Effects in the use of a genetically engineered strain of Lactococcus lactis delivering in situ IL-10 as a therapy to treat low-grade colon inflammation.

Abstract

Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain, discomfort, and bloating. Interestingly, there is now evidence of the presence of a low-grade inflammatory status in many IBS patients, including histopathological and mucosal cytokine levels in the colon, as well as the presence of IBS-like symptoms in quiescent inflammatory bowel disease (IBD). The use of a genetically engineered food-grade bacterium, such as Lactococcus lactis, secreting the anti-inflammatory cytokine IL-10 has been proven by many pre-clinical studies to be a successful therapy to treat colon inflammation. In this study, we first reproduced the recovery-recurrence periods observed in IBS-patients in a new chronic model characterized by 2 episodes of DiNitro-BenzeneSulfonic-acid (DNBS)-challenge and we tested the effects of a recombinant strain of L. lactis secreting IL-10 under a Stress-Inducible Controlled Expression (SICE) system. In vivo gut permeability, colonic serotonin levels, cytokine profiles, and spleen cell populations were then measured as readouts of a low-grade inflammation. In addition, since there is increasing evidence that gut microbiota tightly regulates gut barrier function, tight junction proteins were also measured by qRT-PCR after administration of recombinant L. lactis in DNBS-treated mice. Strikingly, oral administration of L. lactis secreting active IL-10 in mice resulted in significant protective effects in terms of permeability, immune activation, and gut-function parameters. Although genetically engineered bacteria are, for now, used only as a "proof-of-concept," our study validates the interest in the use of the novel SICE system in L. lactis to express therapeutic molecules, such as IL-10, locally at mucosal surfaces.

• Authors: Rebeca Martín, Florian Chain, Sylvie Miquel, Jane M Natividad, Harry Sokol, Elena F Verdu, Philippe Langella, Luis G Bermúdez-Humarán
• Journal: Human vaccines & immunotherapeutics (Hum Vaccin Immunother) Vol. 10 Issue 6 Pg. 1611-21 ( 2014) ISSN: 2164-554X [Electronic] United States
• PMID: 24732667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Immunologic Factors
• Recombinant Proteins
• Interleukin-10
• Serotonin

Topics

• Animals
• Biological Therapy (methods)
• Colitis (pathology, therapy)
• Cytokines (analysis)
• Disease Models, Animal
• Gene Expression Profiling
• Humans
• Immunologic Factors (genetics, immunology, metabolism)
• Immunotherapy (methods)
• Interleukin-10 (genetics, immunology, metabolism)
• Lactococcus lactis (genetics, growth & development, metabolism)
• Male
• Mice, Inbred C57BL
• Real-Time Polymerase Chain Reaction
• Recombinant Proteins (genetics, immunology, metabolism)
• Serotonin (analysis)
• Spleen (immunology)
• Treatment Outcome