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

Abstract

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 CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint .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 CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint .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...

Gut Microbiota in NSAID Enteropathy: New Insights From Inside

“…reported that the risk of Clostridium difficile -associated diarrhea was increased among patients exposed to NSAIDs ( Permpalung et al., 2016 ), and indomethacin can increase severity of Clostridium difficile infection in mouse model ( Muñoz-Miralles et al., 2018 ). Further research showed that NSAIDs alter the gut microbiota and exacerbate Clostridium difficile colitis ( Maseda et al., 2019 ). These results revealed that NSAIDs could cause Clostridium difficile infection, which exacerbates intestinal damage by releasing two protein exotoxins (TcdA and TcdB) ( Leffler and Lamont, 2015 ).…”

Environmental Exposures and Autoimmune Diseases: Contribution of Gut Microbiome

“…Treatment of vancomycin reshaped the gut microbiome composition and improved intestinal barrier function by increasing the tight junction proteins (Occludin, ZO-1) (89). Traditional standard treatments for autoimmunity have been immunosuppressive medications that dampen the immune system non-specifically and alter the gut microbiome composition (111,112). Furthermore, microbiome-drug interactions also provide mechanistic insight into the role of gut microbiota in drug efficacy and toxicity (113).…”

The adaptive immune response toClostridioides difficile: A tricky balance between immunoprotection and immunopathogenesis

“…Moreover, in the work from Saleh et almice have been exposed to gut inflammation; they actually showed that colitis induces a population of Th17 cells that persists beyond the resolution of inflammation, and that this population predisposes the host to severe subsequent CDI. In another work, mice treated with nonsteroidal anti-inflammatory drugs, such as indomethacin, developed a more severe CDI that was correlated with an increase of the Th17 response 123. However, since they do not show a causal relationship, it remains unclear whether Th17 cells alone are necessary and sufficient to exacerbate CDI severity in indomethacintreated mice.It is important to highlight that even less is known about the role of IL-17 in human.…”