title: 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.affiliation: INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. luis.bermudez@jouy.inra.fr.|AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France. luis.bermudez@jouy.inra.fr.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Bermúdez-Humarán
authors.affiliation: Inserm, U1043, Toulouse, F-31300, France. jpmotta@ucalgary.ca.|CNRS, U5282, Toulouse, F-31300, France. jpmotta@ucalgary.ca.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France. jpmotta@ucalgary.ca.|Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada. jpmotta@ucalgary.ca.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Motta
authors.affiliation: INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. camille.aubry@jouy.inra.fr.|AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France. camille.aubry@jouy.inra.fr.
authors.forename: Camille
authors.initials: C
authors.lastname: Aubry
authors.affiliation: INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. pkchevalier@gmail.com.|AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France. pkchevalier@gmail.com.
authors.forename: Pascale
authors.initials: P
authors.lastname: Kharrat
authors.affiliation: Inserm, U1043, Toulouse, F-31300, France. laurence_tlse@yahoo.fr.|CNRS, U5282, Toulouse, F-31300, France. laurence_tlse@yahoo.fr.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France. laurence_tlse@yahoo.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Rous-Martin
authors.affiliation: INSERM U874, Institut Pasteur, 25 rue du Dr Roux, 75015, Paris, France. jean-michel.sallenave@inserm.fr.|INSERM U1152, Faculté de Médecine site Bichat, Université Paris Diderot, 16, rue Henri Huchard, 75018, Paris, France. jean-michel.sallenave@inserm.fr.|Université Sorbonne Paris Cité, Université Paris Diderot, rue du Dr Roux, 75015, Paris, France. jean-michel.sallenave@inserm.fr.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sallenave
authors.affiliation: Inserm, U1043, Toulouse, F-31300, France. celine.deraison@inserm.fr.|CNRS, U5282, Toulouse, F-31300, France. celine.deraison@inserm.fr.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France. celine.deraison@inserm.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Deraison
authors.affiliation: Inserm, U1043, Toulouse, F-31300, France. nathalie.vergnolle@inserm.fr.|CNRS, U5282, Toulouse, F-31300, France. nathalie.vergnolle@inserm.fr.|Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France. nathalie.vergnolle@inserm.fr.|Université Sorbonne Paris Cité, Université Paris Diderot, rue du Dr Roux, 75015, Paris, France. nathalie.vergnolle@inserm.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.affiliation: INRA, Commensal and Probiotics-Host Interactions Laboratory, UMR 1319 Micalis, F-78350, Jouy-en-Josas, France. philippe.langella@jouy.inra.fr.|AgroParisTech, UMR1319 Micalis, F-78350, Jouy-en-Josas, France. philippe.langella@jouy.inra.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Langella
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003092:Colitis / Q000382:microbiology / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D053492:Elafin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D013294:Lactococcus lactis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009561:Nisin / Q000494:pharmacology; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D053492:Elafin; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors; C506815:Slpi protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D009561:Nisin