Serine protease inhibitors protect better than IL-10 and TGF-β 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-β1) 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 L. lactis strains expressing either IL-10 or TGF-β1 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 recLAB led to a significant reduction of intestinal inflammation for all clinical parameters tested. Since the best results were obtained with Elafin-producing L. lactis strain, we then tried to enhance Elafin expression and hence its delivery rate by producing it in a L. 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 recLAB at the mucosal level for IBD treatment.

• Authors: Luis G Bermúdez-Humarán, Jean-Paul Motta, Camille Aubry, Pascale Kharrat, Laurence Rous-Martin, Jean-Michel Sallenave, Céline Deraison, Nathalie Vergnolle, Philippe Langella
• Journal: Microbial cell factories (Microb Cell Fact) Vol. 14 Pg. 26 (Feb 26 2015) ISSN: 1475-2859 [Electronic] England
• PMID: 25889561 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Elafin
• Secretory Leukocyte Peptidase Inhibitor
• Serine Proteinase Inhibitors
• Slpi protein, mouse
• Transforming Growth Factor beta
• Interleukin-10
• Nisin

Topics

• Administration, Oral
• Animals
• Colitis (microbiology, pathology, therapy)
• Disease Models, Animal
• Elafin (genetics, metabolism)
• Gene Expression (drug effects)
• Interleukin-10 (genetics, metabolism)
• Lactococcus lactis (metabolism)
• Mice
• Mice, Inbred C57BL
• Nisin (pharmacology)
• Secretory Leukocyte Peptidase Inhibitor (genetics, metabolism)
• Serine Proteinase Inhibitors (genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)