Prevention and treatment of colitis with Lactococcus lactis secreting the immunomodulatory Yersinia LcrV protein

Benoit Foligne, Rodrigue Dessein, Michael Marceau, Sabine Poiret, Mathias Chamaillard, Bruno Pot, Michel Simonet, Catherine Daniel

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

BACKGROUND & AIMS: 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.

Original languageEnglish
Pages (from-to)862-874
Number of pages13
JournalGASTROENTEROLOGY
Volume133
Issue number3
DOIs
Publication statusPublished - Sep 2007

Keywords

  • Administration, Oral
  • Animals
  • Antigens, Bacterial/administration & dosage
  • Cells, Cultured
  • Colitis/chemically induced
  • Dextran Sulfate
  • Disease Models, Animal
  • Female
  • Interleukin-10/genetics
  • Intestinal Mucosa/drug effects
  • Lactococcus lactis/metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pore Forming Cytotoxic Proteins/administration & dosage
  • Toll-Like Receptor 2/genetics
  • Trinitrobenzenesulfonic Acid

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