Background:
Intestinal epithelial expression of antioxidants and nuclear factor kappa b (nf-κb) contribute to mucosal barrier integrity and epithelial homeostasis, two key events in the pathogenesis of inflammatory bowel disease (ibd). genetic restoration of intestinal epithelial prohibitin 1 (phb) levels during experimental colitis reduces the severity of disease through sustained epithelial antioxidant expression and reduced nf-κb activation. to determine the therapeutic potential of restoring epithelial phb during experimental colitis in mice, we assessed two methods of phb colonic mucosal delivery: adenovirus-directed administration by enema and poly(lactic acid) nanoparticle (nps) delivery by gavage.
Methods:
As a proof-of-principle to demonstrate the therapeutic efficacy of phb, we utilized adenovirus-directed administration by enema. second, we used nps-based colonic delivery of biologically active phb to demonstrate therapeutic use for human ibd. colitis was induced by oral administration of dextran sodium sulfate (dss) in water for 6-7 days. wildtype mice receiving normal tap water served as controls.
Results:
Both methods of delivery resulted in increased levels of phb in the surface epithelial cells of the colon and reduced severity of dss-induced colitis in mice as measured by body weight loss, clinical score, myeloperoxidase activity, proinflammatory cytokine expression, histological score, and protein carbonyl content.
Conclusions:
This is the first study to show oral delivery of a biologically active protein by nps encapsulated in hydrogel to the colon. here we show that therapeutic delivery of phb to the colon reduces the severity of dss-induced colitis in mice. phb may represent a novel therapeutic target in ibd.