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Journal of Gastroenterology
Erschienen in: Journal of Gastroenterology 4/2017

21.06.2016 | Original Article—Alimentary Tract

A human gut ecosystem protects against C. difficile disease by targeting TcdA

verfasst von: Sarah Lynn Martz, Mabel Guzman-Rodriguez, Shu-Mei He, Curtis Noordhof, David John Hurlbut, Gregory Brian Gloor, Christian Carlucci, Scott Weese, Emma Allen-Vercoe, Jun Sun, Erika Chiong Claud, Elaine Olga Petrof

Erschienen in: Journal of Gastroenterology | Ausgabe 4/2017

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Abstract

Background

A defined Microbial Ecosystem Therapeutic (MET-1, or “RePOOPulate”) derived from the feces of a healthy volunteer can cure recurrent C. difficile infection (rCDI) in humans. The mechanisms of action whereby healthy microbiota protect against rCDI remain unclear. Since C. difficile toxins are largely responsible for the disease pathology of CDI, we hypothesized that MET-1 exerts its protective effects by inhibiting the effects of these toxins on the host.

Methods

A combination of in vivo (antibiotic-associated mouse model of C. difficile colitis, mouse ileal loop model) and in vitro models (FITC-phalloidin staining, F actin Western blots and apoptosis assay in Caco2 cells, transepithelial electrical resistance measurements in T84 cells) were employed.

Results

MET-1 decreased both local and systemic inflammation in infection and decreased both the cytotoxicity and the amount of TcdA detected in stool, without an effect on C. difficile viability. MET-1 protected against TcdA-mediated damage in a murine ileal loop model. MET-1 protected the integrity of the cytoskeleton in cells treated with purified TcdA, as indicated by FITC-phalloidin staining, F:G actin assays and preservation of transepithelial electrical resistance. Finally, co-incubation of MET-1 with purified TcdA resulted in decreased detectable TcdA by Western blot analysis.

Conclusions

MET-1 intestinal microbiota confers protection against C. difficile and decreases C. difficile-mediated inflammation through its protective effects against C. difficile toxins, including enhancement of host barrier function and degradation of TcdA. The effect of MET-1 on C. difficile viability seems to offer little, if any, contribution to its protective effects on the host.
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Metadaten
Titel
A human gut ecosystem protects against C. difficile disease by targeting TcdA
verfasst von
Sarah Lynn Martz
Mabel Guzman-Rodriguez
Shu-Mei He
Curtis Noordhof
David John Hurlbut
Gregory Brian Gloor
Christian Carlucci
Scott Weese
Emma Allen-Vercoe
Jun Sun
Erika Chiong Claud
Elaine Olga Petrof
Publikationsdatum
21.06.2016
Verlag
Springer Japan
Erschienen in
Journal of Gastroenterology / Ausgabe 4/2017
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-016-1232-y

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