Admission Gut and Plasma-Derived Signatures Associated With Severity and 90-day Outcome in Hepatitis A-Related and Drug-Induced Acute Liver Failure.

Abstract

Acute liver failure (ALF) due to hepatitis A (ALF-A) has high mortality, but admission-day markers associated with disease severity and outcome are unknown. We aimed to define gut microbiome and plasma multi-omics signatures associated with severity and 90-day outcomes in ALF-A, compared to drug-induced ALF (ALF-D) as non-viral ALF group. ALF patients (aged 26&#x2009;&#xb1;&#x2009;9&#x2009;years; 50.7% male, 49.3% female) with IgM HAV positive (ALF-A, n&#x2009;=&#x2009;33), ALF-D (n&#x2009;=&#x2009;38) were recruited along with acute viral hepatitis (AVH-A, n&#x2009;=&#x2009;27) and healthy subjects (HC, n&#x2009;=&#x2009;20). Stool bacteria profiling was done at D0; plasma cytokines, metabolites and barrier markers were analysed at D0, 3, 5, 7. Correlations with clinical severity parameters were assessed. Associations with 90-day mortality were assessed using severity-adjusted association analyses. ALF-A patients were more severe at the time of admission than ALF-D. In ALF-A, 90-day mortality was 33% versus 18.4% with increased severity scores like KCH 21% versus 10.5%, SOFA score 7.97&#x2009;&#xb1;&#x2009;2.89 versus 5.87&#x2009;&#xb1;&#x2009;2.32, SIRS 60.6% versus 18.4%, mechanical ventilation 39% versus 21%. At D0, ALF-A was enriched for lactate/ammonia/bile salt hydrolase/histamine-producing pathobionts like Enterococcus, Ruminococcus gnavus, Flavonifractor, Thomasclavelia correlating positively with severity (|r|&#x2009;>&#x2009;0.4, p&#x2009;<&#x2009;0.05) showing higher baseline abundance in ALF-A non-survivors (NS). At D0 in ALF-A, histamine accumulation, reduced tryptophan, butyrate metabolism inversely correlated with severity and worsened in ALF-A_NS by D7. Pro-inflammatory cytokines, IFABP2 were elevated at Day 0 in ALF-A, correlated positively with severity, and remained increased through Day 7 in ALF-A_NS. In contrast, ALF-D_NS retained commensals, showed increased fatty acid, bile acid biosynthesis with low levels of pro-inflammatory cytokines. In ALF-A, gut and plasma integrated multi-omics features were associated with disease severity, 90-day outcomes and identified candidate biomarkers for future validation.