Mechanisms of action of Elafin-expressing probiotics: A possible use to treat Inflammatory Bowel Disease? – ELAPROB-IBD

The treatment of Inflammatory Bowel Disease (IBD) represents a major medical challenge. IBD is a highly debilitating disease, which incidence is constantly growing in developed countries. The current therapies are costly, present severe side effects, and a number of patients are resistant to any forms of treatment. Therefore, intensive research has aimed at understanding the mechanisms of those diseases, to define new potential targets. Using pre-clinical models, we have identified previously unknown anti-inflammatory properties for Elafin, a protein naturally expressed in the human gut, that is able to inhibit elastolytic activity. We then have cloned the gene of human Elafin and expressed it in recombinant bacteria that are present in daily food: the Lactococcus lactis, assuming that Elafin delivery to the gut by such a probiotic strain, would exert protective effects against colitis. Treatments with those recombinant bacteria drastically reduced inflammatory symptoms associated with IBD in animal models. However, animal models provide limited knowledge as they have an etiology different from the human disease, and very often do not implicate the same mediators. In addition, the mechanisms by which Elafin delivery to the gut would be protective are unclear. Protease inhibition is probably implicated, but potentially antimicrobial properties and inhibition of nuclear factors are also involved. The cells on which Elafin exerts its anti-inflammatory properties are also undefined. If Elafin-recombinant L. lactis has to be considered as a possible treatment for IBD in human, there is an absolute need to define the mechanisms by which such recombinant L. lactis strains protects against intestinal inflammation, in a context that would be as close as possible to the human disease and its mediators. The general objective of the project is to investigate the mechanisms by which Elafin delivery is protective against intestinal inflammation, and to determine whether Elafin delivery by lactic acid bacteria protects from the deleterious environment present in tissues from IBD patients.
Specifically, we aim at determining the effects of Elafin-recombinant L. lactis on three general types of cells that are in contact with the recombinant LAB:
1/ Intestinal Epithelial Cells
2/ Mucosal Immune Cells
3/ Microbiota
For all those cellular targets, we will determine whether Elafin’s effects are due to protease inhibition or to other properties, by comparing the effects of wild-type or mutated forms of Elafin recombined in L. lactis. This approach will shed definitive and unique light on the mechanisms of action of Elafin upon mucosal inflammation.