Several investigations (like the LOGICA and the GIRANO studies) have shown that patients requiring NSAID therapy often display gastrointestinal or/and cardiovascular risk factors ( Lanas et al., 2010 Vanderstraeten et al., 2016).
While NSAID-induced renal adverse events are well-known, those concerning cardiovascular system ( Grosser et al., 2017 Patrono and Baigent, 2017) have been appreciated only recently, after the rofecoxib fallout ( DeMaria, 2004). Those concerning the gastrointestinal tract are the most common and can cause both symptoms (dyspepsia, heartburn, and/or abdominal discomfort) and lesions (mucosal erosions and/or peptic ulcers, with their life-threatening ulcer complications of bleeding and perforation) ( Lanas and Hunt, 2006 Scarpignato and Hunt, 2010). Despite they confer important clinical benefits across multiple indications, their use is associated with a wide array of adverse events involving different organs and systems (i.e., liver, kidney, cardiovascular system, skin, and gut). Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most widely used classes of drugs ( McGettigan and Henry, 2013). In conclusion, rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities. In conclusion, diclofenac induced ileal mucosal lesions, driving inflammatory pathways and microbiota changes. 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. This drug was also capable of increasing the proportion of Lactobacilli, a genus depleted by the NSAID. All these changes were counterbalanced by rifaximin co-administration. In addition, the NSAID decreased ileal occludin expression and provoked a shift of bacterial phyla toward an increase in Proteobacteria and Bacteroidetes abundance. 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 modulating effect of rifaximin on NLRP3 inflammasome was tested in an in vitro cell system. At the end of treatments, parameters dealing with ileal damage, inflammation, barrier integrity, microbiota composition, and TLR-NF-κB-inflammasome pathway were evaluated. Rifaximin (delayed release formulation) was administered (50 mg/kg BID) 1 h before the NSAID. Enteropathy was induced in 40-week old male rats by intragastric diclofenac (4 mg/kg BID, 14 days). 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. Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine, mainly through an involvement of enteric bacteria. 6Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Parma, Italy.5Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom.4Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
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