Gut microbiome and plasma multi-omics signatures at admission differ between hepatitis A-related and drug-induced acute liver failure, with distinct pathobiont enrichment, metabolic disruptions, and inflammatory markers associated with disease severity and 90-day mortality in ALF-A.
ALF-A patients had greater clinical severity at admission compared to ALF-D patients.
ALF-A patients were enriched at admission (D0) for pathobionts producing lactate, ammonia, bile salt hydrolase, and histamine.
Histamine accumulation was elevated and tryptophan and butyrate metabolism were reduced at Day 0 in ALF-A, with worsening by Day 7 in non-survivors.
Pro-inflammatory cytokines and intestinal fatty acid binding protein 2 (IFABP2) were elevated at Day 0 in ALF-A, correlated with severity, and remained elevated through Day 7 in non-survivors.
ALF-D non-survivors showed a distinct biological profile compared to ALF-A non-survivors, retaining commensals and exhibiting increased fatty acid and bile acid biosynthesis with low pro-inflammatory cytokine levels.
Integrated gut and plasma multi-omics features in ALF-A were associated with disease severity and 90-day outcomes and identified candidate biomarkers.
This research suggests that when the liver fails suddenly due to hepatitis A infection versus drug toxicity, the biological processes driving the disease are fundamentally different. In patients with hepatitis A-related acute liver failure (ALF-A), the gut was overrun by harmful bacteria that produce toxic substances like ammonia, histamine, and lactate, while beneficial gut processes (like butyrate and tryptophan metabolism) were suppressed. At the same time, markers of gut leakiness and widespread inflammation were elevated from the very first day of hospital admission. These patients were also sicker overall, with higher rates of organ failure, need for mechanical ventilation, and 33% death within 90 days compared to 18.4% in drug-induced cases. In contrast, patients whose liver failed due to drugs had a different profile: their gut bacteria were less disrupted, their inflammatory response was milder, but they showed alterations in fat and bile acid metabolism instead. This suggests that drug-induced liver failure kills through different biological mechanisms than viral liver failure. Importantly, the harmful gut bacterial patterns and inflammatory signals seen in hepatitis A patients who ultimately died were already detectable on the day of admission, before the disease fully declared itself. This research suggests that measuring gut microbiome composition and plasma markers of inflammation and gut barrier integrity at the time of hospital admission could help identify which acute liver failure patients — particularly those with hepatitis A — are at highest risk of dying within 90 days. These findings point toward potential new biomarkers that, if validated in larger studies, could help clinicians make faster and more accurate decisions about treatment intensity and organ transplant priority.
Saxena A, Maiwall R, Meena B, Maras J, Suroliya V, Kumar G, et al.. (2026). Admission Gut and Plasma-Derived Signatures Associated With Severity and 90-day Outcome in Hepatitis A-Related and Drug-Induced Acute Liver Failure.. Journal of medical virology. https://doi.org/10.1002/jmv.71150