Abstract
Background
Preventing hepatic encephalopathy (HE) recurrence in cirrhosis, which is associated with an altered gut-liver-brain axis, is an unmet need. Fecal microbiota transplantation (FMT) is beneficial in phase-1 studies, but route and dose-related questions remain.
Methods
We performed a phase-2 randomized, placebo-controlled, double-blind, clinical trial of capsule and enema FMT in cirrhosis and HE on lactulose and rifaximin. Subjects were randomized into 4 groups receiving 3 active and 0-placebo, 2 active and 1-placebo, 1 active and 2-placebo, or all 3-placebo doses. Each patient received two capsule and one enema FMT and were followed for six months. Primary outcome: FMT-related serious adverse events/AEs using intention-to-treat analysis. Secondary outcomes were HE recurrence, all-cause hospitalizations, death, donor engraftment, and quality-of-life (QOL). FMT was from a vegan or omnivorous donor.
Results
60 patients (15/group) with similar baseline characteristics were enrolled. Primary outcomes: FMT was safe without any FMT-related SAEs/ AEs. Secondary outcomes: Overall SAEs (p=0.96) or death (p=1.0) were similar. There were significant differences in HE recurrence between groups (p=0.035, Cramer’s V=0.39). Post-hoc, recurrence was highest in all-placebo vs FMT [40% vs 9%, OR:0.15 (95% CI: 0.04, 0.64)]. Within FMT, HE-recurrence rates were similar regardless of route, doses, or donor type. QOL improved in FMT-recipient groups. Engraftment was highest in those with high pre-FMT Lachnospiraceae and lower in those whose HE recurred.
Conclusions
In a Phase 2 double-blind, placebo-controlled, randomized clinical trial in cirrhosis with HE on maximal therapy, FMT regardless of dose, route, or donor was safe without any FMT-related adverse events. On post-hoc analysis, groups differed on HE recurrence, which was highest in the placebo-only group and linked with lower baseline Lachnospiraceae and reduced donor engraftment.
Graphical abstract
