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NSAID-induced enteropathy may be more clinically significant than upper GI damage.NSAID-enteropathy is significantly worsened by inhibitors of gastric acid secretion.Changes in enteric bacteria and bile are critical in the pathogenesis of NSAID-enteropathy.Hydrogen sulfide is a potent protective factor throughout the GI tract.Nonsteroidal anti-inflammatory drugs (NSAIDs) remain among the most commonly used medications because of their effectiveness in reducing pain and inflammation. Inhibitors of gastric acid secretion can substantially reduce the damaging effects of NSAIDs in the stomach and duodenum. However, there are no proven effective preventative or curative treatments for NSAID-induced enteropathy. In recent years, substantial progress has been made in better understanding the pathogenesis of NSAID-enteropathy, and in particular the interplay of enteric bacteria, bile and the enterohepatic recirculation of the NSAIDs. Moreover, it is becoming clear that suppression of gastric acid secretion significantly worsens NSAID-enteropathy.