title: Effects in the use of a genetically engineered strain of Lactococcus lactis delivering in situ IL-10 as a therapy to treat low-grade colon inflammation.
abstract: Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain, discomfort, and bloating. Interestingly, there is now evidence of the presence of a low-grade inflammatory status in many IBS patients, including histopathological and mucosal cytokine levels in the colon, as well as the presence of IBS-like symptoms in quiescent inflammatory bowel disease (IBD). The use of a genetically engineered food-grade bacterium, such as Lactococcus lactis, secreting the anti-inflammatory cytokine IL-10 has been proven by many pre-clinical studies to be a successful therapy to treat colon inflammation. In this study, we first reproduced the recovery-recurrence periods observed in IBS-patients in a new chronic model characterized by 2 episodes of DiNitro-BenzeneSulfonic-acid (DNBS)-challenge and we tested the effects of a recombinant strain of L. lactis secreting IL-10 under a Stress-Inducible Controlled Expression (SICE) system. In vivo gut permeability, colonic serotonin levels, cytokine profiles, and spleen cell populations were then measured as readouts of a low-grade inflammation. In addition, since there is increasing evidence that gut microbiota tightly regulates gut barrier function, tight junction proteins were also measured by qRT-PCR after administration of recombinant L. lactis in DNBS-treated mice. Strikingly, oral administration of L. lactis secreting active IL-10 in mice resulted in significant protective effects in terms of permeability, immune activation, and gut-function parameters. Although genetically engineered bacteria are, for now, used only as a "proof-of-concept," our study validates the interest in the use of the novel SICE system in L. lactis to express therapeutic molecules, such as IL-10, locally at mucosal surfaces.
authors.affiliation: INRA; Commensal and Probiotics-Host Interactions Laboratory; UMR 1319 Micalis; Jouy-en-Josas, France; AgroParisTech; UMR1319 Micalis; Jouy-en-Josas, France.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Martín
authors.affiliation: INRA; Commensal and Probiotics-Host Interactions Laboratory; UMR 1319 Micalis; Jouy-en-Josas, France; AgroParisTech; UMR1319 Micalis; Jouy-en-Josas, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Chain
authors.affiliation: INRA; Commensal and Probiotics-Host Interactions Laboratory; UMR 1319 Micalis; Jouy-en-Josas, France; AgroParisTech; UMR1319 Micalis; Jouy-en-Josas, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Miquel
authors.affiliation: Farncombe Family Digestive Health Research Institute; McMaster University; Hamilton, ON Canada.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Natividad
authors.affiliation: INRA; Commensal and Probiotics-Host Interactions Laboratory; UMR 1319 Micalis; Jouy-en-Josas, France; AgroParisTech; UMR1319 Micalis; Jouy-en-Josas, France; Department of Gastroenterology and Nutrition; AP-HP; Hôpital Saint-Antoine F-75012 and UPMC Univ Paris; Paris, France; INSERM; Equipe AVENIR U1057 / UMR CNRS 7203; Paris, France.
authors.forename: Harry
authors.initials: H
authors.lastname: Sokol
authors.affiliation: Farncombe Family Digestive Health Research Institute; McMaster University; Hamilton, ON Canada.
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
authors.affiliation: INRA; Commensal and Probiotics-Host Interactions Laboratory; UMR 1319 Micalis; Jouy-en-Josas, France; AgroParisTech; UMR1319 Micalis; Jouy-en-Josas, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Langella
authors.affiliation: INRA; Commensal and Probiotics-Host Interactions Laboratory; UMR 1319 Micalis; Jouy-en-Josas, France; AgroParisTech; UMR1319 Micalis; Jouy-en-Josas, France.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Bermúdez-Humarán
mesh_terms: D000818:Animals; D001691:Biological Therapy / Q000379:methods*; D003092:Colitis / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013294:Lactococcus lactis / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012701:Serotonin / Q000032:analysis; D013154:Spleen / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D011994:Recombinant Proteins; D016753:Interleukin-10; D012701:Serotonin
keywords: IBS; IL-10; Lactococcis lactis; genetically engineered bacteria; gut hyperpermeability; probiotic
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