Fornai Matteo, Antonioli Luca, Pellegrini Carolina, Colucci Rocchina, Sacco Deborah, Tirotta Erika, Natale Gianfranco, Bartalucci Alessia, Flaibani Marina, Renzulli Cecilia, Ghelardi Emilia, Blandizzi Corrado, Scarpignato Carmelo
Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Pharmacol Res. 2016 Feb;104:186-96. doi: 10.1016/j.phrs.2015.12.031. Epub 2015 Dec 30.
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.
非甾体抗炎药除了对上消化道有不良影响外，还会损害小肠和大肠。尽管其潜在机制尚不清楚，但有证据表明肠道细菌起着关键作用。本研究在吲哚美辛（IND，1.5mg/kg，每日两次，共14天）诱导的大鼠肠病模型中，研究了利福昔明缓释制剂-EIR（R-EIR，50mg/kg，每日两次，灌胃）的肠保护作用，利福昔明是一种吸收不良的抗生素，具有广谱抗菌活性。R-EIR在IND给药前7天开始给药或与IND同时给药。治疗结束时，采集血样以评估血红蛋白（Hb）浓度（作为消化性出血的指标）。对小肠进行如下处理：（1）肠道损伤的组织学评估（病变长度占检查总长度的百分比）；（2）检测组织髓过氧化物酶（MPO）和TNF水平，作为炎症标志物；（3）检测组织丙二醛（MDA）和蛋白质羰基浓度，分别作为脂质和蛋白质过氧化的指标；（4）评估主要细菌门类。IND显著降低了Hb水平，而R-EIR可显著减轻这一作用。IND还诱导空肠和回肠出现病变。在两个肠道区域，与单独接受IND的大鼠相比，R-EIR显著降低了病变百分比。IND处理的大鼠空肠和回肠中炎症和组织过氧化标志物均显著增加。然而，在接受R-EIR治疗的大鼠中，这些参数与对照组观察到的参数无显著差异。R-EIR还能够抵消IND诱导的变形菌门和厚壁菌门丰度的增加。总之，R-EIR治疗可显著预防IND诱导的肠道损伤，这种肠保护作用与组织炎症、氧化应激和消化性出血的减少以及非甾体抗炎药诱导的细菌群落改变的逆转有关。
