title: The glucocorticoid budesonide has protective and deleterious effects in experimental colitis in mice.
abstract: Glucocorticoids are widely used for the management of inflammatory bowel disease, albeit with known limitations for long-term use and relevant adverse effects. In turn, they have harmful effects in experimental colitis. We aimed to explore the mechanism and possible implications of this phenomenon. Regular and microbiota depleted C57BL/6 mice were exposed to dextran sulfate sodium (DSS) to induce colitis and treated with budesonide. Colonic inflammation and animal status were compared. In vitro epithelial models of wound healing were used to confirm the effects of glucocorticoids. Budesonide was also tested in lymphocyte transfer colitis. Budesonide (1-60μg/day) exerted substantial colonic antiinflammatory effects in DSS colitis. At the same time, it aggravated body weight loss, increased rectal bleeding, and induced general deterioration of animal status, bacterial translocation and endotoxemia. As a result, there was an associated increase in parameters of sepsis, such as plasma NOx, IL-1β, IL-6, lung myeloperoxidase and iNOS, as well as significant hypothermia. Budesonide also enhanced DSS induced colonic damage in microbiota depleted mice. These effects were correlated with antiproliferative effects at the epithelial level, which are expected to impair wound healing. In contrast, budesonide had significant but greatly diminished deleterious effects in noncolitic mice or in mice with lymphocyte transfer colitis. We conclude that budesonide weakens mucosal barrier function by interfering with epithelial dynamics and dampening the immune response in the context of significant mucosal injury, causing sepsis. This may be a contributing factor, at least in part, limiting clinical usefulness of corticoids in inflammatory bowel disease.
authors.affiliation: Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Ocón
authors.affiliation: Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Aranda
authors.affiliation: Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Reyes
authors.initials: R
authors.lastname: Gámez-Belmonte
authors.affiliation: Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Suárez
authors.affiliation: Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zarzuelo
authors.affiliation: Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Martínez-Augustin
authors.affiliation: Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain. Electronic address: fsanchez@ugr.es.
authors.forename: Fermín
authors.initials: F
authors.lastname: Sánchez de Medina
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018988:Bacterial Translocation / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D019819:Budesonide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D064806:Dysbiosis / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D019446:Endotoxemia / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D005938:Glucocorticoids / Q000627:therapeutic use*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013047:Specific Pathogen-Free Organisms; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D005765:Gastrointestinal Agents; D005938:Glucocorticoids; D018398:Homeodomain Proteins; C064658:RAG-1 protein; D019819:Budesonide; D016264:Dextran Sulfate
keywords: Budesonide (PubChem CID: 5281004); Dexamethasone (PubChem CID: 5743); Glucocorticoid; Hydrocortisone (PubChem CID: 5754); Mucosal barrier function; Prednisolone (PubChem CID: 5755); Sepsis; Translocation; Wound healing