Pathophysiology of NSAID-Associated Intestinal Lesions in the Rat: Luminal Bacteria and Mucosal Inflammation as Targets for Prevention

Frontiers in Pharmacology

Emilia Ghelardi¹  Matteo Fornai²  Carmelo Scarpignato²  Gianfranco Natale²  Laura Benvenuti²  Luca Antonioli²  Erika Tirotta²  Carolina Pellegrini²  Rocchina Colucci³  Daniela Gentile⁴  Elena Piccoli⁴  Federica Fulceri⁴  Pablo Palazón-Riquelme⁴  Gloria López-Castejón⁵  Corrado Blandizzi⁵  Cecilia Renzulli⁶ 

[1] Development Department, Alfasigma SpA, Bologna, Italy;Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy;Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy;Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy;Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom;;Reasearch &

关键词: non-steroidal anti-inflammatory drugs;    intestinal damage;    intestinal bleeding;    rifaximin;    enteroprotection;    microbiota;   

DOI  :  10.3389/fphar.2018.01340

来源: DOAJ

【 摘 要 】

Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine, mainly through an involvement of enteric bacteria. This study examined the pathophysiology of NSAID-associated intestinal lesions in a rat model of diclofenac-enteropathy and evaluated the effect of rifaximin on small bowel damage. Enteropathy was induced in 40-week old male rats by intragastric diclofenac (4 mg/kg BID, 14 days). Rifaximin (delayed release formulation) was administered (50 mg/kg BID) 1 h before the NSAID. At the end of treatments, parameters dealing with ileal damage, inflammation, barrier integrity, microbiota composition, and TLR-NF-κB-inflammasome pathway were evaluated. In addition, the modulating effect of rifaximin on NLRP3 inflammasome was tested in an in vitro cell system. Diclofenac induced intestinal damage and inflammation, triggering an increase in tissue concentrations of tumor necrosis factor and interleukin-1β, higher expression of TLR-2 and TLR-4, MyD88, NF-κB and activation of caspase-1. In addition, the NSAID decreased ileal occludin expression and provoked a shift of bacterial phyla toward an increase in Proteobacteria and Bacteroidetes abundance. All these changes were counterbalanced by rifaximin co-administration. This drug was also capable of increasing the proportion of Lactobacilli, a genus depleted by the NSAID. In LPS-primed THP-1 cells stimulated by nigericin (a model to study the NLRP3 inflammasome), rifaximin reduced IL-1β production in a concentration-dependent fashion, this effect being associated with inhibition of the up-stream caspase-1 activation. In conclusion, diclofenac induced ileal mucosal lesions, driving inflammatory pathways and microbiota changes. In conclusion, rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities.

【 授权许可】

Unknown