Integrated metagenomic and bile acid metabolomic analysis of human fecal microbiota transplantation for recurrent Clostridioides difficile and/or inflammatory bowel diseases

Abstract

AbstractBackgroundFecal microbiota transplantation (FMT) is an effective treatment of recurrent Clostridioides difficile infections (rCDI). In comparison, FMT has more limited efficacy in treating either ulcerative colitis (UC) or Crohn’s disease (CD), two major forms of inflammatory bowel diseases (IBD). We hypothesize that FMT recipients with rCDI and/or IBD have baseline fecal bile acid (BA) compositions that differ significantly from that of their healthy donors and may be normalized by FMT.AimTo study the effect of single colonoscopic FMT on the microbial composition and function of recipients with rCDI and/or IBD.MethodsMulti-omic analysis was performed on stools from 55 pairs of subjects and donors enrolled in two prospective single arm FMT clinical trials [ClinicalTrials.gov ID:NCT03268213, 479696, (IND) 15642, ClinicalTrials.gov ID: NCT03267238, IND 16795]. Fitted linear mixed models were used to examine the effects of four recipient groups (rCDI - IBD, rCDI + IBD, UC - rCDI, CD - rCDI), FMT status (Donor, pre-FMT, 1-week post-FMT, 3-months post-FMT) and first order Group*FMT interactions.ResultsFMT was effective in preventing rCDI for up to one year in 92% of the rCDI - IBD group and 75% of the rCDI + IBD recipients. The donor-recipient Sørensen similarity index was < 0.6 in all donor-CDI recipient pairs but > 0.6 in some donor-IBD only recipient pairs at baseline. Increasing post-FMT similarity indices > 0.6 in IBD recipients, was not clearly associated with reduced fecal calprotectin levels. Fecal secondary BA levels were lower in rCDI ± IBD and CD – rCDI recipients compared to donors. FMT restored secondary BA levels in these recipients. Metagenomic baiE gene and some of the 8 bile salt hydrolase (BSH) phylotype abundances were significantly correlated with fecal BA levels.ConclusionRestoration of multiple secondary BA levels, including those recently implicated in immunomodulation, are associated with restoration of fecal baiE gene counts, suggesting that the 7-α-dehydroxylation step is rate-limiting.