title: Host lysozyme-mediated lysis of Lactococcus lactis facilitates delivery of colitis-attenuating superoxide dismutase to inflamed colons.
abstract: Beneficial microbes that target molecules and pathways, such as oxidative stress, which can negatively affect both host and microbiota, may hold promise as an inflammatory bowel disease therapy. Prior work showed that a five-strain fermented milk product (FMP) improved colitis in T-bet(-/-) Rag2(-/-) mice. By varying the number of strains used in the FMP, we found that Lactococcus lactis I-1631 was sufficient to ameliorate colitis. Using comparative genomic analyses, we identified genes unique to L. lactis I-1631 involved in oxygen respiration. Respiration of oxygen results in reactive oxygen species (ROS) generation. Also, ROS are produced at high levels during intestinal inflammation and cause tissue damage. L. lactis I-1631 possesses genes encoding enzymes that detoxify ROS, such as superoxide dismutase (SodA). Thus, we hypothesized that lactococcal SodA played a role in attenuating colitis. Inactivation of the sodA gene abolished L. lactis I-1631's beneficial effect in the T-bet(-/-) Rag2(-/-) model. Similar effects were obtained in two additional colonic inflammation models, Il10(-/-) mice and dextran sulfate sodium-treated mice. Efforts to understand how a lipophobic superoxide anion (O2 (-)) can be detoxified by cytoplasmic lactoccocal SodA led to the finding that host antimicrobial-mediated lysis is a prerequisite for SodA release and SodA's extracytoplasmic O2 (-) scavenging. L. lactis I-1631 may represent a promising vehicle to deliver antioxidant, colitis-attenuating SodA to the inflamed intestinal mucosa, and host antimicrobials may play a critical role in mediating SodA's bioaccessibility.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA 02115; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115;
authors.forename: Sonia A
authors.initials: SA
authors.lastname: Ballal
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Danone Nutricia Research, 91767 Palaiseau, France;
authors.forename: Patrick
authors.initials: P
authors.lastname: Veiga
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Fenn
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115;
authors.forename: Monia
authors.initials: M
authors.lastname: Michaud
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115;
authors.forename: Jason H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115;
authors.forename: Carey Ann
authors.initials: CA
authors.lastname: Gallini
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115; Miraca Life Sciences, Newton, MA 02464;
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.affiliation: Danone Nutricia Research, 91767 Palaiseau, France;
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Quéré
authors.affiliation: Danone Nutricia Research, 91767 Palaiseau, France;
authors.forename: Peggy
authors.initials: P
authors.lastname: Garault
authors.affiliation: Danone Nutricia Research, 91767 Palaiseau, France;
authors.forename: Chloé
authors.initials: C
authors.lastname: Béal
authors.affiliation: Danone Nutricia Research, 91767 Palaiseau, France;
authors.forename: Muriel
authors.initials: M
authors.lastname: Derrien
authors.affiliation: Institut National de la Recherche Agronomique, UMR 1319 Micalis, 78352 Jouy-en-Josas, France; AgroParisTech, UMR Micalis, 78352 Jouy-en-Josas, France;
authors.forename: Pascal
authors.initials: P
authors.lastname: Courtin
authors.affiliation: Institut National de la Recherche Agronomique, UMR 1319 Micalis, 78352 Jouy-en-Josas, France; AgroParisTech, UMR Micalis, 78352 Jouy-en-Josas, France;
authors.forename: Saulius
authors.initials: S
authors.lastname: Kulakauskas
authors.affiliation: Institut National de la Recherche Agronomique, UMR 1319 Micalis, 78352 Jouy-en-Josas, France; AgroParisTech, UMR Micalis, 78352 Jouy-en-Josas, France;
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Chapot-Chartier
authors.affiliation: Danone Nutricia Research, 91767 Palaiseau, France;
authors.forename: Johan
authors.initials: J
authors.lastname: van Hylckama Vlieg
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Medicine, Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142 wgarrett@hsph.harvard.edu.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Garrett
mesh_terms: D000818:Animals; D003092:Colitis / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D013294:Lactococcus lactis / Q000378:metabolism*; D051379:Mice; D009113:Muramidase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D009113:Muramidase
keywords: Lactococcus lactis; colitis; lysozyme; oxidative stress; probiotics