A Double-Blind, Randomized, Placebo-Control Pilot Trial of Fecal Microbiota Transplantation Capsules from Rationally Selected Donors in Active Ulcerative Colitis

INTRODUCTION Fecal microbiota transplantation (FMT) has shown promise in treating ulcerative colitis (UC); however, the characteristics of an ideal stool donor are unknown. Butyrate, a short-chain fatty acid (SCFA), may modulate UC remission. We investigated the safety, efficacy and the translational impact of FMT capsules (FMTc) in active UC using rationally selected donors high in butyrate. METHODS A double blind, randomized, placebo-control pilot trial was conducted in patients with mild to moderate UC (Mayo Score 4-10) utilizing FMT by colonoscopy (50g stool) followed by daily FMTc (0.375g stool). The placebo arm received sham FMT and daily placebo capsules. All subjects were pre-treated with a 7-days of antibiotics. FMT material was derived from 2 healthy donors with high stool butyrate. Adverse events (AEs), histologic activity, endoscopic score, clinical response, and inflammatory markers were monitored. Exploratory endpoints included measurements of stool butyrate and other SCFAs (gas chromatography), mucosal serotonin transporter (SERT) and tryptophan hydroxylase 1 (TPH1) mRNA by qPCR. RESULTS Fifteen patients met initial eligibility criteria and were randomized to the FMT (n=7) or placebo (n=8) arm. Baseline patient characteristics were similar between FMT (mean age=39yrs, female=3, baseline Mayo score=4.6) and placebo (mean age=49yrs, female=4, baseline Mayo score=4.4) arms. After baseline colonoscopy, 3 participants were excluded due to a lack of endoscopic disease activity. Overall, there were no statistically significant differences in AEs and no serious AE related to FMT. At week 12, histologic inflammation decreased in 4/6 (66%) subjects in the FMT arm vs. 1/6 (16.6%) the placebo arm. Histologic remission (lack of neutrophils) was achieved in 3 (50%) FMT vs. 0 placebo subjects. Endoscopic response (decrease in Mayo subscore > 1 or UCEIS > 2) was achieved in 3/7 (43%) FMT vs. 0/8 (0%) placebo. Endoscopic Mayo score and IBDQ bowel symptoms were superior in the FMT arm at week 12 (p=0.05) and week 18 (p=0.05). Clinical remission (Mayo score < 3) or response (>3 point reduction in Mayo Score) was achieved in 2/7 (29%) and 2/7 (29%) vs. 1/8 (13%) and 0/8 (0%) in FMT compared to placebo. Fecal lactoferrin was positive in 50% FMT subjects vs. 100% of placebo subjects at week 18. Stool SCFAs initially increased in the FMT (acetate, propionate in 4/4; butyrate, valerate in 3/4) vs. placebo arm (butyrate, acetate, propionate in 1/3; valerate in 0/3). TPH1 and SERT were lower in subjects compared to healthy controls; FMT did not affect levels from baseline. CONCLUSION To our knowledge, this is the first report of FMT capsules in the treatment of UC. These data suggest that FMTc are safe and potentially decrease histologic, endoscopic and clinical evidence of disease. These effects may be related to changes in SCFA production. [Figure Presented]