Oral delivery of Lactococcus lactis that secretes bioactive heme oxygenase-1 alleviates development of acute colitis in mice

Microb Cell Fact. 2015 Nov 25:14:189. doi: 10.1186/s12934-015-0378-2.

Abstract

Background: Mucosal delivery of therapeutic proteins using genetically modified strains of lactic acid bacteria (gmLAB) is being investigated as a new therapeutic strategy.

Methods: We 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).

Results: We 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.

Conclusions: Oral 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Administration, Oral
  • Animals
  • Colitis / chemically induced
  • Colitis / pathology
  • Colitis / therapy*
  • Dextran Sulfate / toxicity
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation, Bacterial / drug effects
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Interleukin-10 / metabolism
  • Interleukin-1alpha / metabolism
  • Interleukin-6 / metabolism
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • Lactococcus lactis / growth & development
  • Lactococcus lactis / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nisin / pharmacology
  • Recombinant Proteins / analysis
  • Recombinant Proteins / biosynthesis

Substances

  • Interleukin-1alpha
  • Interleukin-6
  • Recombinant Proteins
  • Interleukin-10
  • Nisin
  • Dextran Sulfate
  • Heme Oxygenase-1