Gut Microbiota in NSAID Enteropathy: Current Evidence and Future Perspectives for Therapeutic Strategies

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed worldwide for their analgesic, antipyretic, and anti-inflammatory properties. However, their long-term use is associated with substantial gastrointestinal (GI) toxicity. Although upper GI injury has traditionally received greater attention, NSAID-induced enteropathy is now increasingly recognized as a common yet underdiagnosed condition. Advances in small-bowel imaging, particularly capsule endoscopy, have demonstrated that mucosal injury of the small intestine occurs in up to 70-80% of chronic NSAID users and may also develop after short-term exposure in otherwise healthy individuals, often without overt clinical symptoms. When symptoms do occur, NSAID-induced enteropathy is characterized by non-specific clinical manifestations and may lead to severe complications in approximately 1% of cases. The pathogenesis of NSAID-induced enteropathy is multifactorial and more complex than that underlying upper GI damage. It involves prostaglandin depletion, increased intestinal permeability, bile acid-mediated toxicity, enterohepatic recirculation of NSAIDs, and, importantly, interactions with the gut microbiota. Concomitant therapies, particularly proton pump inhibitors, may further aggravate small-bowel injury by promoting intestinal dysbiosis. Growing evidence supports a relevant contributory role for the gut microbiota as both a mediator and a modulator of NSAID-induced toxicity, affecting epithelial barrier function, oxidative stress, immune responses, and bile acid metabolism. This review provides an overview of current knowledge of NSAID-induced enteropathy, with a particular emphasis on the microbiota-driven mechanisms underlying mucosal injury. By integrating emerging microbiota-targeted therapeutic approaches, we propose a management algorithm that may help modify disease progression in a condition that remains frequently overlooked in clinical practice.