Nonsteroidal anti-inflammatory drugs alter the microbiota and exacerbate Clostridium difficile colitis while dysregulating the inflammatory response

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 nosocomial CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alt...

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Published inbioRxiv
Main Authors Maseda, Damian, Zackular, Joseph P, Trindade, Bruno, Kirk, Leslie, Crofford, Leslie J, Schloss, Patrick D, Jennifer Lising Roxas, Viswanathan, V K, Vedantam, Gayatri, Rogers, Lisa M, Washington, Mary Kay, Skaar, Eric P, Aronoff, David M
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.08.2018
Subjects
CD4 antigen
Cell junctions
Colitis
Epithelial cells
Health risk assessment
Hospitals
Immune response
Immunosuppressive agents
Indomethacin
Inflammation
Intestinal microflora
Intestine
Leukocytes (neutrophilic)
Microbiota
Nonsteroidal anti-inflammatory drugs
Prostaglandin endoperoxide synthase
Public health
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Summary: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 nosocomial 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 intestinal pathology associated with CDI in mice. We demonstrate that in C. difficile-infected animals, indomethacin leads to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by an increased recruitment of intestinal neutrophils and CD4+ cells. Together, these data implicate NSAIDs in perturbation of the gut microbiota and disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses.
DOI:10.1101/391607