Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Neutrophils are potent inducers of hepatocyte injury in AH through the release of reactive oxygen species (ROS) and via degranulation.
“Neutrophils are also potent inducers of hepatocyte injury in AH through the release of reactive oxygen species (ROS) [85] and via degranulation [86].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [86]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters
Yu, G., Wang, L.-G., Han, Y., & He, Q.-Y. (2012) · OMICS: A Journal of Integrative Biology · doi:10.1089/omi.2011.0118 · Cited by 36,259 · see citing works
Eng, J. K., McCormack, A. L., & Yates, J. R. (1994) · Journal of the American Society for Mass Spectrometry · doi:10.1016/1044-0305(94)80016-2 · Cited by 6,484 · see citing works
Griswold, M. G., Fullman, N., Hawley, C., Arian, N., Zimsen, S. R. M., Tymeson, H. D., Venkateswaran, V., Tapp, A. D., Forouzanfar, M. H., Salama, J. S., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(18)31310-2 · Cited by 3,524 · see citing works
Self-citationAlcoholic Liver Disease: Pathogenesis and New Therapeutic Targets
Gao, B., & Bataller, R. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.09.002 · Cited by 1,963 · see citing works
Self-citationThe multifaceted functions of neutrophils
Mayadas, T. N., Cullere, X., & Lowell, C. A. (2014) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-164023 · Cited by 1,356 · see citing works
Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease
Duan, Y., Llorente, C., Lang, S., Brandl, K., Chu, H., Jiang, L., White, R. C., Clarke, T. H., Nguyen, K., Torralba, M., et al. (2019) · Nature · doi:10.1038/s41586-019-1742-x · Cited by 851 · see citing works
Self-citationACG Clinical Guideline: Alcoholic Liver Disease
Singal, A. K., Bataller, R. A., Ahn, J. C., Kamath, P. S., & Shah, V. H. (2018) · The American Journal of Gastroenterology · doi:10.1038/ajg.2017.469 · Cited by 834 · see citing works
Self-citationA genome-wide transcriptomic analysis of protein-coding genes in human blood cells
Uhlen, M., Karlsson, M. J., Zhong, W., Tebani, A., Pou, C., Mikes, J., Lakshmikanth, T., Forsström, B., Edfors, F., Odeberg, J., et al. (2019) · Science · doi:10.1126/science.aax9198 · Cited by 594 · see citing works
Younossi, Z. M., Stepanova, M., Ong, J. P., Trimble, G., Alqahtani, S. A., Younossi, I. M., Ahmed, A., Racila, A., & Henry, L. L. (2020) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2020.05.064 · Cited by 587 · see citing works
Calprotectin: from biomarker to biological function
Jukic, A., Bakiri, L., Wagner, E. F., Tilg, H., & Adolph, T. E. (2021) · Gut · doi:10.1136/gutjnl-2021-324855 · Cited by 500 · see citing works
A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis
Altamirano, J., Miquel, R., Katoonizadeh, A., Abraldeṣ, J. G., Duarte‐Rojo, A., Louvet, A., Augustín, S., Mookerjee, R. P., Michelena, J., Smyrk, T. C., et al. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.01.018 · Cited by 421 · see citing works
Self-citationMills, R. H., Dulai, P. S., Vázquez-Baeza, Y., Sauceda, C., Daniel, N., Gerner, R. R., Batachari, L. E., Malfavon, M., Zhu, Q., Weldon, K., et al. (2022) · Nature Microbiology · doi:10.1038/s41564-021-01050-3 · Cited by 385 · see citing works
Self-citationYang, W., Tao, Y., Wu, Y., Zhao, X., Ye, W., Zhao, D., Fu, L., Tian, C., Yang, J., He, F., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09046-8 · Cited by 367 · see citing works
Fitting Multivariate Models to Community Data: A Comment on Distance-Based Redundancy Analysis
McArdle, B. H., & Anderson, M. J. (2001) · Ecology · doi:10.2307/2680104 · Cited by 359 · see citing works
Mookerjee, R. P., Stadlbauer, V., Lidder, S., Wright, G. A. K., Hodges, S. J., Davies, N. A., & Jalan, R. (2007) · Hepatology · doi:10.1002/hep.21737 · Cited by 332 · see citing works
Noninvasive proteomic biomarkers for alcohol-related liver disease
Niu, L., Thiele, M. S., Geyer, P. E., Rasmussen, D. N., Webel, H. E., Santos, A., Gupta, R., Meier, F., Strauss, M. T., Kjærgaard, M., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01850-y · Cited by 320 · see citing works
Chen, P., Stärkel, P., Turner, J. R., Ho, S. B., & Schnabl, B. (2015) · Hepatology · doi:10.1002/hep.27489 · Cited by 312 · see citing works
Self-citationBataller, R., Arab, J. P., & Shah, V. H. (2022) · New England Journal of Medicine · doi:10.1056/nejmra2207599 · Cited by 259 · see citing works
Self-citationGranule protein processing and regulated secretion in neutrophils
