Dataset Information

Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids.

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 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-?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 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.

SUBMITTER: Winston JA

PROVIDER: S-EPMC7240095 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids.

Winston Jenessa A JA Rivera Alissa J AJ Cai Jingwei J Thanissery Rajani R Montgomery Stephanie A SA Patterson Andrew D AD Theriot Casey M CM

Infection and immunity 20200520 6

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. difficilein vitro, suggesting that the FDA-approved formula ...[more]

PMID: 32205405

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Project description:The anaerobic bacterium Clostridioides difficile represents one of the most problematic pathogens, especially in hospitals. Dysbiosis has been proven to largely reduce colonization resistance against this intestinal pathogen. The beneficial effect of the microbiota is closely associated with the metabolic activity of intestinal microbes such as the ability to transform primary bile acids into secondary ones. However, the basis and the molecular action of bile acids (BAs) on the pathogen are not well understood. We stressed the pathogen with the four most abundant human bile acids: cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) and lithocholic acid (LCA). Thin layer chromatography (TLC), confocal laser scanning microscopy (CLSM), and electron microscopy (EM) were employed to track the enrichment and destination of bile acids in the bacterial cell. TLC not only revealed a strong accumulation of LCA in C. difficile, but also indicated changes in the composition of membrane lipids in BA-treated cells. Furthermore, morphological changes induced by BAs were determined, most pronounced in the virtually complete loss of flagella in LCA-stressed cells and a flagella reduction after DCA and CDCA challenge. Quantification of both, protein and RNA of the main flagella component FliC proved the decrease in flagella to originate from a change in gene expression on transcriptional level. Notably, the loss of flagella provoked by LCA did not reduce adhesion ability of C. difficile to Caco-2 cells. Most remarkably, extracellular toxin A levels in the presence of BAs showed a similar pattern as flagella expression. That is, CA did not affect toxin expression, whereas lower secretion of toxin A was determined in cells stressed with LCA, DCA or CDCA. In summary, the various BAs were shown to differentially modify virulence determinants, such as flagella expression, host cell adhesion and toxin synthesis. Our results indicate differences of BAs in cellular localization and impact on membrane composition, which could be a reason of their diverse effects. This study is a starting point in the elucidation of the molecular mechanisms underlying the differences in BA action, which in turn can be vital regarding the outcome of a C. difficile infection.

Project description:BackgroundClostridioides difficile infection (CDI) is the most common hospital acquired infection in the USA, with recurrence rates > 15%. Although primary CDI has been extensively linked to gut microbial dysbiosis, less is known about the factors that promote or mitigate recurrence. Moreover, previous studies have not shown that microbial abundances in the gut measured by 16S rRNA amplicon sequencing alone can accurately predict CDI recurrence.ResultsWe conducted a prospective, longitudinal study of 53 non-immunocompromised participants with primary CDI. Stool sample collection began pre-CDI antibiotic treatment at the time of diagnosis, and continued up to 8 weeks post-antibiotic treatment, with weekly or twice weekly collections. Samples were analyzed using (1) 16S rRNA amplicon sequencing, (2) liquid chromatography/mass-spectrometry metabolomics measuring 1387 annotated metabolites, and (3) short-chain fatty acid profiling. The amplicon sequencing data showed significantly delayed recovery of microbial diversity in recurrent participants, and depletion of key anaerobic taxa at multiple time-points, including Clostridium cluster XIVa and IV taxa. The metabolomic data also showed delayed recovery in recurrent participants, and moreover mapped to pathways suggesting distinct functional abnormalities in the microbiome or host, such as decreased microbial deconjugation activity, lowered levels of endocannabinoids, and elevated markers of host cell damage. Further, using predictive statistical/machine learning models, we demonstrated that the metabolomic data, but not the other data sources, can accurately predict future recurrence at 1 week (AUC 0.77 [0.71, 0.86; 95% interval]) and 2 weeks (AUC 0.77 [0.69, 0.85; 95% interval]) post-treatment for primary CDI.ConclusionsThe prospective, longitudinal, and multi-omic nature of our CDI recurrence study allowed us to uncover previously unrecognized dynamics in the microbiome and host presaging recurrence, and, in particular, to elucidate changes in the understudied gut metabolome. Moreover, we demonstrated that a small set of metabolites can accurately predict future recurrence. Our findings have implications for development of diagnostic tests and treatments that could ultimately short-circuit the cycle of CDI recurrence, by providing candidate metabolic biomarkers for diagnostics development, as well as offering insights into the complex microbial and metabolic alterations that are protective or permissive for recurrence. Video Abstract.

Project description:Antibiotic treatment is a standard therapy for Clostridioides difficile infection, but dysbiosis of the gut microbiota due to antibiotic exposure is also a major risk factor for the disease. Following an initial episode of C. difficile infection, a relentless cycle of recurrence can occur, where persistent treatment-related dysbiosis predisposes the patient to subsequent relapse. This study uses a longitudinal study design to compare the effects of a narrow-spectrum (ridinilazole) or broad-spectrum antibiotic (vancomycin) on intestinal bile acid profiles and their associations with gut bacteria over the course of C. difficile infection treatment. At the end of treatment (day 10), subjects receiving vancomycin showed a nearly 100-fold increase in the ratio of conjugated to secondary bile acids in their stool compared with baseline, whereas subjects receiving ridinilazole maintained this ratio near baseline levels. Correlation analysis detected significant positive associations between secondary bile acids and several Bacteroidales and Clostridiales families. These families were depleted in the vancomycin group but preserved at near-baseline abundance in the ridinilazole group. Enterobacteriaceae, which expanded to a greater extent in the vancomycin group, correlated negatively and positively with secondary and conjugated primary bile acids, respectively. Bile acid ratios at the end of treatment were significantly different between those who recurred and those who did not. These results indicate that a narrow-spectrum antibiotic maintains an intestinal bile acid profile associated with a lowered risk of recurrence.NEW & NOTEWORTHY This is the first study to demonstrate in humans the relationships between Clostridioides difficile antibiotic treatment choice and bile acid metabolism both during therapy and after treatment cessation. The results show a microbiota- and metabolome-preserving property of a novel narrow-spectrum agent that correlates with the agent's favorable sustained clinical response rates compared with broad-spectrum antibiotic treatment.

Dataset Information

Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids.

Publications

Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids.

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