Nonsteroidal Anti-Inflammatory Drug-Induced Gastrointestinal Injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely consumed therapies for pain, inflammation and fever. Their use extends from acute relief after injury to chronic management of arthritides, with billions of doses administered annually. Yet such benefits are offset by damage to the gastrointestinal tract, which may involve the oesophagus, stomach, small intestine and colon. The spectrum ranges from superficial mucosal erythema and erosions to deep ulcers, bleeding, strictures and, in severe cases, perforation. While upper-tract events have historically dominated clinical concern, growing evidence reveals that small intestinal enteropathy is both common and often asymptomatic, with modern imaging techniques uncovering mucosal breaks in around half of long-term users. Susceptibility to injury rises with advanced age, history of peptic ulcer disease, high NSAID dose, co-medication with antithrombotic agents and Helicobacter pylori infection. At a mechanistic level, NSAIDs inhibit cyclooxygenase isoforms, depleting cytoprotective prostaglandins and directly perturbing mitochondrial function, thereby compromising epithelial integrity. Consequently, luminal bacteria traverse the weakened barrier, activating innate sensors such as Toll-like receptor 4 and triggering NLRP3 inflammasome assembly, interleukin release and neutrophil influx. Clinical strategies to mitigate injury include selective inhibition of COX-2, acid suppression, prophylactic prostaglandin analogues and emerging approaches to modulate the microbiome. Better understanding of these interlinked pathways underpins efforts to reduce the global burden of NSAID-induced enteropathy and improve patient safety.

Research from Nature Portfolio

Recent work has illuminated the central role of the intestinal microbiome in determining susceptibility to NSAID enteropathy. Investigations using rodent models show that acid-suppressing therapies can exacerbate small-intestinal damage by depleting protective commensals, notably Lactobacillus johnsonii, thereby facilitating deeper mucosal injury by indomethacin. Complementary studies demonstrate that adaptive shifts in bacterial communities following initial NSAID exposure confer resilience against subsequent indomethacin challenges; mice harbouring these altered microbiota exhibit reduced cytokine production and epithelial ulceration. Together, these findings reveal that both microbiota depletion and restoration critically influence NSAID toxicity, pointing to microbial manipulation as a promising strategy for prevention.

Nonsteroidal Anti-Inflammatory Drug-Induced Gastrointestinal Injury publication trend

The graph below shows the total number of articles in nonsteroidal anti-inflammatory drug-induced gastrointestinal injury across all publications each year (not limited to Nature Index journals).

Technical terms

Cyclooxygenase (COX): Enzymes (COX-1 and COX-2) responsible for prostaglandin synthesis; inhibition by NSAIDs reduces inflammation but also depletes protective mucosal prostaglandins.

Enteropathy: Any disease of the intestine; NSAID-induced enteropathy specifically refers to mucosal damage in the small intestine, including erosions, ulcers and bleeding.

Dysbiosis: An imbalance in the composition or function of the gut microbiota, which can exacerbate barrier dysfunction and inflammation in NSAID users.

NLRP3 Inflammasome: A multiprotein intracellular complex that activates caspase-1, leading to interleukin-1β maturation and the amplification of mucosal inflammation.

Capsule Endoscopy: A non-invasive imaging technique employing an ingestible camera capsule to visualise and detect lesions throughout the small intestine.

References

1. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Research & Therapy (2013).
2. Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review. Journal of Gastroenterology (2019).
3. Current Perspectives in NSAID‐Induced Gastropathy. Mediators of Inflammation (2013).
4. NSAID–Gut Microbiota Interactions. Frontiers in Pharmacology (2020).
5. Gastric acid inhibitor aggravates indomethacin-induced small intestinal injury via reducing Lactobacillus johnsonii. Scientific Reports (2019).
6. Gut Microbiota Mediates Protection Against Enteropathy Induced by Indomethacin. Scientific Reports (2017).
7. Pathophysiology of NSAID-Associated Intestinal Lesions in the Rat: Luminal Bacteria and Mucosal Inflammation as Targets for Prevention. Frontiers in Pharmacology (2018).