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.