A11 EFFECT OF FECAL MICROBIAL TRANSPLANT ON MICROBIAL AND PHAGE COMPOSITION IN PATIENTS WITH CLOSTRIDIUM DIFFICILE INFECTION

The gut microbiome contains a diverse bacteriophage community that plays a largely unknown role in shaping microbial colonization and disease pathogenesis. Fecal microbial transplantation (FMT) is the most effective therapy for recurrent Clostridium difficile infection (RCDI) and has been shown to transfer phages along with gut microbes. The aim of this study was to examine the effects of FMT on microbial and phage composition in RCDI patients. Patients with RCDI (n=19) received FMT from 1 of 3 donors via colonoscopy. Stool samples were collected prior to and following FMT. DNA was extracted and indexed paired-end DNA libraries constructed using an Illumina Nextera® XT DNA kit, then sequenced on a MiSeq. Reads from individual samples were mapped to >5 kb assembled contigs using Metaphlan 2 for taxonomy, HUMAnN for gene function, and Bowtie2 with NCBI RefSeq database for prophage. To assess the metabolic state of the microbial community in RDCI patients, growth dynamics of E. coli were inferred from the metagenomic data by measuring the proportion of DNA copies near the origin to those near the terminus (peak-to-trough ratio (PTR)). In RCDI patients prior to FMT, Escherichia and Klebsiella dominated. RCDI patients also harbored numerous phages within the Siphoviridae family, including Enterobacteria, Escherichia, Salmonella, Klebsiella and Lactobacillus phages. In contrast, the gut microbiome of donors consisted primarily of Bacteroides and Firmicutes; donors also had a much reduced phage population which consisted primarily of crAssphage, a phage predicted to infect Bacteroides. Eleven patients were successfully treated with a single FMT (FMT-S) while 8 patients required multiple FMTs (FMT-M). A successful FMT resulted in the appearance of crAssphage in the RCDI recipients with a complete loss or reduction of Siphoviridae phages and increased Bacteroidetes and Firmicutes. There were no significant differences in microbial composition or predicted gene function between the FMT-S and FMT-M groups; however, the patients requiring multiple FMT had increased abundances of Enterobacteria phages HK542, mEp237, and phiP27. This was associated with an increased inferred growth rate of Escherichia coli suggesting that E. coli and associated phages may be driving disease pathogenesis in some RCDI patients that fail to respond to FMT. RCDI patients had decreased microbial but increased diversity of phages compared with healthy individuals. FMT altered both bacterial and phage composition to resemble the donor. Patients who required at least 2 FMT had significant differences in their phage population suggesting that the presence of particular phages may have a role in modulating response of patients to fecal transplantation. CIHRAlberta Health Services; Alberta Innovates

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