title: 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.affiliation: Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. 14st504a@shinshu-u.ac.jp.|Research Fellow of the Japan Society for the Promotion of Science, Japan Society for the Promotion of Science (JSPS), 5-3-1, Kojimachi, Chiyoda-ku, Tokyo, 102-0083, Japan. 14st504a@shinshu-u.ac.jp.
authors.forename: Suguru
authors.initials: S
authors.lastname: Shigemori
authors.affiliation: Department of Food Production Science, Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. yosenabe@shinshu-u.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. 14st503b@shinshu-u.ac.jp.
authors.forename: Kai
authors.initials: K
authors.lastname: Kudoh
authors.affiliation: Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. m_ihara@shinshu-u.ac.jp.|Department of Bioscience and Biotechnology, Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. m_ihara@shinshu-u.ac.jp.|Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences (IBS), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. m_ihara@shinshu-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. 14ac402k@shinshu-u.ac.jp.
authors.forename: Shireen
authors.initials: S
authors.lastname: Nigar
authors.affiliation: Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. 15st505b@shinshu-u.ac.jp.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Food, Agriculture and Environment, Miyagi University, 2-2-1 Hatadate, Taihaku-ku, Sendai, Miyagi, 982-0215, Japan. suda@myu.ac.jp.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Suda
authors.affiliation: Department of Internal Medicine and Clinical Immunology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. takashisato1220@gmail.com.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Food and Feed Immunology Group, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi, 981-8555, Japan. haruki@bios.tohoku.ac.jp.|Livestock Immunology Unit, International Education and Research Center for Food and Agricultural Immunology (CFAI), Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi, 981-8555, Japan. haruki@bios.tohoku.ac.jp.
authors.forename: Haruki
authors.initials: H
authors.lastname: Kitazawa
authors.affiliation: Department of Bioscience and Food Production Science, Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. shimot@shinshu-u.ac.jp.|Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences (IBS), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. shimot@shinshu-u.ac.jp.|Department of Sciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598, Japan. shimot@shinshu-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimosato
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D016264:Dextran Sulfate / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D013294:Lactococcus lactis / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009561:Nisin / Q000494:pharmacology; D011994:Recombinant Proteins / Q000032:analysis / Q000096:biosynthesis
chemical_list: D053582:Interleukin-1alpha; D015850:Interleukin-6; D011994:Recombinant Proteins; D016753:Interleukin-10; D009561:Nisin; D016264:Dextran Sulfate; D051547:Heme Oxygenase-1