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Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice

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Vandenbroucke, Klaas, Hans, Wolfgang, Van Huysse, Jacques, Neirynck, Sabine, Demetter, Pieter, Remaut, Erik, Rottiers, Pieter, Steidler, Lothar·2004·Gastroenterology
DOI 10.1053/j.gastro.2004.05.020
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Abstract

Background & aims Effective therapeutics for treating acute colitis, caused by disruption of the intestinal epithelial barrier, are scarce. Trefoil factors (TFF) are cytoprotective and promote epithelial wound healing and reconstitution of the gastrointestinal tract, which makes them good candidate therapeutics for acute colitis. However, orally administered TFF stick to the mucus of the small intestine and are absorbed at the cecum.Methods We have engineered the food-grade bacterium Lactococcus lactis to secrete bioactive murine TFF. The protective and therapeutic potentials of these TFF-secreting L. lactis were evaluated in parallel with purified TFF in the dextran sodium sulfate (DSS)-induced murine model for acute colitis and in established chronic colitis in interleukin (IL)-10(-/-) mice. Disease was evaluated by blinded macroscopic and microscopic inflammatory scores and by myeloperoxidase activity.Results Intragastric administration of TFF-secreting L. lactis led to active delivery of TFF at the mucosa of the colon and, in contrast to administration of purified TFF, proved to be very effective in prevention and healing of acute DSS-induced colitis. The in situ secreted murine TFF significantly decreased morbidity and mortality and stimulated prostaglandin-endoperoxide synthase 2 expression, which represents a major therapeutic pathway. In addition, this approach was successful in improving established chronic colitis in IL-10(-/-) mice.Conclusions We have positively evaluated a new therapeutic approach for acute and chronic colitis that involves in situ secretion of murine TFF by orally administered L. lactis. This novel approach may lead to effective management of acute and chronic colitis and epithelial damage in humans.

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  • A recombinant bacterium that produces TFF can deliver the factor straight to the colonic mucosa.

    “Instead of traditional orogastric administration of TFF, which sticks to the mucus layer in the small bowel preventing its localization in the colon, use of the recombinant bacterium enables delivery of TFF directly to the colonic mucosa and results in amelioration of DSS-induced disease in mice.123”

    From Probiotics and the gut microbiota in intestinal health and disease (2010) · cites this paper as [123]

  • When TFF is given by the traditional orogastric route, it adheres to small-bowel mucus and does not reach the colon.

    “Instead of traditional orogastric administration of TFF, which sticks to the mucus layer in the small bowel preventing its localization in the colon, use of the recombinant bacterium enables delivery of TFF directly to the colonic mucosa and results in amelioration of DSS-induced disease in mice.123”

    From Probiotics and the gut microbiota in intestinal health and disease (2010) · cites this paper as [123]

  • The recombinant TFF-producing L. lactis reduces DSS-induced disease in mice.

    “Instead of traditional orogastric administration of TFF, which sticks to the mucus layer in the small bowel preventing its localization in the colon, use of the recombinant bacterium enables delivery of TFF directly to the colonic mucosa and results in amelioration of DSS-induced disease in mice.123”

    From Probiotics and the gut microbiota in intestinal health and disease (2010) · cites this paper as [123]

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  1. Noble S, Balfour JA. Meloxicam. Drugs 1996;51:424 -430; dis- cussion 431-432.

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Authors
Vandenbroucke, K., Hans, W., Van Huysse, J., Neirynck, S., Demetter, P., Remaut, E., Rottiers, P., & Steidler, L.
Affiliations
  • Vlaams Instituut voor Biotechnologie (BE)
  • University College Cork (IE)
  • Ghent University Hospital (BE)
Corresponding author
Steidler, Lothar
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2004-08
Volume
127
Issue
2
Pages
502-513
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2004.05.020
OpenAlex
W2116185627
Cited by
277
References
50
Citations by year
2026: 4 · 2025: 9 · 2024: 9 · 2023: 10 · 2022: 12 · 2021: 13 · 2020: 17 · 2019: 9 · 2018: 14 · 2017: 7 · 2016: 4 · 2015: 13 · 2014: 9 · 2013: 13 · 2012: 8
FWCI
13.52
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
Keywords
trefoil factor, Lactococcus lactis, acute colitis, chronic colitis, IL-10 knockout mice, DSS-induced colitis, epithelial repair, intestinal epithelial barrier, cyclooxygenase-2, mucosal protection, engineered bacteria
MeSH terms
Trefoil Factor-2, Trefoil Factor-3, Acute Disease, Administration, Oral, Animals, Chronic Disease, Colitis, Female, Isoenzymes, Mice, Inbred BALB C, Mucins, Muscle Proteins, Neuropeptides, Peptides, Prostaglandin-Endoperoxide Synthases, Recombinant Proteins, Lactococcus lactis, Wound Healing, Genetic Therapy, Gene Expression Regulation, Enzymologic, Mice, Cyclooxygenase 2, In Vitro Techniques

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