title: Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic.
abstract: Nonsteroidal anti-inflammatory drugs, besides exerting detrimental effects on the upper digestive tract, can also damage the small and large intestine. Although the underlying mechanisms remain unclear, there is evidence that enteric bacteria play a pivotal role. The present study examined the enteroprotective effects of a delayed-release formulation of rifaximin-EIR (R-EIR, 50mg/kg BID, i.g.), a poorly absorbed antibiotic with a broad spectrum of antibacterial activity, in a rat model of enteropathy induced by indomethacin (IND, 1.5mg/kg BID for 14 days) administration. R-EIR was administered starting 7 days before or in concomitance with IND administration. At the end of treatments, blood samples were collected to evaluate hemoglobin (Hb) concentration (as an index of digestive bleeding). Small intestine was processed for: (1) histological assessment of intestinal damage (percentage length of lesions over the total length examined); (2) assay of tissue myeloperoxidase (MPO) and TNF levels, as markers of inflammation; (3) assay of tissue malondialdehyde (MDA) and protein carbonyl concentrations, as an index of lipid and protein peroxidation, respectively; (4) evaluation of the major bacterial phyla. IND significantly decreased Hb levels, this effect being significantly blunted by R-EIR. IND also induced the occurrence of lesions in the jejunum and ileum. In both intestinal regions, R-EIR significantly reduced the percentage of lesions, as compared with rats receiving IND alone. Either the markers of inflammation and tissue peroxidation were significantly increased in jejunum and ileum from IND-treated rats. However, in rats treated with R-EIR, these parameters were not significantly different from those observed in controls. R-EIR was also able to counterbalance the increase in Proteobacteria and Firmicutes abundance induced by INDO. To summarize, R-EIR treatment significantly prevents IND-induced intestinal damage, this enteroprotective effect being associated with a decrease in tissue inflammation, oxidative stress and digestive bleeding as well as reversal of NSAID-induced alterations in bacterial population.
authors.affiliation: Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fornai
authors.affiliation: Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Antonioli
authors.affiliation: Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Pellegrini
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.affiliation: Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Sacco
authors.affiliation: Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Tirotta
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Natale
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bartalucci
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Flaibani
authors.affiliation: Department of Research & Development, Alfa Wassermann SpA, Via Ragazzi del'99, 5, 40133 Bologna, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Renzulli
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via San Zeno 37, 56127 Pisa, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Ghelardi
authors.affiliation: Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.affiliation: Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Via Gramsci 14, 43125 Parma, Italy. Electronic address: scarpi@tin.it.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Scarpignato
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D004269:DNA, Bacterial / Q000032:analysis; D000068536:Bacillota / Q000302:isolation & purification; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007213:Indomethacin / Q000009:adverse effects; D007408:Intestinal Absorption; D007410:Intestinal Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D020560:Proteobacteria / Q000302:isolation & purification; D017208:Rats, Wistar; D012294:Rifamycins / Q000494:pharmacology / Q000627:therapeutic use*; D000078262:Rifaximin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004269:DNA, Bacterial; D012294:Rifamycins; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D009195:Peroxidase; D000078262:Rifaximin; D007213:Indomethacin
keywords: Bacterial flora; Enteroprotection; Intestinal bleeding; Intestinal damage; Nonsteroidal anti-inflammatory drugs; Rifaximin