1. Results from a Dual-center, Randomized, Placebo-controlled Trial
Characterization of Fecal Microbiota in Response to Heterologous versus Autologous (Placebo) Fecal Microbial Transplantation:
Results from a Dual-center, Randomized, Placebo-controlled Trial
Contact:
1479 Gortner Ave, Suite 140
St. Paul, MN 55108
Christopher Staley1, Colleen R. Kelly2, Lawrence J. Brandt3,4, Alexander Khoruts1,5, and Michael J. Sadowsky1
1BioTechnology Institute, University of Minnesota, St. Paul, MN; 2Lifespan Women’s Medicine Collaborative, Division of Gastroenterology, Alpert Medical School of Brown University, Providence, Rhode Island, 3Albert Einstein College of Medicine, Bronx, New York
4Division of Gastroenterology, Montefiore Medical Center, Bronx, New York, 5Division of Gastroenterology, Department of Medicine, Center for Immunology University of Minnesota, Minneapolis, Minnesota
Recurrent Clostridium difficile infections (RCDI) are associated with low- diversity microbiomes showing lower abundances of Firmicutes and Bacteroidetes and expansion of the Proteobacteria1.
Fecal microbial transplantation (FMT) is an alternative treatment for RCDI, with an average curative success rate of 90% and restoration of a healthy microbiome1,2.
A dual-center, randomized, clinical trial recently found heterologous FMT was significantly more effective than autologous (placebo) FMT (91% vs 63%)3.
A notably higher success rate for autologous FMT was observed at the Bronx, NY site (90%), compared with the Providence, RI site (43%)3.
Transfer of a defined consortium of bacteria, e.g. C. scindens, may also effectively treat RCDI4, but likely will take longer to restore gut health.
The aim of this study was to determine differences in microbial communities between sites that may account for differences in efficacy of autologous FMT. Furthermore, microbial communities were interrogated to determine potential microbial signatures associated with recovery from RCDI following autologous FMT.
Introduction
Results
*** *
Rhode Island
New York
Fig. 3. Distribution of phyla in donor and patient samples initially treated by H-FMT or A-FMT at both sites
Significantly longer periods of infection and vancomycin in New York (Fig. 1)
Differences in pre-FMT communities between sites (P < 0.001; Fig. 2)
Proteobacteria: Rhode Island > New York (P < ) (Klebsiella, Escherichia/Shigella, Parasutterella, and Sutterella)
Verrucomicrobia: New York > Rhode Island (P = 0.049) (Akkermansia)
Veillonella: Rhode Island > New York (P = 0.009)
Streptococcus: New York > Rhode Island (P = 0.001)
Duration of infection and vancomycin negatively correlated with Firmicutes in New York (ρ = and , P ≤ 0.001)
No relationships with bacterial community found in Rhode Island
Fig. 1. Duration of infection and pre-FMT vancomycin (mean ± SE) at both sites
Fig. 2. Distribution of phyla in pre-FMT samples at both sites
Fig. 4. Principal coordinate analysis of donor and A-FMT samples in New York
Fig. 5. Principal coordinate analysis of donor and A-FMT samples in Rhode Island
Donor communities differ between sites (P < 0.001; Fig. 3)
A-FMT communities differ from H-FMT communities at 8-weeks post-FMT (clinical cures, P ≤ 0.025; Fig. 3)
At both sites, H-FMT patients become statistically similar to donor samples post-FMT
New York: post-A-FMT samples differ from pre-FMT and donor samples (P < 0.001) but not between 2- and 8-weeks (P = 0.219; Fig. 4)
Rhode Island: post-A-FMT samples differ from pre-FMT (P ≤ ) and donor samples (P < 0.001) but not between 2- and 8- weeks (P = 0.219; Fig. 5)
No significant difference between clinical outcomes post- FMT (P ≥ 0.061)
Lactobacillus and Klebsiella are prominent in pre-FMT samples in Rhode Island, but not New York
A-FMT clinical cures at Rhode Island tend to have C. scindens or Holdemania in pre-FMT samples
Screened for enrollment
3rd relapse of C. difficile
Failed vancomycin therapy
≥10-day course of vancomycin, discontinued 3 days prior to FMT
Randomization
Heterologous H-FMT
Autologous
A-FMT
Clinical cure
Clinical failure
*Offered open-label follow-up FMT (F/U-FMT)
Fecal samples collected at baseline, 2 weeks, and 8 weeks post-FMT *
Methods
Bacterial community sequencing targeting V5-V6 of 16S rRNA gene
Discussion
Demographic differences affected pre-FMT community structure, where pre-FMT New York samples showed a lower degree of dysbiosis relative to Rhode Island. At both sites, H-FMT resulted in a significant shift of patient communities to resemble donor communities at 2-weeks post-FMT, while A-FMT samples remained dysbiotic. Communities in New York A-FMT patients saw shifts to more closely resemble donor communities, with expansions of Clostridium spp. However, Rhode Island A-FMT patient communities showed slower recovery, and only those communities that initially had species associated with secondary bile acid metabolism were clinically cured. Therefore, pre-FMT communities in which Firmicutes are suppressed and those that may be metabolically capable of suppressing C. difficile germination through bile acid biosynthesis may recover without H-FMT, when antibiotic pressure is removed.
Weingarden A, González A, Vázquez-Baeza Y, et al Microbiome 3:10
Kassam Z, Lee CH, Yuan Y, Hunt RH Am J Gastroenterol 108:
Kelly CR, Khoruts A, Staley C, et al Ann Intern Med
Buffie CG, Bucci V, Stein RR, et al Nature 517:
References