Higher alpha diversity and Lactobacillus blooms are associated with better engraftment after fecal microbiota transplant in inflammatory bowel disease

Abstract

Fecal Microbiota Transplant (FMT) has shown some success in treating inflammatory bowel diseases (IBD). There is emerging evidence that host engraftment of donor taxa is a tenet of successful FMT. We undertook a double-blind, randomized, placebo-controlled pilot study to characterize the response to FMT in children and young adults with mild to moderate active Crohn's disease (CD) and ulcerative colitis (UC). Subjects with CD or UC were randomized to receive antibiotics and weekly FMT or placebo in addition to baseline medications. We enrolled 15 subjects aged 14-29 years. Four subjects had CD, and 11 had UC. Subjects exhibited a wide range of microbial diversity and donor engraftment. Specifically, engraftment ranged from 26 to 90% at week 2 and 3-92% at 2 months. Consistent with the current literature, increases over time of both alpha diversity (p < 0.05) and donor engraftment (p < 0.05) correlated with improved clinical response. We discovered that the post-antibiotic but pre-FMT time point was rich in microbial correlates of eventual engraftment. Greater residual alpha diversity after antibiotic treatment was positively correlated with engraftment and subsequent clinical response. Interestingly, a transient rise in the relative abundance of Lactobacillus was also positively correlated with engraftment, a finding that we recapitulated with our analysis of another FMT trial.

Figure 1

(A) Consort diagram. (B) Clinical symptom scores (PUCAI for UC and PCDAI for CD) for individual participants (top) and for responders vs non-responders (bottom). Responders were defined as subjects with a drop in disease activity indexes of at least 12.5 (CD) or 20 (UC) or subjects in remission (disease activity indexes of 10 or less at 2–7 weeks after FMT).

Figure 2

(A) Stool alpha diversity (Shannon index) time series for all subjects, clinical non-responders (blue) vs. clinical responders (red), and for individual subjects, each in a unique shade of gray (inset). *Corrected p-value < 0.05, Mann–Whitney with Bonferroni correction. (B) Correlation between clinical symptom score (PUCAI for Ulcerative Colitis, PCDAI for Crohn's Disease) and alpha diversity (Shannon index) for clinical responders (top) and non-responders (bottom). (C) Correlation between PUCAI and alpha diversity at 5, 6 and 7 weeks post-FMT (large panel). Smaller panels: top panels show a correlation between PUCAI and alpha diversity at the pre-and post-antibiotic time points, and bottom panels show the correlation between the late post-FMT PUCAI and earlier (pre- and post-antibiotic) alpha diversity metrics.

Figure 3

(A) Percent Donor Engraftment, as estimated by SourceTracker, in responders vs. non-responders and for each subject, each in a unique shade of orange (responders) or blue (non-responders) (inset) (B) Beta diversity plots (Bray–Curtis) for three example responders. (C) Beta diversity plots for three example non-responders. High-engrafters are highlighted with red boxes. (D) Correlation between alpha diversity (Shannon Index) and engraftment at the pre-antibiotic (Left) and post-antibiotic (Right) time points.

Figure 4

(A) Important features (on the genus level) from a random forest classifier using the post-antibiotic microbiome to classify high vs. low engrafters (AUC = 1.00). All taxa are genera, and the lowest identified taxonomic level is labeled. *Asterisks denote members of the Family Lactobacillaceae. (B) Boxplot of relative abundance (proportion of total reads) of species in the Family Lactobacillaceae detected in at least three individuals. ***FDR p-value < 0.001; **FDR p-value < 0.01; *FDR p-value < 0.05. (C) Time series of relative abundance of genus Lactobacillus (top left) and three species within genus Lactobacillus, comparing high (each participant represented in a unique shade of blue) vs. low (each participant represented in a unique shade of orange) engrafters in this study. (D) Time series of relative abundance of the genus Lactobacillus (top) and two species within genus Lactobacillus, comparing responders (each participant represented in a unique shade of blue) vs. non-responders (each participant represented in a unique shade of orange) in an independent (n = 6) FMT study in IBD (Chu et al.).