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OP019 In faecal microbiota transplantation (FMT) for ulcerative colitis, fusobacterium is associated with lack of remission, while metabolic shifts to starch degradation and short-chain fatty acid production are associated with remission (FOCUS study)

S. Paramsothy1,2*, M. Kamm3,4, S. Nielsen1, N. Deshpande1, J. Faith2, J. Clemente2, R. Paramsothy5, A. Walsh6, J. van den Bogaerde7, D. Samuel8, R. Leong8, S. Connor5, W. Ng5, E. Lin9, M. Wilkins1, J.-F. Colombel2, T. Borody9, H. Mitchell1, N. Kaakoush1

1University of New South Wales, Sydney, Australia, 2Icahn School of Medicine at Mount Sinai, New York, USA, 3St Vincent’s Hospital, Melbourne, Australia, 4University of Melbourne, Melbourne, Australia, 5Liverpool Hospital, Sydney, Australia, 6St Vincent’s Hospital, Sydney, Australia, 7Nambour General Hospital, Nambour, Australia, 8Bankstown-Lidcombe Hospital, Sydney, Australia, 9Centre for Digestive Diseases, Sydney, Australia

Background

In the FOCUS study, multidonor FMT was effective in the treatment of active ulcerative colitis (UC).1 Here we characterise the bacterial taxonomic and functional changes associated with outcome.

Methods

A total of 314 fecal and 160 colonic biopsy samples were collected at specific intervals from 70 patients. A total of 113 fecal samples were collected from the 14 individual donors and 21 multidonor batches. DNA and RNA were extracted, RNA converted to cDNA, then 16S rRNA gene sequencing performed using 2x300 bp Illumina MiSeq chemistry. Sequences were analysed using MOTHUR. Shotgun metagenomics was performed on 285 fecal samples using 2x250bp HiSeq 2500 chemistry, with samples analysed using MetaPhlAn2 and HUMANn2 for taxonomic and functional inferences, respectively.

Results

Patients: α-Diversity consistently increased following FMT across all datasets (fecal 16S DNA and RNA/cDNA, colonic mucosa 16S DNA and RNA/cDNA, shotgun metagenomics—taxonomic; p < 0.005). α-Diversity saturated by Week 4 with trends to greater α-diversity with remission. β-Diversity across all datasets showed FMT significantly shifted global microbial composition (t = 2.85, p = 0.001, df=104; Figure 1), from Bacteroides to Prevotella dominance. Fusobacterium was most consistently associated with lack of remission (LDA=3.34, p = 0.028), as were Sutterella, Veillonella, and Haemophilus. There was less consistency in taxa associated with remission (most commonly Firmicutes members, e.g. Clostridium XVIII, Ruminococcus, Lachnospiraceae). High concordance was observed between fecal and colonic mucosal microbiota. Donors: The presence of a Streptococcus OTU was associated with ineffective batches. Metabolic function: Fecal shotgun metagenomics demonstrated FMT-associated shifts in bacterial metabolic function—remission was associated with starch degradation pathways and SCFA production, while lack of remission was associated with heme biosynthesis. Biopsy PICRUSt data corroborated the association of SCFA production with remission. Taxa contributing to beneficial pathways included Eubacterium, Ruminococcus, Lachnospiraceae, and Roseburia.

Figure 1. PCA of transformed relative abundances inferred from shotgun metagenomics.

Conclusion

FMT treatment consistently increased diversity and changed microbial composition. Fusobacterium appears critical in relation to outcomes of FMT for UC. Changes in bacterial metabolic activity may also play a key role in FMT success or failure. These specific bacterial findings may have important aetiological relevance, help identify suitable donors and patients for treatment, and guide refinement of future bacterial therapy.

Reference

1.Paramsothy S. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet, 2017;389:1218–28.