ECCO'18 IIS Award Winner: Sudarshan Paramsothy
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)
The randomised controlled FOCUS study , along with other trials [2–4], suggests that FMT is effective in the treatment of patients with active Ulcerative Colitis (UC). However, the underlying microbial basis and predictors of therapeutic outcome in UC are largely unknown. We therefore performed in-depth microbial analyses on the samples collected during the FOCUS study to help identify bacterial taxonomic and functional changes associated with FMT in UC, particularly those predictive of therapeutic success or failure.
16S rRNA gene and transcript sequencing (2×300 bp Illumina MiSeq chemistry) was conducted on all the serial faecal and colonic biopsy samples collected from 70 FOCUS trial patients as well as the faecal samples of their respective individual donors and donor batches. Additional shotgun metagenomics was performed on 285 representative faecal samples from patients, donors and donor batches using 2×250 bp HiSeq 2500 chemistry.
The results showed that FMT induced substantial changes in microbial diversity and composition independent of therapeutic outcome. FMT consistently increased α-diversity, as measured by number of operational taxonomic units (OTUs) and Shannon’s diversity. A significant shift in global microbial composition on β-diversity measures was also observed in the faecal and colonic mucosal microbiota post FMT but not post placebo. These changes showed some durability, being sustained 8 weeks after completion of FMT. A range of OTUs were either transplanted or depleted post FMT but not during placebo, including those belonging to Prevotella and Bacteroides.
Specific bacterial taxa were strongly associated with therapeutic outcome. Lack of remission was associated with the presence of a number of taxa, most notably Fusobacterium, as well as Sutterella and Escherichia, with high concordance between the faecal and colonic mucosal microbiota. On shotgun metagenomics, remission was most strongly associated with members of Firmicutes, including Clostridium XVIII, Ruminococcus and Lachnospiraceae.
Microbial functional changes across FMT therapy and therapeutic outcome were also characterised. FMT, but not placebo, resulted in significant changes in global bacterial metabolic function. Importantly, FMT resulted in functional changes that were associated with therapeutic outcome, with remission being associated with metabolic shifts towards short chain fatty acid production, starch degradation and biosynthesis of ansamycins. Taxa found to contribute to such beneficial pathways included Eubacterium, Ruminococcus, Lachnospiraceae and Roseburia. In contrast, heme biosynthesis, lipopolysaccharide biosynthesis, and oxidative phosphorylation pathways were associated with therapeutic failure.
In summary, FMT markedly increases diversity and shifts microbial composition, while specific FMT-induced changes in taxonomy and metabolic pathways are associated with therapeutic remission or failure. These findings may have important implications for donor and patient selection and shaping future bacterial therapy for UC.
Sudarshan Paramsothy at ECCO'18 © ECCO
1. Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389:1218–28.
2. Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149:102–9 e6.
3. Costello S, Waters O, Bryant R, et al. Short duration, low intensity pooled faecal microbiota transplantation induces remission in patients with mild-moderately active ulcerative colitis: a randomised controlled trial. 12th Congress of ECCO, Barcelona, Spain, 2017.
4. Paramsothy S, Paramsothy R, Rubin DT, et al. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis 2017;11:1180–99.