P: 11 Cognitive Improvement After Capsular Fecal Microbial Transplant in Hepatic Encephalopathy Is Associated With Changes in Microbial Function and Inflammation

Abstract

BACKGROUND: Hepatic encephalopathy(HE) can recur despite standard of care therapies. Our trial of capsular fecal microbiota transplant (FMT) demonstrated improvement in dysbiosis and cognition in pts randomized to FMT versus placebo. Despite compositional improvement, interaction of inflammation, bacterial translocation, microbial function (bile acid, BA) with cognition needs to be evaluation. Gut microbiota can transform BAs by deconjugating, converting primary to secondary BAs & tertiary(oxo, sulfated, urso and iso-BA) formation. Aim: Determine changes in fecal BA moieties as modulators of microbial function, inflammation and their linkage with cognition in FMT in cirrhosis and recurrent HE. METHODS: 20 cirrhotics with recurrent HE on lactulose/rifaximin were randomized 1:1 into 15 FMT capsules once vs identical placebo. FMT was from a single donor enriched in Lachnospiraceae/Ruminococcaceae, which are associated with secondary BA generation. We collected stool/blood & analyzed cognition (EncephalApp; high = worse) at baseline and 30 days post-intervention (Figure 1a red arrows). Stool microbiota was analyzed using 16srRNA & BAs using LC/MS. Fecal BA moieties analyzed were (a) total (b) primary (c) secondary (d) deconjugated (e) tertiary BAs. Secondary/primary BA ratios were calculated. Serum was also analyzed for lipopolysaccharide-binding protein (LBP) & IL-6. Correlation networks between BAs, microbiota, LBP, IL-6 and cognition were created. Correlation network complexity was compared between post-FMT vs post-placebo states. RESULTS: All subjects completed the follow-up without any serious AEs related to FMT/placebo. EncephalApp total score (P < 0.05) improved in FMT pts only Microbiota: there was a significant engraftment of donor microbiota with higher Ruminoccaceae & Lachnospiraceae in stool/duodenum in FMT pts. Inflammation/translocation: A reduction in LBP & IL-6 was seen only in FMT pts (Figure 1b,d). BAs: There was a significant increase in secondary/primary BA ratio (Figure 1c) in FMT pts. Deconjugation and tertiary BAs remained similar between groups. Correlation network showed higher complexity after FMT compared to post-placebo (Figure 1e). Beneficial bacteria (Ruminococcaeae and Verrucomicrobiaceae) became significantly positively correlated with each other (blue lines) and negatively with inflammation (IL6 redlines) and associated with better EncephalApp score post-FMT (Figure 1f) compared to placebo at study end. CONCLUSIONS: Capsular FMT is safe and improves cognition in pts with cirrhosis and HE compared to placebo. These improvements are associated with beneficial changes in microbial composition and function and differential correlations with bacterial translocation and inflammation.