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 antiinflammatory 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-a and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1b 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 Non-steroidal anti-inflammatory drug Á Lowdose aspirin Á Enteropathy Á Innate immunity Á Misoprostol Abbreviations NSAID Non-steroidal anti-inflammatory drug RA Rheumatoid arthritis

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

“…However, both NSAID-mediated PG depletion and mitochondrial pathology have been found to be instrumental in the early stage of injury leading to impairment of intestinal mucosal barrier function. As a consequence, the invasion of gram negative enterobacteria initiate the inflammatory cascade wherein Toll like receptor-4 (TLR-4)-induced proinflammatory cytokine upsurge along with NLRP3 inflammosome activation attract the neutrophils eventually leading to oxidative burst, chronic inflammation, apoptosis and ultimately intestinal ulceration [140]. Although, the pathogenesis of enteropathy differs with that of gastropathy in the later stages, uncoupling of mitochondrial oxidative phosphorylation, ATP deficiency, elevation of cytosolic Ca 2+ and Na + / K + imbalance and consequent induction of apoptosis are some of the hall mark and common events triggered in both these gut compartments by NSAIDs.…”

The Role of Autophagy in Inflammatory Bowel Disease

“…However, the disturbance of microbiota balance and damage of intestinal mucosal barrier tend to trigger the over-induction of self-defensive processes, including oxidative stress, inflammasome formation, and so on. The overwhelming induction of those self-defensive mechanisms results in several intestinal disorders such as inflammatory bowel disease (IBD; Ramos and Papadakis, 2019 ; Han et al, 2020 ; Watanabe et al, 2020 ). As a result, targeting on the maintaining of intestinal microbiota homeostasis and suppressing the overwhelmingly induced self-defensive inflammatory and immune responses serves as an effective pathway for the treatment of IBD.…”

Impact of concurrent treatment with omeprazole on phenylbutazone‐induced equine gastric ulcer syndrome (EGUS)

“…Across species, inhibition of prostaglandin synthesis is considered a key contributor to NSAID‐induced gastric damage 10 . However, prostaglandins appear to play a lesser role in NSAID‐induced enteropathy 11,12 . In horses, decreases in neither glandular gastric nor colonic prostaglandin concentration (PGE ± PGI) were observed despite induction of glandular ulceration or clinical (hypoalbuminemia and neutropenia) or pathological findings consistent with right dorsal colitis 4,13‐15 .…”