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Blocking Toxin function and Modulating Gut Microbiota: Caffeic Acid and its Derivatives as Potential Treatments for Clostridioides difficile Infections

ABSTRACT:

Clostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea that seriously threaten public health. Disruption of normal gut microbiota by the use of broad-spectrum antimicrobial agents enables C. difficile to proliferate in the colon. The emergence and prevalence of hypervirulent C. difficile strains result in increased morbidity, mortality and recurrence rates of CDI, thus creating a pressing need for novel therapeutics. The multi-domain toxins TcdA and TcdB are the primary determinant of CDI pathogenesis, renders them ideal drug targets in the anti-virulence paradigm. In this study, we identified caffeic acid and its derivatives as active inhibitors of TcdB via a cell-based high-throughput phenotypic screening. Further mechanistic investigations revealed that caffeic acid phenethyl ester (CAPE) could directly bind to TcdB, thus suppressing InsP6-induced autoproteolysis and inhibiting the glucosyltransferase activity. CAPE-treatment remarkably reduces the pathology of CDI in a murine infection model in terms of alleviated diarrhea symptom, decreased bacterial colonization and relieved histopathological lesions. Moreover, CAPE-treatment of C. difficile-challenged mice induces remarkable increase in the diversity and composition of the gut microbiota (e.g. Bacteroides) and alterations of gut metabolites (e.g. adenosine, D-proline and melatonin), which might partially contribute to the therapeutic outcomes of CAPE against CDI. Our results reveal the potential of CAPE as a therapeutic for the management of CDI, or CAPE might be served as a lead compound for the development of anti-virulence drug targeting TcdB.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

SUBMITTER: Yan Guo

PROVIDER: MTBLS9938 | MetaboLights | 2024-06-04

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS9938	Other
	FILES	Other
	a_MTBLS9938_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS9938_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Project description:Leber2015 - Mucosal immunity and gut microbiome interaction during C. difficile infection This model is described in the article: Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection. Leber A, Viladomiu M, Hontecillas R, Abedi V, Philipson C, Hoops S, Howard B, Bassaganya-Riera J. PLoS ONE 2015; 10(7): e0134849 Abstract: Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17) effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg) cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re-growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions. This model is hosted on BioModels Database and identified by: BIOMD0000000583. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Blocking Toxin function and Modulating Gut Microbiota: Caffeic Acid and its Derivatives as Potential Treatments for Clostridioides difficile Infections

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