Abstract
BACKGROUND Hepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular fecal microbial transplant (FMT) in HE, with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. The aim of this study was to determine the effect of FMT on the gut-brain axis compared with placebo, using microbial function based on bile acids (BAs), inflammation (serum IL-6, LPS-binding protein [LBP]), and their association with EncephalApp.METHODS Twenty cirrhotic patients were randomized 1:1 into groups that received 1-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae or placebo capsules, with 5-month follow-up for safety outcomes. Stool microbiota and BA; serum IL-6, BA, and LBP; and EncephalApp were analyzed at baseline and 4 weeks after FMT/placebo. Correlation networks among microbiota, BAs, EncephalApp, IL-6, and LBP were performed before/after FMT.RESULTS FMT-assigned participants had 1 HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared with baseline. No change was seen in placebo. Correlation networks showed greater complexity after FMT compared with baseline. Beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, were correlated with cognitive improvement and decrease in inflammation after FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes.CONCLUSION Gut microbial function in cirrhosis is beneficially affected by capsular FMT, with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.TRIAL REGISTRATION Clinicaltrials.gov NCT03152188.FUNDING National Center for Advancing Translational Sciences NIH grant R21TR002024, VA Merit Review grant 2I0CX001076, the United Kingdom National Institute for Health Research Biomedical Facility at Imperial College London, the British Heart Foundation, Wellcome Trust, and King’s College London.
Authors
Jasmohan S. Bajaj, Nita Salzman, Chathur Acharya, Hajime Takei, Genta Kakiyama, Andrew Fagan, Melanie B. White, Edith A. Gavis, Mary L. Holtz, Michael Hayward, Hiroshi Nittono, Phillip B. Hylemon, I. Jane Cox, Roger Williams, Simon D. Taylor-Robinson, Richard K. Sterling, Scott C. Matherly, Michael Fuchs, Hannah Lee, Puneet Puri, R. Todd Stravitz, Arun J. Sanyal, Lola Ajayi, Adrien Le Guennec, R. Andrew Atkinson, Mohammad S. Siddiqui, Velimir Luketic, William M. Pandak, Masoumeh Sikaroodi, Patrick M. Gillevet
Figure 1
Schema of Study and Changes in serum IL-6 values.
