Potential of fecal microbiota transplantation to prevent acute graft-versus-host disease: Analysis from a phase 2 trial

Intestinal microbiota disruptions early after allogeneic hematopoietic cell transplantation have been associated with increased risk for acute graft-versus-host disease (aGVHD). In our recent randomized phase 2 trial of oral, encapsulated, third-party fecal microbiota transplantation (FMT) versus placebo, FMT at the time of neutrophil recovery was safe and ameliorated dysbiosis. Here, we evaluated in post hoc analysis whether donor microbiota engraftment after FMT may protect against acute GVHD.We analyzed pre- and post-FMT stool samples and estimated donor microbiota engraftment (a pre-planned secondary endpoint) by determining the fraction of post-FMT microbiota formed by unique donor taxa (donor microbiota fraction; dMf).dMf was higher in patients who later developed grade I or no aGVHD (median 33.9%, range 1.6-74.3%) than those who developed grade II-IV aGVHD (median 25.3%, range 2.2-34.8%) (P = 0.006). The cumulative incidence of grade II-IV aGVHD by day 180 was lower in the group with greater-than-median dMf than the group with less-than-median dMf (14.3% [95%CI, 2.1-37.5%] vs. 76.9% [95% CI, 39.7-92.8%], P = 0.008). The only determinant of dMf in cross-validated LASSO-regularized regression was the patient's pre-FMT microbiota diversity (Pearson's correlation coefficient -0.82, P = 1.6x10-9), indicating more potent microbiota modulation by FMT in patients with more severe dysbiosis. Microbiota network analysis revealed major rewiring including changes in the most central nodes, without emergence of keystone species, as a potential mechanism of FMT effect.FMT may have protective effects against aGVHD, especially in patients with more severe microbiota disruptions.