Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

in Hepatology (Baltimore, Md.) by Tomoo Yamazaki, Tetsuya Kouno, Cynthia L Hsu, Phillipp Hartmann, Susan Mayo, Xinlian Zhang, Peter Stärkel, Francisco Bosques-Padilla, Elizabeth C Verna, Juan G Abraldes, Robert S Brown, Victor Vargas, Jose Altamirano, Juan Caballería, Debbie L Shawcross, Alexandre Louvet, Michael R Lucey, Philippe Mathurin, Guadalupe Garcia-Tsao, Ramon Bataller, Bernd Schnabl,

TLDR

  • The study looked at how the liver is affected by alcohol and found that people with alcohol-associated hepatitis (AH) have a different way of breaking down a chemical called tryptophan. This chemical is important for the body to function properly. The study also looked at how this chemical is related to a protein called AhR. The study found that people with AH have more of this chemical in their blood and that this chemical is related to a higher risk of death. The study suggests that this chemical could be used as a way to predict who is at risk of dying from AH.

Abstract

Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

Overview

  • The study aimed to assess serum AhR ligand activity in patients with AH using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196).
  • Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001).
  • The primary objective of the study was to determine the association between serum AhR activity and mortality in patients with AH.

Comparative Analysis & Findings

  • Serum AhR activity was significantly higher in patients with AH compared with both controls and individuals with AUD. The study found that patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. The study also found that serum AhR activity was associated with higher mortality in patients with AH.

Implications and Future Directions

  • The study's findings suggest that serum AhR activity holds potential as a prognostic marker for mortality in patients with AH. However, the study has some limitations, such as the small sample size and the lack of a control group for the AhR activity ≥ 2.09 group. Future research should address these limitations and explore the potential of serum AhR activity as a diagnostic and therapeutic target for AH. Additionally, the study highlights the importance of understanding the role of the microbiome in AH and how it may influence AhR ligand activity and mortality.
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