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

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.

• Authors: Suguru Shigemori, Takafumi Watanabe, Kai Kudoh, Masaki Ihara, Shireen Nigar, Yoshinari Yamamoto, Yoshihito Suda, Takashi Sato, Haruki Kitazawa, Takeshi Shimosato
• Journal: Microbial cell factories (Microb Cell Fact) Vol. 14 Pg. 189 (Nov 25 2015) ISSN: 1475-2859 [Electronic] England
• PMID: 26608030 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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