Background: Hepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular FMT in HE with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. Aim: Determine impact of FMT on gut-brain axis compared to placebo using microbial function based on bile acids (BA), inflammation (serum IL-6, lipopolysaccharide-binding protein,LBP), and EncephalApp. Methods: 20 cirrhotic patients were randomized 1:1 into receiving one-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 post-FMT/placebo. Correlation networks between microbiota, BAs, EncephalApp, IL-6 and LBP were performed pre/post-FMT. Results: FMT-assigned participants had one 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 to baseline. No change was seen in placebo. Correlation networks showed greater complexity post-FMT compared to baseline. Beneficial taxa such as Ruminococcaceae, Verrucomicrobiaceae and Lachnospiraceae were correlated with cognitive improvement and decrease in inflammation post-FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes. Conclusions: 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.
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, Philip 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 A. Luketic, William M. Pandak, Masoumeh Sikaroodi, Patrick M. Gillevet
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