Fecal microbiota transplant improves cognition in hepatic encephalopathy and its effect varies by donor and recipient

Abstract

Early data suggest fecal microbiota transplant (FMT) may treat hepatic encephalopathy (HE). Optimal FMT donor and recipient characteristics are unknown. We assessed the safety and efficacy of FMT in patients with prior overt HE, comparing five FMT donors. We performed an open-label study of FMT capsules, administered 5 times over 3 weeks. Primary outcomes were change in psychometric HE score (PHES) and serious adverse events (SAEs). Serial stool samples underwent shallow shotgun metagenomic sequencing. Ten patients completed FMT administration and 6-month follow-up. Model for End-Stage Liver Disease (MELD) score did not change after FMT (14 versus 14, p = 0.51). Thirteen minor adverse events and three serious adverse events (two unrelated to FMT) were reported. One SAE was extended-spectrum beta-lactamase Escherichia coli bacteremia. The PHES improved after three doses of FMT (+2.1, p < 0.05), after five doses of FMT (+2.9, p = 0.007), and 4 weeks after the fifth dose of FMT (+3.1, p = 0.02). Mean change in the PHES ranged from -1 to +6 by donor. Two taxa were identified by random forest analysis and confirmed by linear regression to predict the PHES- Bifidobacterium adolescentis (adjusted R2 = 0.27) and B. angulatum (adjusted R2 = 0.25)-both short-chain fatty acid (SCFA) producers. Patients who responded to FMT had higher levels of Bifidobacterium as well as other known beneficial taxa at baseline and throughout the study. The FMT donor with poorest cognitive outcomes in recipients had the lowest fecal SCFA levels. Conclusion: FMT capsules improved cognition in HE, with an effect varying by donor and recipient factors (NCT03420482).

Conflict of interest statement

Patricia Bloom received a research grant from Vedanta Biosciences. Elizabeth Hohmann received a research grant from Seres Therapeutics and MicrobiomX and consults for Gilead. Raymond Chung has received research grants from Synlogic and Kaleido.

© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.

Figures

FIGURE 1

Study design. Patients received 15 oral FMT capsules on 5 days over 3 weeks. Cognitive testing and serum and stool collections occurred at 4 time points. Standard of care with lactulose and rifaximin were continued throughout the study. Abbreviation: FMT, fecal microbiota transplant

FIGURE 2

Subject enrollment flowchart. *For the first five subjects, MELD >17 was excluded. Per protocol, after the first five patients, MELD >20 was excluded. However, after a serious adverse event, MELD >17 was again excluded. Abbreviations: HE, hepatic encephalopathy; MELD, Model for End‐Stage Liver Disease; PHES, psychometric hepatic encephalopathy score

FIGURE 3

Illustration of PHES over time. The first time point was before FMT delivery, the second time point was day 14 (1 week after three doses of FMT), the third time point was day 21 + 1 week (1 week after the fifth FMT dose), and the fourth time point was day 21 + 4 weeks (4 weeks after the fifth FMT dose). (A) PHES over time for all patients and mean change in PHES by donor. (B) PHES over time by history of TIPS. Abbreviations: FMT, fecal microbiota transplant; PHES, psychometric hepatic encephalopathy score; TIPS, transjugular intrahepatic portosystemic shunt

FIGURE 4

In a random forest analysis, variables were ranked by importance in predicting PHES. Of the important variables, those bolded and starred were additionally found to be significantly associated with PHES by linear regression. Abbreviations: MELD, Model for End‐Stage Liver Disease; PHES, psychometric hepatic encephalopathy score; B. of B. adolescentis, B. angulatum, and B. breve, Bifidobacterium; B. producta, Blautia producta; R. of R. hominis, R. intestinalis, R. faecis, and R. inulinivorans, Roseburia; R. lactaris, Ruminococcus lactaris; R. massiliensis, Raoultibacter massiliensis; R. lactatiformans, Ruthenibacterium lactatiformans; F. praustnitzii, Faecalibacterium prausnitzi; E. asburiae, Enterobacter asburiae; N. massiliensis, Negativibacillus massiliensis; C. eutactus, Coprococcus eutactus; I. butyriciproducens, Intestinimonas butyriciproducens; E. ventriosum, Eubacterium ventriosum; L. rhamnosus, Lactobacillus rhamnosus

FIGURE 5

Comparison of bacterial families. (A,B) Bacterial families identified a priori as beneficial or harmful in HE were compared between FMT responders and nonresponders. (C) Bifidobacterium abundance appeared to be higher in responders compared to nonresponders. Abbreviations: FMT, fecal microbiota transplant; HE, hepatic encephalopathy

FIGURE 6

The presence of the rpoB gene over time. Each column represents a study subject. Donors (A–E) are show along the bottom. Abbreviations: +, presence of rpoB gene in that subject at that time point; −, absence of rpoB gene; FMT, fecal microbiota transplant; NR, nonresponder; R, fecal microbiota transplant responder; rpoB, RNA polymerase β subunit (resistance to rifampicin)