Prevention and treatment of colitis with Lactococcus lactis secreting the immunomodulatory Yersinia LcrV protein.
OBJECTIVE
The low calcium response V (LcrV) protein synthesized by gram-negative, pathogenic yersiniae participates in bacterial evasion of the host's innate immune response by stimulating synthesis of the anti-inflammatory interleukin (IL)-10 and preventing the activation of proinflammatory cytokines.


METHODS
We genetically engineered the food-grade bacterium Lactococcus lactis to secrete the LcrV protein from the enteropathogenic species Yersinia pseudotuberculosis. The protective and therapeutic potential of orally administered LcrV-secreting L lactis was evaluated in 2 models of acute experimental colitis (induced by trinitrobenzene sulfonic acid [TNBS] and dextran sodium sulfate [DSS], respectively) in wild-type and knockout mice.


RESULTS
Oral administration of LcrV-secreting L lactis led to active delivery of LcrV and induction of IL-10 (via a Toll-like receptor 2-dependent pathway) in the colon and prevented TNBS-induced colitis, in contrast to the L lactis control not producing LcrV. Down-regulation of tissue inflammatory markers correlated well with the reduction in damage to the colonic mucosa. In contrast, TNBS-induced colitis was not prevented in IL-10(-/-) mice pretreated with LcrV-secreting L lactis, thus showing that IL-10 is required for LcrV protection. Administration of LcrV-secreting L lactis also proved to be very effective in preventing and treating acute DSS-induced colitis.


CONCLUSIONS
LcrV-secreting L lactis decreased experimentally induced intestinal inflammation in 2 murine models of colitis. This novel approach highlights the potential of using pathogen-derived immunomodulating molecules in vivo as novel therapeutics for inflammatory bowel diseases.
Foligne
Benoit
B
Laboratoire des Bactéries Lactiques et Immunité des Muqueuses, Institut Pasteur de Lille, Lille, France.
Dessein
Rodrigue
R
Marceau
Michael
M
Poiret
Sabine
S
Chamaillard
Mathias
M
Pot
Bruno
B
Simonet
Michel
M
Daniel
Catherine
C
D000284:Administration, Oral; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D013294:Lactococcus lactis / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052899:Pore Forming Cytotoxic Proteins / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid
D000942:Antigens, Bacterial; C043908:LcrV protein, Yersinia; D052899:Pore Forming Cytotoxic Proteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate