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Hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease

BACKGROUND AND AIM: Anti‐tumor necrosis factor‐α (anti‐TNF‐α) agents have been used for inflammatory bowel disease; however, it has up to 30% nonresponse rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti‐TNF‐α treatment are needed. METHODS:...

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Autores principales: Yau, Tung On, Vadakekolathu, Jayakumar, Foulds, Gemma Ann, Du, Guodong, Dickins, Benjamin, Polytarchou, Christos, Rutella, Sergio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303672/
https://www.ncbi.nlm.nih.gov/pubmed/34931384
http://dx.doi.org/10.1111/jgh.15764
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author Yau, Tung On
Vadakekolathu, Jayakumar
Foulds, Gemma Ann
Du, Guodong
Dickins, Benjamin
Polytarchou, Christos
Rutella, Sergio
author_facet Yau, Tung On
Vadakekolathu, Jayakumar
Foulds, Gemma Ann
Du, Guodong
Dickins, Benjamin
Polytarchou, Christos
Rutella, Sergio
author_sort Yau, Tung On
collection PubMed
description BACKGROUND AND AIM: Anti‐tumor necrosis factor‐α (anti‐TNF‐α) agents have been used for inflammatory bowel disease; however, it has up to 30% nonresponse rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti‐TNF‐α treatment are needed. METHODS: Publicly available transcriptomic data from inflammatory bowel disease patients receiving anti‐TNF‐α therapy were systemically collected and integrated. In silico flow cytometry approaches and Metascape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti‐TNF‐α‐treated animal model (with lipopolysaccharide‐induced inflammation). The receiver operating characteristic curve was applied to all genes to identify the best prediction biomarkers. RESULTS: A total of 449 samples were retrieved from control, baseline, and after primary anti‐TNF‐α therapy or placebo. No statistically significant differences were observed between anti‐TNF‐α treatment responders and nonresponders at baseline in immune microenvironment scores. Neutrophil, endothelial cell, and B‐cell populations were higher in baseline nonresponders, and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly upregulated in lipopolysaccharide‐induced neutrophils, but no statistically significant changes were observed in neutrophils treated with anti‐TNF‐α. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (receiver operating characteristic curve: 80.7%, 95% confidence interval: 73.8–87.5%), with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in nonresponders compared with responders (P < 0.0001). CONCLUSIONS: Hyperactive neutrophil chemotaxis influences responses to anti‐TNF‐α treatment, and IL13RA2 is a potential biomarker to predict anti‐TNF‐α treatment response.
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spelling pubmed-93036722022-07-28 Hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease Yau, Tung On Vadakekolathu, Jayakumar Foulds, Gemma Ann Du, Guodong Dickins, Benjamin Polytarchou, Christos Rutella, Sergio J Gastroenterol Hepatol Original Articles ‐ Gastroenterology (Experimental) BACKGROUND AND AIM: Anti‐tumor necrosis factor‐α (anti‐TNF‐α) agents have been used for inflammatory bowel disease; however, it has up to 30% nonresponse rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti‐TNF‐α treatment are needed. METHODS: Publicly available transcriptomic data from inflammatory bowel disease patients receiving anti‐TNF‐α therapy were systemically collected and integrated. In silico flow cytometry approaches and Metascape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti‐TNF‐α‐treated animal model (with lipopolysaccharide‐induced inflammation). The receiver operating characteristic curve was applied to all genes to identify the best prediction biomarkers. RESULTS: A total of 449 samples were retrieved from control, baseline, and after primary anti‐TNF‐α therapy or placebo. No statistically significant differences were observed between anti‐TNF‐α treatment responders and nonresponders at baseline in immune microenvironment scores. Neutrophil, endothelial cell, and B‐cell populations were higher in baseline nonresponders, and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly upregulated in lipopolysaccharide‐induced neutrophils, but no statistically significant changes were observed in neutrophils treated with anti‐TNF‐α. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (receiver operating characteristic curve: 80.7%, 95% confidence interval: 73.8–87.5%), with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in nonresponders compared with responders (P < 0.0001). CONCLUSIONS: Hyperactive neutrophil chemotaxis influences responses to anti‐TNF‐α treatment, and IL13RA2 is a potential biomarker to predict anti‐TNF‐α treatment response. John Wiley and Sons Inc. 2022-02-02 2022-03 /pmc/articles/PMC9303672/ /pubmed/34931384 http://dx.doi.org/10.1111/jgh.15764 Text en © 2021 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles ‐ Gastroenterology (Experimental)
Yau, Tung On
Vadakekolathu, Jayakumar
Foulds, Gemma Ann
Du, Guodong
Dickins, Benjamin
Polytarchou, Christos
Rutella, Sergio
Hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease
title Hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease
title_full Hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease
title_fullStr Hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease
title_full_unstemmed Hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease
title_short Hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease
title_sort hyperactive neutrophil chemotaxis contributes to anti‐tumor necrosis factor‐α treatment resistance in inflammatory bowel disease
topic Original Articles ‐ Gastroenterology (Experimental)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303672/
https://www.ncbi.nlm.nih.gov/pubmed/34931384
http://dx.doi.org/10.1111/jgh.15764
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