Development and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions

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dc.contributor.authorSharma, Neha
dc.contributor.authorChwastek, Damian
dc.contributor.authorDwivedi, Dhruva J.
dc.contributor.authorSchlechte, Jared
dc.contributor.authorYu, Ian-Ling
dc.contributor.authorMcDonald, Braedon
dc.contributor.authorArora, Jaskirat
dc.contributor.authorCani, Erblin
dc.contributor.authorEng, Mikaela
dc.contributor.authorEngelberts, Doreen
dc.contributor.authorKuhar, Eva
dc.contributor.authorMedeiros, Sarah K.
dc.contributor.authorBourque, Stephane L.
dc.contributor.authorCepinskas, Gediminas
dc.contributor.authorGill, Sean E.
dc.contributor.authorJahandideh, Forough
dc.contributor.authorMacala, Kimberly F.
dc.contributor.authorPanahi, Sareh
dc.contributor.authorPape, Cynthia
dc.contributor.authorSontag, David
dc.contributor.authorSunohara-Neilson, Janet
dc.contributor.authorFergusson, Dean A.
dc.contributor.authorFox-Robichaud, Alison E.
dc.contributor.authorLiaw, Patricia C.
dc.contributor.authorLalu, Manoj M.
dc.contributor.authorMendelson, Asher A.
dc.date.accessioned2023-07-23T00:03:54Z
dc.date.available2023-07-23T00:03:54Z
dc.date.issued2023-07-17
dc.date.updated2023-07-23T00:03:54Z
dc.description.abstractAbstract Background Preclinical sepsis models have been criticized for their inability to recapitulate human sepsis and suffer from methodological shortcomings that limit external validity and reproducibility. The National Preclinical Sepsis Platform (NPSP) is a consortium of basic science researchers, veterinarians, and stakeholders in Canada undertaking standardized multi-laboratory sepsis research to increase the efficacy and efficiency of bench-to-bedside translation. In this study, we aimed to develop and characterize a 72-h fecal-induced peritonitis (FIP) model of murine sepsis conducted in two independent laboratories. The experimental protocol was optimized by sequentially modifying dose of fecal slurry and timing of antibiotics in an iterative fashion, and then repeating the experimental series at site 1 and site 2. Results Escalating doses of fecal slurry (0.5ā€“2.5 mg/g) resulted in increased disease severity, as assessed by the modified Murine Sepsis Score (MSS). However, the MSS was poorly associated with progression to death during the experiments, and mice were found dead without elevated MSS scores. Administration of early antibiotics within 4 h of inoculation rescued the animals from sepsis compared with late administration of antibiotics after 12 h, as evidenced by 100% survival and reduced bacterial load in peritoneum and blood in the early antibiotic group. Site 1 and site 2 had statistically significant differences in mortality (60% vs 88%; pā€‰<ā€‰0.05) for the same dose of fecal slurry (0.75 mg/g) and marked differences in body temperature between groups. Conclusions We demonstrate a systematic approach to optimizing a 72-h FIP model of murine sepsis for use in multi-laboratory studies. Alterations to experimental conditions, such as dose of fecal slurry and timing of antibiotics, have clear impact on outcomes. Differences in mortality between sites despite rigorous standardization warrants further investigations to better understand inter-laboratory variation and methodological design in preclinical studies.
dc.identifier.citationIntensive Care Medicine Experimental. 2023 Jul 17;11(1):45
dc.identifier.urihttps://doi.org/10.1186/s40635-023-00533-3
dc.identifier.urihttps://hdl.handle.net/1880/116788
dc.identifier.urihttps://dx.doi.org/10.11575/PRISM/41630
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dc.titleDevelopment and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions
dc.typeJournal Article
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