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Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin–mediated mitochondrial damage
Clostridioides difficile damages the colonic mucosa through the action of two potent exotoxins. Factors shaping C. difficile pathogenesis are incompletely understood but are likely due to the ecological factors in the gastrointestinal ecosystem, mucosal immune responses, and environmental factors. L...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355836/ https://www.ncbi.nlm.nih.gov/pubmed/37467340 http://dx.doi.org/10.1126/sciadv.adh5552 |
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author | Soto Ocaña, Joshua Bayard, Nile U. Hart, Jessica L. Thomas, Audrey K. Furth, Emma E. Lacy, D. Borden Aronoff, David M. Zackular, Joseph P. |
author_facet | Soto Ocaña, Joshua Bayard, Nile U. Hart, Jessica L. Thomas, Audrey K. Furth, Emma E. Lacy, D. Borden Aronoff, David M. Zackular, Joseph P. |
author_sort | Soto Ocaña, Joshua |
collection | PubMed |
description | Clostridioides difficile damages the colonic mucosa through the action of two potent exotoxins. Factors shaping C. difficile pathogenesis are incompletely understood but are likely due to the ecological factors in the gastrointestinal ecosystem, mucosal immune responses, and environmental factors. Little is known about the role of pharmaceutical drugs during C. difficile infection (CDI), but recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI. The mechanism underlying this phenomenon remains unclear. Here, we show that NSAIDs exacerbate CDI by disrupting colonic epithelial cells (CECs) and sensitizing cells to C. difficile toxin–mediated damage independent of their canonical role of inhibiting cyclooxygenase (COX) enzymes. Notably, we find that NSAIDs and C. difficile toxins target the mitochondria of CECs and enhance C. difficile toxin–mediated damage. Our results demonstrate that NSAIDs exacerbate CDI by synergizing with C. difficile toxins to damage host cell mitochondria. Together, this work highlights a role for NSAIDs in exacerbating microbial infection in the colon. |
format | Online Article Text |
id | pubmed-10355836 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-103558362023-07-20 Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin–mediated mitochondrial damage Soto Ocaña, Joshua Bayard, Nile U. Hart, Jessica L. Thomas, Audrey K. Furth, Emma E. Lacy, D. Borden Aronoff, David M. Zackular, Joseph P. Sci Adv Biomedicine and Life Sciences Clostridioides difficile damages the colonic mucosa through the action of two potent exotoxins. Factors shaping C. difficile pathogenesis are incompletely understood but are likely due to the ecological factors in the gastrointestinal ecosystem, mucosal immune responses, and environmental factors. Little is known about the role of pharmaceutical drugs during C. difficile infection (CDI), but recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI. The mechanism underlying this phenomenon remains unclear. Here, we show that NSAIDs exacerbate CDI by disrupting colonic epithelial cells (CECs) and sensitizing cells to C. difficile toxin–mediated damage independent of their canonical role of inhibiting cyclooxygenase (COX) enzymes. Notably, we find that NSAIDs and C. difficile toxins target the mitochondria of CECs and enhance C. difficile toxin–mediated damage. Our results demonstrate that NSAIDs exacerbate CDI by synergizing with C. difficile toxins to damage host cell mitochondria. Together, this work highlights a role for NSAIDs in exacerbating microbial infection in the colon. American Association for the Advancement of Science 2023-07-19 /pmc/articles/PMC10355836/ /pubmed/37467340 http://dx.doi.org/10.1126/sciadv.adh5552 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Soto Ocaña, Joshua Bayard, Nile U. Hart, Jessica L. Thomas, Audrey K. Furth, Emma E. Lacy, D. Borden Aronoff, David M. Zackular, Joseph P. Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin–mediated mitochondrial damage |
title | Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin–mediated mitochondrial damage |
title_full | Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin–mediated mitochondrial damage |
title_fullStr | Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin–mediated mitochondrial damage |
title_full_unstemmed | Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin–mediated mitochondrial damage |
title_short | Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin–mediated mitochondrial damage |
title_sort | nonsteroidal anti-inflammatory drugs sensitize epithelial cells to clostridioides difficile toxin–mediated mitochondrial damage |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355836/ https://www.ncbi.nlm.nih.gov/pubmed/37467340 http://dx.doi.org/10.1126/sciadv.adh5552 |
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