P409 FMT induced increase in gut microbial diversity and Clostridia is associated with clinical response in patients with ulcerative colitis – results from STOP Colitis trial

Abstract

Abstract Background Findings from five randomised trials using faecal microbiota transplantation (FMT) in adults with ulcerative colitis (UC) demonstrate therapeutic potential. The optimum methodology for administration of FMT is unclear. We describe a prospective, three centre, open-label randomised trial (STOP-Colitis pilot) that compared tolerability and efficacy of nasogastric (NG) versus colonic (COLON) routes of administration and identified potentially important host microbial interactions. Methods Adult participants with active UC (partial Mayo score of ≥4 and ≤8) were randomised for administration of, 8 infusions of FMT over an, 8 week period either via the naso-gastric (NG) or colonic (COLON) route. Each patient was matched to a single FMT donor. Clinical response was defined as ≥3 point and ≥30% reduction in full Mayo score at week, 8 compared to baseline. Changes in faecal gut microbial diversity (Shannon’s diversity) and composition before/after FMT were analysed with, 16S rRNA sequencing. Correlation between datasets was evaluated with Kendall’s Tau coefficient. Results Sixteen patients were randomised to NG;, 14 to COLON FMT. Seven participants in the NG and, 2 in the COLON arm withdrew before completion. Clinical response was achieved in, 9/12 [75%] for COLON vs, 2/8 [25%] for NG)., 12/14 (86%) COLON participants were protocol-adherent compared with, 8/16 (50%) for NG. For the COLON patients (N=8) an increase in alpha diversity was observed (P=0.01). For those patients that responded to FMT overall (N=9) there was a significant increase in alpha diversity (P<0.005) and lower faecal calprotectin levels in responders vs. non-responders (week, 4 to week, 8 mean, 508.6 ug/g vs, 853.6 ug/g respectively; P=0.03). Overall, there was a negative association between calprotectin levels and alpha diversity (tau =-0.29; P <, 0.005). Operational taxonomic units belonging to Clostridia deriving from the Christensenellaceae and Lachnospiracae families correlated with both reduced calprotectin and had high engraftment frequency (both false discovery rate corrected P<0.10). In a cohort of patients with mucosal immune cell analysis Clostridia positively correlated with gut homing Treg populations and negatively correlated with Th17 cells populations (P<0.005), suggesting that this group may play an important role in the immune response to FMT in UC. Conclusion This pilot study suggests that in participants with active UC, FMT delivered via the colonic route appears to be better tolerated than via NG with a greater efficacy signal. There are signals linking gut microbial diversity and taxa belonging to Clostridia (short chain fatty acid producers) with clinical response, calprotectin and a shift towards an immunoregulatory phenotype.