title: A transgenic probiotic secreting a parasite immunomodulator for site-directed treatment of gut inflammation.
abstract: New treatment strategies for inflammatory bowel disease are needed and parasitic nematode infections or application of helminth components improve clinical and experimental gut inflammation. We genetically modified the probiotic bacterium Escherichia coli Nissle 1917 to secrete the powerful nematode immunomodulator cystatin in the gut. This treatment was tested in a murine colitis model and on post-weaning intestinal inflammation in pigs, an outbred model with a gastrointestinal system similar to humans. Application of the transgenic probiotic significantly decreased intestinal inflammation in murine acute colitis, associated with increased frequencies of Foxp3(+) Tregs, suppressed local interleukin (IL)-6 and IL-17A production, decreased macrophage inflammatory protein-1α/β, monocyte chemoattractant protein -1/3, and regulated upon activation, normal T-cell expressed, and secreted expression and fewer inflammatory macrophages in the colon. High dosages of the transgenic probiotic were well tolerated by post-weaning piglets. Despite being recognized by T cells, secreted cystatin did not lead to changes in cytokine expression or macrophage activation in the colon. However, colon transepithelial resistance and barrier function were significantly improved in pigs receiving the transgenic probotic and post-weaning colon inflammation was reduced. Thus, the anti-inflammatory efficiency of a probiotic can be improved by a nematode-derived immunoregulatory transgene. This treatment regimen should be further investigated as a potential therapeutic option for inflammatory bowel disease.
authors.affiliation: Center for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Rose A
authors.initials: RA
authors.lastname: Whelan
authors.affiliation: Center for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rausch
authors.affiliation: Center for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Ebner
authors.affiliation: Institute of Clinical Physiology, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Günzel
authors.affiliation: 1] Institute of Clinical Physiology, Charité-University Medicine Berlin, Berlin, Germany [2] Current address: Institute for Anatomy II, Friedrich-Schiller-University, Jena, Germany.
authors.forename: Jan F
authors.initials: JF
authors.lastname: Richter
authors.affiliation: Department of Gastroenterology, Division of Nutritional Medicine, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Nina A
authors.initials: NA
authors.lastname: Hering
authors.affiliation: Department of Gastroenterology, Division of Nutritional Medicine, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Jörg-Dieter
authors.initials: JD
authors.lastname: Schulzke
authors.affiliation: Department of Internal Medicine, Rheumatology and Clinical Immunology/Research Center ImmunoSciences (RCIS), Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Institute of Clinical Physiology, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Keles
authors.affiliation: Unit for Molecular Diagnostics, Genetics and Pathogen Characterisation, Department of Biological Safety Federal Institute for Risk Assessment, Berlin, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Janczyk
authors.affiliation: Unit for Molecular Diagnostics, Genetics and Pathogen Characterisation, Department of Biological Safety Federal Institute for Risk Assessment, Berlin, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Nöckler
authors.affiliation: Institute for Microbiology and Animal Health, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
authors.forename: Lothar H
authors.initials: LH
authors.lastname: Wieler
authors.affiliation: Center for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015891:Cystatins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005759:Gastroenteritis / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000628:therapy*; D015870:Gene Expression; D007155:Immunologic Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D019936:Probiotics / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use*; D013552:Swine
chemical_list: D018925:Chemokines; D015891:Cystatins; D007155:Immunologic Factors