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Multicenter Study
. 2024 Aug 1;80(2):403-417.
doi: 10.1097/HEP.0000000000000777. Epub 2024 Feb 20.

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

Tomoo Yamazaki  1   2 , Tetsuya Kouno  1 , Cynthia L Hsu  1   3 , Phillipp Hartmann  4   5 , Susan Mayo  1   3 , Xinlian Zhang  6 , Peter Stärkel  7 , Francisco Bosques-Padilla  8 , Elizabeth C Verna  9 , Juan G Abraldes  10 , Robert S Brown Jr  11 , Victor Vargas  12   13 , Jose Altamirano  12 , Juan Caballería  13   14 , Debbie L Shawcross  15 , Alexandre Louvet  16 , Michael R Lucey  17 , Philippe Mathurin  16 , Guadalupe Garcia-Tsao  18   19 , Ramon Bataller  20 , Bernd Schnabl  1   3 ; AlcHepNet Investigators
Affiliations
Multicenter Study

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

Tomoo Yamazaki et al. Hepatology. .

Abstract

Background and aims: 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.

Approach and results: 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.

Conclusions: 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.

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Conflict of interest statement

B.S. has been consulting for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen and Takeda. B.S.’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. B.S. is founder of Nterica Bio. UC San Diego has filed several patents with B.S. as inventor related to this work. D.L.S. has consulted for EnteroBiotix and delivered paid lectures for Norgine. J.G.A. received grants from Cook and Gilead (paid to the University of Alberta) and received consulting fees from Boehringer Ingelheim, AstraZeneca, Advanz and 89Bio. V.V. served on Ipsen Pharma: advisory board, and has travel grant from Intercept Pharmaceuticals.

Figures

Figure 1.
Figure 1.
Comparison of serum AhR activity between controls, patients with alcohol use disorder (AUD) and patients with alcohol-associated hepatitis (AH). (a) Serum AhR activity was compared in 74 controls without AUD, 97 patients with AUD, and 330 patients with AH. Kruskal-Wallis test for nonparametric data and Dunn post-hoc test. (b) The AH group was divided into two independent cohorts (AlcHepNet: 196 cases, InTeam: 134 cases) and serum AhR activity was compared between each group. Kruskal-Wallis test for nonparametric data and Dunn post-hoc test. ****p < 0.0001 denotes the significant difference between the groups. AhR, aryl hydrocarbon receptor; AUD, Alcohol Use Disorder; AH, alcohol-associated hepatitis
Figure 2.
Figure 2.
Correlations between serum AhR activity and clinical parameters in patients with AH. Serum AhR activity and clinical parameters (A: Albumin, B: Total Bilirubin, C: Prothrombin time, D: WBC, E: MELD, F: MDF) were correlated in patients with AH. r indicates Spearman’s rank correlation coefficient. Abbreviations: AH, alcohol-associated hepatitis; AhR, aryl hydrocarbon receptor; MDF, Maddrey’s discriminant function; MELD, Model for End-Stage Liver Disease; WBC, white blood cells.
Figure 3.
Figure 3.
Kaplan-Meier survival curves for AH patients from the start of observation to 180 days AH patients were stratified into two groups using a cutoff value of 2.09 for serum AhR activity. Survival rates in AlcHepNet cohort (a) and InTeam cohort (b) were compared at 30, 60, 90, and 180 days. P-values were calculated at each point using the log-rank test. The number of patients at risk at each point is shown at the bottom of the figure. (c) Restricted cubic spline Cox model comparing log relative hazard of 90-day mortality with AhR activity (black line), with 95% confidence interval (grey). AhR, aryl hydrocarbon receptor
Figure 4.
Figure 4.
Kaplan-Meier survival curves stratified by the combination of existing prognostic markers and serum AhR activity (a) All AH cases were stratified into two groups by MELD 21, the defined criterium for severe AH. Survival rates between the two groups (MELD < 21, MELD ≥ 21) were compared at 30, 60, 90, and 180 days. P-values were calculated at each point using the log-rank test. (b) Severe AH cases with MELD 21 or higher were further stratified using a cutoff value of 2.09 for serum AhR activity. Survival rates between the two groups (MELD ≥ 21 and AhR activity < 2.09, MELD ≥ 21 and AhR activity ≥ 2.09) were compared at 30, 60, 90, and 180 days. P-values were calculated at each point using the log-rank test. (c) All AH cases were stratified into two groups by MDF 32, the defined criterium for severe AH. Survival rates between the two groups (MDF < 32, MDF ≥ 32) were compared at 30, 60, 90, and 180 days. (d) Severe AH cases with MDF 32 or higher were further stratified using a cutoff value of 2.09 for serum AhR activity. Survival rates between the two groups (MDF ≥ 32 and AhR activity < 2.09, MDF ≥ 32 and AhR activity ≥ 2.09) were compared at 30, 60, 90, and 180 days. P-values were calculated at each point using the log-rank test. The number of patients at risk at each point is shown at the bottom of the figure. AhR, aryl hydrocarbon receptor; MELD, The Model for End-stage Liver Disease score; MDF, Maddrey’s discriminant function
Figure 5.
Figure 5.
Serum AhR ligands (a) Heatmap of AhR ligands in serum from controls, patients with AUD and AH. (b) Verification of the function of bilirubin as an AhR ligand using HepG2-Lucia AhR reporter cells. Data are presented as mean ± S.E.M. **p < 0.01 and ***p < 0.001 denotes the significant difference between the groups. AhR, aryl hydrocarbon receptor
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