A new therapeutic association to manage relapsing experimental colitis: Doxycycline plus Saccharomyces boulardii.
Immunomodulatory antibiotics have been proposed for the treatment of multifactorial conditions such as inflammatory bowel disease. Probiotics are able to attenuate intestinal inflammation, being considered as safe when chronically administered. The aim of the study was to evaluate the anti-inflammatory effects of doxycycline, a tetracycline with immunomodulatory properties, alone and in association with the probiotic Saccharomyces boulardii CNCMI-745. Doxycycline was assayed both in vitro (Caco-2 epithelial cells and RAW 264.7 macrophages) and in vivo, in the trinitrobenzenesulfonic acid (TNBS) model of rat colitis and the dextran sodium sulfate (DSS) model of mouse colitis. In addition, the anti-inflammatory effect of the association of doxycycline and the probiotic was evaluated in vitro and in vivo in a DSS model of reactivated colitis in mice. Doxycycline displayed immunomodulatory activity in vitro, reducing IL-8 production by intestinal epithelial cells and nitric oxide by macrophages. Doxycycline administration to TNBS-colitic rats (5, 10 and 25 mg/kg) ameliorated the intestinal inflammatory process, being its efficacy comparable to that previously showed by minocycline. Doxycycline treatment was also effective in reducing acute intestinal inflammation in the DSS model of mouse colitis. The association of doxycycline and S. boulardii helped managing colitis in a reactivated model of colitis, by reducing intestinal inflammation and accelerating the recovery and attenuating the relapse. This was evidenced by a reduced disease activity index, colonic tissue damage and expression of inflammatory mediators. This study confirms the intestinal anti-inflammatory activity of doxycycline and supports the potential use of its therapeutic association with S. boulardii for the treatment of inflammatory bowel diseases, in which doxycycline is used to induce remission and long term probiotic administration helps to prevent the relapses.
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
José
J
Garrido-Mesa
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
Francesca
F
Algieri
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
Alba
A
Rodriguez-Nogales
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
Maria Pilar
MP
Utrilla
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
Maria Elena
ME
Rodriguez-Cabezas
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
Antonio
A
Zarzuelo
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain.
Maria Angeles
MA
Ocete
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain; Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.
Natividad
N
Garrido-Mesa
CIBER-EHD, Department of Pharmacology, ibs.GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain. Electronic address: jgalvez@ugr.es.
Julio
J
Galvez
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D018938:Caco-2 Cells; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004318:Doxycycline / Q000627:therapeutic use*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D019936:Probiotics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012440:Saccharomyces; D014302:Trinitrobenzenesulfonic Acid
D000900:Anti-Bacterial Agents; D016207:Cytokines; D016209:Interleukin-8; D009569:Nitric Oxide; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D004318:Doxycycline
Cytokines; Doxycycline; Experimental colitis; Inflammatory bowel disease; Saccharomyces boulardii CNCMI-745