Sheshachalam, A., Srivastava, N., Mitchell, T., Lacy, P., & Eitzen, G. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00448 · Cited by 247 · see citing works
Lang, S., Duan, Y., Liu, J., Torralba, M., Kuelbs, C., Cots, M. V., Abraldeṣ, J. G., Bosques‐Padilla, F., Verna, E. C., Brown, R. S., et al. (2019) · Hepatology · doi:10.1002/hep.30832 · Cited by 239 · see citing works
Self-citationMuthas, D., Reznichenko, A., Balendran, C. A., Böttcher, G., Clausen, I. G., Mårdh, C. K., Ottosson, T., Uddin, M., MacDonald, T. T., Danese, S., et al. (2016) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365521.2016.1235224 · Cited by 179 · see citing works
Intestinal Virome in Patients With Alcoholic Hepatitis
Jiang, L., Lang, S., Duan, Y., Zhang, X., Gao, B., Chopyk, J., Schwanemann, L. K., Cots, M. V., Bataller, R. A., Bosques‐Padilla, F., et al. (2020) · Hepatology · doi:10.1002/hep.31459 · Cited by 149 · see citing works
Self-citationCho, Y., Bukong, T. N., Tornai, D., Babuta, M., Vlachos, I. S., Kanata, E., Catalano, D., & Szabo, G. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2022.08.029 · Cited by 143 · see citing works
Louvet, A., Labreuche, J., Moreno, C., Vanlemmens, C., Moirand, R., Féray, C., Dumortier, J., Pageaux, G.-P., Bureau, C., Chermak, F., et al. (2022) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(21)00430-1 · Cited by 136 · see citing works
Self-citationTaı̈eb, J., Mathurin, P., Elbim, C., et al. (2000) · Journal of Hepatology · doi:10.1016/s0168-8278(00)80219-6 · Cited by 132 · see citing works
Self-citationDavies, M. J. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107685 · Cited by 119 · see citing works
Carbone, M., Nardi, A., Flack, S., Carpino, G., Varvaropoulou, N., Gavrila, C., Spicer, A., Badrock, J., Bernuzzi, F., Cardinale, V., et al. (2018) · HAL · doi:10.1016/s2468-1253 · Cited by 119 · see citing works
Lang, S., Fairfied, B., Gao, B., et al. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1785251 · Cited by 104 · see citing works
Morales-Arráez, D. E., Cots, M. V., Altamirano, J., Abraldeṣ, J. G., Cruz-Lemini, M., Thursz, M. R., Atkinson, S. R., Sarin, S. K., Kim, W. K., Chavez-Araujo, R., et al. (2021) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000001596 · Cited by 92 · see citing works
Self-citationMa, J., Guillot, A., Yang, Z., Mackowiak, B., Hwang, S., Park, O., Peiffer, B. J., Ahmadi, A. R., Melo, L., Kusumanchi, P., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci157780 · Cited by 90 · see citing works
Self-citationQuast, J.-P., Schuster, D., & Picotti, P. (2021) · Bioinformatics Advances · doi:10.1093/bioadv/vbab041 · Cited by 89 · see citing works
Fecal levels of leukocyte markers reflect disease activity in patients with ulcerative colitis
Peterson, C. G. B., Sangfelt, P., Wagner, M., Hansson, T., Lettesjö, H., & Carlson, M. (2007) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365510701452838 · Cited by 85 · see citing works
Taı̈eb, J., Delarche, C., Paradis, V., Mathurin, P., Grenier, A., Crestani, B., Dehoux, M., Thabut, D., Gougerot-Pocidalo, M.-A., Poynard, T., et al. (2002) · Journal of Hepatology · doi:10.1016/s0168-8278(01)00276-8 · Cited by 73 · see citing works
Self-citationLi, X., Schwacha, M. G., Chaudry, I. H., & Choudhry, M. A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.10.6933 · Cited by 65 · see citing works
The role of neutrophils in alcohol-related hepatitis
Khan, R. S., Lalor, P. F., Thursz, M. R., & Newsome, P. N. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.05.017 · Cited by 63 · see citing works
Lapek, J. D., Lewinski, M. K., Wozniak, J. M., Guatelli, J., & Gonzalez, D. J. (2017) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m116.066019 · Cited by 59 · see citing works
Self-citationSoomro, S., Venkateswaran, S., Vanarsa, K., Kharboutli, M., Nidhi, M., Susarla, R., Zhang, T., Sasidharan, P., Lee, K. H., Rosh, J. R., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24235-0 · Cited by 55 · see citing works
Influence of Serum Sodium on MELD-Based Survival Prediction in Alcoholic Hepatitis
Stelling, B. E. V., Asrani, S. K., Dunn, W., et al. (2010) · Mayo Clinic Proceedings · doi:10.4065/mcp.2010.0281 · Cited by 49 · see citing works
Clinical, histological and molecular profiling of different stages of alcohol-related liver disease
Cots, M. V., Argemí, J., Jones, P. D., Lackner, C., Hag, M. I. E., Abraldeṣ, J. G., Alvarado‐Tápias, E., Clemente, A. P. G., Ravi, S., Alves, A., et al. (2022) · Gut · doi:10.1136/gutjnl-2021-324295 · Cited by 47 · see citing works
