Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response

ABSTRACT Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter...

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Autores principales:	Damian Maseda, Joseph P. Zackular, Bruno Trindade, Leslie Kirk, Jennifer Lising Roxas, Lisa M. Rogers, Mary K. Washington, Liping Du, Tatsuki Koyama, V. K. Viswanathan, Gayatri Vedantam, Patrick D. Schloss, Leslie J. Crofford, Eric P. Skaar, David M. Aronoff
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Clostridium difficile colitis gut inflammation immune dysfunction immune response inflammation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/492be4d6751442bda2d9d927ff64c839
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spelling	oai:doaj.org-article:492be4d6751442bda2d9d927ff64c8392021-11-15T15:55:14ZNonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response10.1128/mBio.02282-182150-7511https://doaj.org/article/492be4d6751442bda2d9d927ff64c8392019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02282-18https://doaj.org/toc/2150-7511ABSTRACT Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in C. difficile-infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4+ cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses. IMPORTANCE Clostridium difficile infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.Damian MasedaJoseph P. ZackularBruno TrindadeLeslie KirkJennifer Lising RoxasLisa M. RogersMary K. WashingtonLiping DuTatsuki KoyamaV. K. ViswanathanGayatri VedantamPatrick D. SchlossLeslie J. CroffordEric P. SkaarDavid M. AronoffAmerican Society for MicrobiologyarticleClostridium difficilecolitisgut inflammationimmune dysfunctionimmune responseinflammationMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium difficile colitis gut inflammation immune dysfunction immune response inflammation Microbiology QR1-502
spellingShingle	Clostridium difficile colitis gut inflammation immune dysfunction immune response inflammation Microbiology QR1-502 Damian Maseda Joseph P. Zackular Bruno Trindade Leslie Kirk Jennifer Lising Roxas Lisa M. Rogers Mary K. Washington Liping Du Tatsuki Koyama V. K. Viswanathan Gayatri Vedantam Patrick D. Schloss Leslie J. Crofford Eric P. Skaar David M. Aronoff Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response
description	ABSTRACT Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in C. difficile-infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4+ cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses. IMPORTANCE Clostridium difficile infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.
format	article
author	Damian Maseda Joseph P. Zackular Bruno Trindade Leslie Kirk Jennifer Lising Roxas Lisa M. Rogers Mary K. Washington Liping Du Tatsuki Koyama V. K. Viswanathan Gayatri Vedantam Patrick D. Schloss Leslie J. Crofford Eric P. Skaar David M. Aronoff
author_facet	Damian Maseda Joseph P. Zackular Bruno Trindade Leslie Kirk Jennifer Lising Roxas Lisa M. Rogers Mary K. Washington Liping Du Tatsuki Koyama V. K. Viswanathan Gayatri Vedantam Patrick D. Schloss Leslie J. Crofford Eric P. Skaar David M. Aronoff
author_sort	Damian Maseda
title	Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response
title_short	Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response
title_full	Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response
title_fullStr	Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response
title_full_unstemmed	Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response
title_sort	nonsteroidal anti-inflammatory drugs alter the microbiota and exacerbate <italic toggle="yes">clostridium difficile</italic> colitis while dysregulating the inflammatory response
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/492be4d6751442bda2d9d927ff64c839
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Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate <italic toggle="yes">Clostridium difficile</italic> Colitis while Dysregulating the Inflammatory Response

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