Word count = 143 23Text word count = 5339 24 . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/391607 doi: bioRxiv preprint first posted online Aug. 14, 2018; 2
Abstract 25Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of 26 nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and 27 severity of nosocomial CDI; however, the mechanisms driving this phenomenon have not been 28 elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) 29 enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered 30 the microbiota and dramatically increased mortality and intestinal pathology associated with CDI 31in mice. We demonstrate that in C. difficile-infected animals, indomethacin lead to PG 32 deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed 33 epithelial cell junctions. These effects were paralleled by an increased recruitment of intestinal 34 neutrophils and CD4 + cells. Together, these data implicate NSAIDs in perturbation of the gut 35 microbiota and disruption of protective COX-mediated PG production during CDI, resulting in 36 altered epithelial integrity and associated immune responses. 37. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/391607 doi: bioRxiv preprint first posted online Aug. 14, 2018; 3 Clostridium difficile is the most commonly reported nosocomial pathogen in the United 38States and an urgent public health threat worldwide(1). C. difficile infection (CDI) manifests as a 39 spectrum of gastrointestinal disorders ranging from mild-diarrhea to toxic megacolon and/or 40 death, particularly in older adults(2). The primary risk factor for CDI is antibiotic treatment, which 41 perturbs the resident gut microbiota and abolishes colonization resistance(3). However, factors 42 other than antibiotic exposure increase the risk for CDI and cases not associated with the use of 43 antimicrobials have been on the rise(4). Defining mechanisms whereby non-antibiotic factors 44 impact CDI pathogenesis promises to reveal actionable targets for preventing or treating this 45
infection. 46Recently, several previously unappreciated immune system, host, microbiota, and 47 dietary factors have emerged as modulators of CDI severity and risk. The food additive 48 trehalose, for example, was recently shown to increase C. difficile virulence in mice and the 49 widespread adoption of trehalose in food products was implicated in the emergence of 50 hypervirulent strains of C. difficile (5). Similarly, excess dietary z...