Self-citationDayam, R. M., Sun, C., Choy, C. H., et al. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601466 · Cited by 45 · see citing works
Elpek, G. O. (2021) · World Journal of Gastroenterology · doi:10.3748/wjg.v27.i45.7739 · Cited by 31 · see citing works
Pharmacological interventions for alcoholic liver disease (alcohol-related liver disease)
Buzzetti, E., Kalafateli, M., Thorburn, D., Davidson, B. R., Thiele, M. S., Gluud, L. L., Giovane, C. D., Askgaard, G., Krag, A. A., Tsochatzis, E. A., et al. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011646.pub2 · Cited by 27 · see citing works
Morales-Arráez, D. E., Cots, M. V., Altamirano, J., et al. (2022) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000001704 · Cited by 20 · see citing works
Self-citationLi, X., Luck, M. E., Herrnreiter, C. J., Cannon, A. R., & Choudhry, M. A. (2022) · ImmunoHorizons · doi:10.4049/immunohorizons.2100109 · Cited by 13 · see citing works
LPS-TLR4 pathway exaggerates alcoholic hepatitis via provoking NETs formation
Liu, Y., Chen, S., Yu, S., Wang, J., Zhang, X., Lv, H., Aboubacar, H., Gao, N., Ran, X., Sun, Y., et al. (2023) · Gastroenterología y Hepatología · doi:10.1016/j.gastrohep.2023.05.002 · Cited by 13 · see citing works
Self-citationMaccioni, L., Horsmans, Y., Leclercq, I., Schnabl, B., & Stärkel, P. (2023) · Alcohol: Clinical and Experimental Research · doi:10.1111/acer.15081 · Cited by 10 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
- Authors
- Kreimeyer, H., Gonzalez, C. G., Fondevila, M. F., Hsu, C. L., Hartmann, P., Zhang, X., Stärkel, P., Bosques-Padilla, F., Verna, E. C., Abraldes, J. G., Brown, R. S., Vargas, V., Altamirano, J., Caballería, J., Shawcross, D. L., Louvet, A., Lucey, M. R., Mathurin, P., Garcia-Tsao, G., Bataller, R., Investigators, A., Gonzalez, D. J., & Schnabl, B.
- Affiliations
- University of California San Diego (US)
- Cliniques Universitaires Saint-Luc (BE)
- Hospital Universitario, Departamento de Gastroenterología, Universidad Autónoma de Nuevo León, Monterrey, Mexico
- Columbia University Irving Medical Center (US)
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada
- Weill Cornell Medicine (US)
- Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- Hospital Clínic de Barcelona (ES)
- King's College London (GB)
- Lille Inflammation Research International Center (FR)
- University of Wisconsin–Madison (US)
- Hôpital Claude Huriez (FR)
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
- Liver Unit, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Roster for authorship, listed in Collaborators
- Corresponding author
- Schnabl, Bernd
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2024-07-20
- Volume
- 74
- Issue
- 1
- Pages
- 103-115
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC11631684
- OpenAlex
- W4400892821
- Cited by
- 12
- References
- 46
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 1
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- HAL (submittedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion)
- Funders
- NIH (P30 DK120515, P50 AA011999, R01 AA020703, R01 AA024726, U01 AA026939, U01 AA026939-04S1)
- Galicia Regional Government and Fulbright Fellowship (ED481B-2022-030)
- Service of the VA Office of Research and Development (Not applicable)
- Biomedical Laboratory Research & Development (BX004594)
- Deutsche Forschungsgemeinschaft (KR 5843 1-1)
- Center for Multiplexed Proteomics (K12GM068524)
- Fond national de recherche scientifique Belgium (J.0146.17, J.0195.24, T.0217.18)
- University of California San Diego (Not Applicable)
- American Association for the Study of Liver Diseases (PNC22-159963, CTORA23-208366)
- National Institutes of Health (KL2TR001444)
- San Diego Digestive Diseases Research Center (P30 DK120515)
- Université Catholique de Louvain, Belgium (Not Applicable)
- National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (J.0146.17, J.0195.24, P50AA011999, T.0217.18, T32 DK007202)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- alcoholic hepatitis, neutrophil degranulation, myeloperoxidase, prognostic factors, mortality prediction, alcoholism, neutrophil granules, disease severity, gut dysbiosis, non-invasive biomarkers
- MeSH terms
- Adult, Feces, Female, Hepatitis, Alcoholic, Humans, Male, Middle Aged, Neutrophils, Prognosis, Biomarkers, Cell Degranulation, Case-Control Studies, Proteomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
