Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review

Abstract

Recent advances in small-bowel endoscopy such as capsule endoscopy have shown that non-steroidal anti-inflammatory drugs (NSAIDs) frequently damage the small intestine, with the prevalence rate of mucosal breaks of around 50% in chronic users. A significant proportion of patients with NSAIDs-induced enteropathy are asymptomatic, but some patients develop symptomatic or complicated ulcers that need therapeutic intervention. Both inhibition of prostaglandins due to the inhibition of cyclooxygenases and mitochondrial dysfunction secondary to the topical effect of NSAIDs play a crucial role in the early process of injury. As a result, the intestinal barrier function is impaired, which allows enterobacteria to invade the mucosa. Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-α and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1β into its mature form. Finally, neutrophils accumulate in the mucosa, resulting in intestinal ulceration. Currently, misoprostol is the only drug that has a proven beneficial effect on bleeding small intestinal ulcers induced by NSAIDs or low-dose aspirin, but its protection is insufficient. Therefore, the efficacy of the combination of misoprostol with other drugs, especially those targeting the innate immune system, should be assessed in the next step.

Keywords: Enteropathy; Innate immunity; Low-dose aspirin; Misoprostol; Non-steroidal anti-inflammatory drug.

Fig. 1

Endoscopic images of NSAIDs-induced small intestinal damage. a–d Images of balloon-assisted endoscopy. a oval-shaped (arrow), b longitudinal ulcer, c circular ulcer, and d diaphragm-like stricture. e–g Images of capsule endoscopy. e Erosion (arrow), f round ulcer, and g circular ulcer

Fig. 2

The mechanism of increased intestinal permeability and activation of innate immune system during development of NSAIDs-induced small intestinal damage. NSAID Non-steroidal anti-inflammatory drug, COX cyclooxygenase, PG prostaglandin, PTP permeability transition pore, HMGB1 high mobility group box 1; LPS, lipopolysaccharide, TLR4 Toll-like receptor 4, NF-κB nuclear factor-κB, NLRP3 NLR family pyrin domain containing 3 protein, IL-1 interleukin-1, TNF-α tumor necrosis factor-α, KC keratinocyte chemoattractant, MCP-1 monocyte chemoattractant protein-1