Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice.
OBJECTIVE
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.
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Belgium.
Klaas
K
Vandenbroucke
Wolfgang
W
Hans
Jacques
J
Van Huysse
Sabine
S
Neirynck
Pieter
P
Demetter
Erik
E
Remaut
Pieter
P
Rottiers
Lothar
L
Steidler
D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000517:prevention & control / Q000628:therapy*; D051546:Cyclooxygenase 2; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy / Q000379:methods*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics; D013294:Lactococcus lactis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D014945:Wound Healing
D007527:Isoenzymes; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D011994:Recombinant Proteins; C099037:TFF3 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases