Abstract
BackgroundMucosal delivery of therapeutic proteins using genetically modified strains of lactic acid bacteria (gmLAB) is being investigated as a new therapeutic strategy.MethodsWe developed a strain of gmLAB, Lactococcus lactis NZ9000 (NZ-HO), which secretes the anti-inflammatory molecule recombinant mouse heme oxygenase-1 (rmHO-1). The effects of short-term continuous oral dosing with NZ-HO were evaluated in mice with dextran sulfate sodium (DSS)-induced acute colitis as a model of inflammatory bowel diseases (IBD).ResultsWe identified the secretion of rmHO-1 by NZ-HO. rmHO-1 was biologically active as determined with spectroscopy. Viable NZ-HO was directly delivered to the colon via oral administration, and rmHO-1 was secreted onto the colonic mucosa in mice. Acute colitis in mice was induced by free drinking of 3 % DSS in water and was accompanied by an increase in the disease activity index score and histopathological changes. Daily oral administration of NZ-HO significantly improved these colitis-associated symptoms. In addition, NZ-HO significantly increased production of the anti-inflammatory cytokine interleukin (IL)-10 and decreased the expression of pro-inflammatory cytokines such as IL-1α and IL-6 in the colon compared to a vector control strain.ConclusionsOral administration of NZ-HO alleviates DSS-induced acute colitis in mice. Our results suggest that NZ-HO may be a useful mucosal therapeutic agent for treating IBD.
Highlights
Mucosal delivery of therapeutic proteins using genetically modified strains of lactic acid bacteria is being investigated as a new therapeutic strategy
SDS-PAGE (Fig. 1b) and western blotting (Fig. 1c) using anti-His tag antibody (Ab) and anti-heme oxygenase-1 (HO-1) Ab showed bands corresponding to the secreted precursor of recombinant mouse heme oxygenase-1 (rmHO-1) and the secreted form of rmHO-1 in cellular extracts of nisin-induced NZ-HO
Western blotting showed that only one band corresponding to rmHO-1 was observed in the culture supernatant from NZ-HO (Fig. 1c)
Summary
Mucosal delivery of therapeutic proteins using genetically modified strains of lactic acid bacteria (gmLAB) is being investigated as a new therapeutic strategy. The anti-inflammatory and cell protective activities of heme oxygenase-1 (HO-1) have been established in several models [13]. HO-1 is an enzyme which can be induced by a number of stimuli, such as inflammatory stimuli and oxidative stress [15,16,17], and the catabolites produced by the HO-1 reaction exert anti-inflammatory and cytoprotective functions [13]. In chemicallyinduced and genetic IBD rodent models, administration of HO-1 inducers alleviates colitis through various mechanisms including suppression of oxidative, pro-apoptotic, and pro-inflammatory responses, as well as facilitation of anti-inflammatory responses and bacterial clearance [18,19,20,21,22,23,24]
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