the Bacteroidetes may be important targets to improve engraftment via cFMT.IMPORTANCE Recurrent Clostridium difficile infection (rCDI) is the most common cause of hospital- and community-acquired diarrheal infection associated with antibiotic use. Fecal microbiota transplantation (FMT), a treatment that involves administration of fecal bacteria from a healthy donor to a recipient patient, is a highly effective rescue therapy for rCDI that is increasingly being incorporated into standard clinical practice. Encapsulated, freeze-dried preparations of fecal microbiota, administered orally, offer the simplest and most convenient route of FMT delivery for patients (cFMT). In this study, we evaluated the extent of bacterial engraftment following cFMT and the duration of donor bacterial persistence. All patients studied recovered clinically but showed differing patterns in long-term microbial community similarity to the donor that were associated with members of the bacterial group Bacteroidetes, previously shown to be prominent contributors to rCDI resistance. Results highlight long-lasting, donor-specific effects on recipient patient microbiota and reveal potential bacterial targets to improve cFMT engraftment.

Dataset Information

Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation.

Publications

Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation.

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