The multi-omic basis for hepatic encephalopathy recurrence: Analysis of the THEMATIC trial

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Background & Aims the THEMATIC trial found that fecal microbiota transplant (FMT) reduced recurrence of hepatic encephalopathy (HE) in patients already on lactulose and rifaximin. Aim: determine multi-omic predictors of HE recurrence in THEMATIC trial participants. Methods THEMATIC trial included cirrhosis+HE patients who were given oral/enema FMT vs placebo ranging from 1 to 3 FMT administrations and followed over 6 months. Safety and HE recurrence were the outcomes. Serum, urine, and stool were collected at baseline, and post-FMT for all participants. Stool metagenomics, serum and urine metabolomics, inflammatory cytokines, and clinical data were collected and compared between those whose HE recurred/not using pathway analysis and combined using random forest (RFA) and latent factor analyses. Results HE recurred in 10 (17%) of the 60 patients enrolled, which was significantly higher in placebo vs FMT (40% vs 8%,p=0.005). Since FMT HE recurrence was low, all HE recurrences were combined and compared with patients who did not recur. Stool metagenomics showed short-chain fatty acid (SCFA) producers ( Faecalibacterium, Eubacterium,Bacteroides, Blautia spp) were lower and GABA producers ( Lactobacillus/Bifidobacterium spp) were higher in those who recurred. Urine and serum metabolites in HE recurred/not separated on PLS-DA with serum butyrate/isobutyrate being most significant (p=0.008). Pathway analyses showed GABA/neurotransmitters were higher with HE recurrence. On combination bioinformatics, both RFA and latent factor analysis showed SCFA producers and secondary bile acids were protective while IL-6, GABA producers, nicotine metabolites, and primary bile acids linked with HE recurrence. Conclusions Further analysis of the THEMATIC RCT showed hepatic encephalopathy recurrence after fecal microbiota transplant vs placebo in patients on lactulose and rifaximin is linked with metabolomic/microbiome changes focused on SCFA, GABA, bile acids, and IL-6. Trial registration www.clinicaltrials.gov: NCT03796598 Impact and implications Using fecal microbiota transplant (FMT), the recurrence of hepatic encephalopathy was reduced in patients on lactulose and rifaximin versus placebo in the THEMATIC trial, but the multi-omic basis for this was unclear. In this further analysis, we found that gut metagenomic alterations [lower short-chain fatty acid (SCFA) producers and higher pathobionts], urinary and serum metabolites (lower SCFA, secondary bile acids, and acetaminophen derivatives, higher GABA-related and nicotine derivatives), and inflammatory cytokines (higher IL-6) were associated with HE recurrence regardless of placebo or FMT assignment. Patients with higher engraftment of the donor had lower recurrence. Recurrence of HE after FMT is a multi-faceted phenomenon that encompasses metagenomics, metabolomics, inflammation and FMT donor engraftment.