Recovery of the gut microbiome following fecal microbiota transplantation

Abstract

Clostridium difficile infection is one of the most common health care-associated infections, and up to 40% of patients suffer from recurrence of disease following standard antibiotic therapy. Recently, fecal microbiota transplantation (FMT) has been successfully used to treat recurrent C. difficile infection. It is hypothesized that FMT aids in recovery of a microbiota capable of colonization resistance to C. difficile. However, it is not fully understood how this occurs. Here we investigated changes in the fecal microbiota structure following FMT in patients with recurrent C. difficile infection, and imputed a hypothetical functional profile based on the 16S rRNA profile using a predictive metagenomic tool. Increased relative abundance of Bacteroidetes and decreased abundance of Proteobacteria were observed following FMT. The fecal microbiota of recipients following transplantation was more diverse and more similar to the donor profile than the microbiota prior to transplantation. Additionally, we observed differences in the imputed metagenomic profile. In particular, amino acid transport systems were overrepresented in samples collected prior to transplantation. These results suggest that functional changes accompany microbial structural changes following this therapy. Further identification of the specific community members and functions that promote colonization resistance may aid in the development of improved treatment methods for C. difficile infection.

Importance: Within the last decade, Clostridium difficile infection has surpassed other bacterial infections to become the leading cause of nosocomial infections. Antibiotic use, which disrupts the gut microbiota and its capability in providing colonization resistance against C. difficile, is a known risk factor in C. difficile infection. In particular, recurrent C. difficile remains difficult to treat with standard antibiotic therapy. Fecal microbiota transplantation (FMT) has provided a successful treatment method for some patients with recurrent C. difficile infection, but its mechanism and long-term effects remain unknown. Our results provide insight into the structural and potential metabolic changes that occur following FMT, which may aid in the development of new treatment methods for C. difficile infection.

Copyright © 2014 Seekatz et al.

Figures

FIG 1

Timeline of sample collection for each recipient-donor pair. Relative sample collection time, history of antibiotic use, and results for C. difficile clinical diagnostic tests (Illumigene assay) for the time of FMT for each recipient are indicated.

FIG 2

Relative abundances of most abundant OTUs in donor and pre- and post-FMT samples. Heat map of most abundant OTUs (>2% of all sequences), classified by phylum, family, and genus. Samples were clustered based on the Morisita-Horn distance matrix using the R package “vegan” and color coded by sample type (donor or pre- or post-FMT sample).

FIG 3

Estimated diversity in donor and pre- and post-FMT samples. The observed species richness (estimated number of OTUs) (A) or Shannon diversity index (B) for donor and pre- and post-FMT samples is shown. Each recipient-donor pair is color coded as indicated by the legend. Box plots specify the median (second), third, and fourth quartiles. The nonparametric Wilcoxon test was used to calculate significance among the different sample groups (*, P < 0.01; **, P < 0.001; ***, P < 0.0001).

FIG 4

Similarity between donor, pre-, and post-FMT samples. Shared species richness (number of shared OTUs) (A) or the Yue-Clayton theta similarity (θYC) (B) between pre-FMT and post-FMT (pre-post), donor and post-FMT (donor-post), and pre-FMT and donor (pre-donor) samples within recipient-donor pairs is shown. The nonparametric Wilcoxon test was used to calculate significance among the different sample groups (*, P < 0.01; **, P < 0.001; ***, P < 0.0001; ns, not significant).

FIG 5

Compositional comparison of donor, pre-, and post-FMT samples. Principal coordinates analysis (PCoA) of the theta similarity (θYC) for all samples, color coded by sample type (donor and pre- and post-FMT). The direction of 15 most abundant significantly correlated operational taxonomic units (OTUs) for axes 1 and 2 are labeled, as calculated using the Spearman correlation (P < 0.001).

FIG 6

Metagenomic functional predictions for donor, pre-, and post-FMT samples. Mean relative gene pathway abundance of significantly differentially abundant modules (ANOVA; P < 0.01) for donor and pre- and post-FMT samples. Gene pathway abundances were calculated using the HUMAnN pipeline and grouped by major functional categories.