TY - JOUR
T1 - Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis
AU - AlcHepNet Investigators
AU - Kreimeyer, Henriette
AU - Gonzalez, Carlos G.
AU - Fondevila, Marcos F.
AU - Hsu, Cynthia L.
AU - Hartmann, Phillipp
AU - Zhang, Xinlian
AU - Stärkel, Peter
AU - Bosques-Padilla, Francisco
AU - Verna, Elizabeth C.
AU - Abraldes, Juan G.
AU - Brown, Robert S.
AU - Vargas, Victor
AU - Altamirano, Jose
AU - Caballería, Juan
AU - Shawcross, Debbie L.
AU - Louvet, Alexandre
AU - Lucey, Michael R.
AU - Mathurin, Philippe
AU - Garcia-Tsao, Guadalupe
AU - Bataller, Ramón
AU - Gonzalez, David J.
AU - Schnabl, Bernd
AU - Chalasani, Naga
AU - Nephew, Lauren
AU - Patidar, Kavish R.
AU - Vuppalanchi, Raj
AU - Samala, Niha
AU - Yoder, Lindsey
AU - Liangpunsakul, Suthat
AU - Prange, Shawna
AU - Shah, Vijay H.
AU - Simonetto, Douglas A.
AU - Kamath, Patrick
AU - Vargas, Hugo E.
AU - Yang, Liu
AU - Dasarathy, Srinivasan
AU - Welch, Nicole
AU - Bellar, Annette
AU - Attaway, Amy
AU - Dasarathy, Jaividhya
AU - Growley, Ashley
AU - Streem, David
AU - Nagy, Laura E.
AU - Mitchell, Mack C.
AU - Herlong, H. Franklin
AU - Kerr, Thomas
AU - Cotter, Thomas
AU - Sanyal, Arun
AU - O'Connor, Sara
AU - Luketic, Velimir
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2025.
PY - 2024/12/10
Y1 - 2024/12/10
N2 - Objective Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils. Design In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet). Result Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days. Conclusions We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.
AB - Objective Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils. Design In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet). Result Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days. Conclusions We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.
KW - ALCOHOL-INDUCED INJURY
KW - ALCOHOLIC LIVER DISEASE
UR - https://www.scopus.com/pages/publications/85199526799
UR - https://www.scopus.com/inward/citedby.url?scp=85199526799&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2024-332730
DO - 10.1136/gutjnl-2024-332730
M3 - Article
C2 - 39033024
AN - SCOPUS:85199526799
SN - 0017-5749
VL - 74
SP - 103
EP - 115
JO - Gut
JF - Gut
IS - 1
ER -