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bioRxiv · 10.1101/2020.01.16.910018

Ursodeoxycholic acid (UDCA) mitigates the host inflammatory response during Clostridioides difficile infection by altering gut bile acids which attenuates NF-κB signaling via bile acid activated receptors

Winston, J. A.·Rivera, A. M.·Cai, J.·Thanissery, R. M.·Montgomery, S. A.·Patterson, A. D.·Theriot, C. M.
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Abstract

Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA, ursodiol) inhibits the life cycle of various strains of C. difficile in vitro, suggesting the FDA approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid activated receptors nuclear farnesoid X receptor (FXR), and transmembrane G protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-{kappa}B. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable non-antibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid activated receptors, FXR and TGR5, represents a new potential treatment strategy for patients with CDI. ImportanceThe clinical utility of ursodiol for prevention of recurrent CDI is currently in Phase 4 clinical trials. However, the mechanism by which ursodiol exerts its impacts on C. difficile pathogenesis is poorly understood. Herein, we demonstrated that ursodiol pretreatment attenuates CDI pathogenesis early in the course of disease in mice, which coincides with alterations in the cecal and colonic inflammatory transcriptome, bile acid activated receptors nuclear farnesoid X receptor (FXR), and transmembrane G protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-{kappa}B. Ursodiol attenuated an overly robust inflammatory response that is detrimental to the host during CDI, and thus remains a viable non-antibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid activated receptors, FXR and TGR5, represents a new potential treatment strategy for patients with CDI. AbbreviationsMCA - -Muricholic acid; {beta}MCA -{beta}-Muricholic acid; {omega}MCA -{omega}-Muricholic acid; CA - Cholic acid; CDCA - Chenodeoxycholic acid; DCA - Deoxycholic acid; GCDCA - Glycochenodeoxycholic acid; GDCA - Glycodeoxycholic acid; GLCA - Glycolithocholic acid; GUDCA - Glycoursodeoxycholic acid; HCA - Hyodeoxycholic acid; iDCA - Isodeoxycholic acid; iLCA - Isolithocholic acid; LCA - Lithocholic acid; TCA - Taurocholic acid; TCDCA - Taurochenodeoxycholic acid; TDCA - Taurodeoxycholic acid; THCA - Taurohyodeoxycholic acid; TUDCA - Tauroursodeoxycholic acid; T{beta}MCA- Tauro-{beta}-muricholic acid; T{omega}MCA -Tauro {omega}-muricholic acid; UDCA Ursodeoxycholic acid.

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Winston, J. A., Rivera, A. M., Cai, J., Thanissery, R. M., Montgomery, S. A., Patterson, A. D., Theriot, C. M.. 2020-01-21. Ursodeoxycholic acid (UDCA) mitigates the host inflammatory response during Clostridioides difficile infection by altering gut bile acids which attenuates NF-κB signaling via bile acid activated receptors. https://doi.org/10.1101/2020.01.16.910018

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