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Serine protease inhibitors protect better than IL-10 and TGF-beta anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci

Abstract : Background: Different studies have described the successful use of recombinant lactic acid bacteria (recLAB) to deliver anti-inflammatory molecules at the mucosal level to treat Inflammatory Bowel Disease (IBD). Methods: In order to identify the best strategy to treat IBD using recLAB, we compared the efficacy of different recombinant strains of Lactococcus lactis (the model LAB) secreting two types of anti-inflammatory molecules: cytokines (IL-10 and TGF-beta 1) and serine protease inhibitors (Elafin and Secretory Leukocyte Protease Inhibitor: SLPI), using a dextran sulfate sodium (DSS)-induced mouse model of colitis. Results: Our results show that oral administration of recombinant Lactococcus lactis strains expressing either IL-10 or TGF-beta 1 display moderate anti-inflammatory effects in inflamed mice and only for some clinical parameters. In contrast, delivery of either serine protease inhibitors Elafin or SLPI by recLled to a significant reduction of intestinal inflammation for all clinical parameters tested. Since the best results were obtained with Elafin-producing Lactococcus lactis strain, we then tried to enhance Elafin expression and hence its delivery rate by producing it in a Lactococcus lactis mutant strain inactivated in its major housekeeping protease, HtrA. Strikingly, a higher reduction of intestinal inflammation in DSS-treated mice was observed with the Elafin-overproducing htrA strain suggesting a dose-dependent Elafin effect. Conclusions: Altogether, these results strongly suggest that serine protease inhibitors are the most efficient anti-inflammatory molecules to be delivered by recLat the mucosal level for IBD treatment.
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Luis Bermudez Humaran, Jean-Paul Motta, Camille Aubry, Pascale Kharrat, Laurence Rous-Martin, et al.. Serine protease inhibitors protect better than IL-10 and TGF-beta anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci. Microbial Cell Factories, BioMed Central, 2015, 14, ⟨10.1186/s12934-015-0198-4⟩. ⟨hal-01204481⟩

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