TY - JOUR
T1 - Ursodeoxycholic acid (udca) mitigates the host inflammatory response during clostridioides difficile infection by altering gut bile acids
AU - Winston, Jenessa A.
AU - Rivera, Alissa J.
AU - Cai, Jingwei
AU - Thanissery, Rajani
AU - Montgomery, Stephanie A.
AU - Patterson, Andrew D.
AU - Theriot, Casey M.
N1 - Funding Information:
J.A.W. was funded by the Ruth L. Kirschstein National Research Service Award Research Training grant T32OD011130 by NIH. This research was supported by work performed by The University of Michigan Microbial Systems Molecular Biology Laboratory (microbiome sequencing). The Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine, is supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. C.M.T. is funded by the National Institute of General Medical Sciences of the National Institutes of Health under award R35GM119438. This project was also funded by an intramural grant from the North Carolina State University College of Veterinary Medicine.
Publisher Copyright:
© 2020 American Society for Microbiology. All Rights Reserved.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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 cycles of various strains of C. difficile in vitro, suggesting that 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-κB. 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 nonantibiotic 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.
AB - 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 cycles of various strains of C. difficile in vitro, suggesting that 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-κB. 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 nonantibiotic 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.
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U2 - 10.1128/IAI.00045-20
DO - 10.1128/IAI.00045-20
M3 - Article
C2 - 32205405
AN - SCOPUS:85085265446
VL - 88
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 6
M1 - e00045
ER -
