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Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection

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dc.contributor.authorLeber, Andrewen
dc.contributor.authorViladomiu, Monicaen
dc.contributor.authorHontecillas, Raquelen
dc.contributor.authorAbedi, Vidaen
dc.contributor.authorPhilipson, Casandraen
dc.contributor.authorHoops, Stefanen
dc.contributor.authorHoward, Braden
dc.contributor.authorBassaganya-Riera, Josepen
dc.date.accessioned2018-09-24T14:37:09Zen
dc.date.available2018-09-24T14:37:09Zen
dc.date.issued2015-07-31en
dc.description.abstractClostridium 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.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0134849en
dc.identifier.eissn1932-6203en
dc.identifier.issue7en
dc.identifier.othere0134849en
dc.identifier.pmid26230099en
dc.identifier.urihttp://hdl.handle.net/10919/85119en
dc.identifier.volume10en
dc.language.isoenen
dc.publisherPLOSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleSystems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infectionen
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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