Non-steroidal anti-inflammatory drugs (NSAIDs) -including aspirin, ibuprofen, naproxen, indomethacin, and piroxicam, among others- constitute one of the most frequently prescribed types of drugs that often cause mucosal lesions, not only in the stomach/duodenum, but also in the small intestine. Although several novel treatments have been explored to prevent or reduce NSAID-induced intestinal lesions (i.e., gastrointestinal-sparing NSAIDs, anti-ulcer drugs, anti-secretory agents, antibiotics, probiotics, and food constituents), little is known whether the gut microbiota is involved in ulcer formation as well as in its treatment.

A recent narrative review, led by Dr. Tetsuo Arakawa from the Department of Gastroenterology at the Osaka City University Graduate School of Medicine in Japan, has suggested that probiotics and rebamipide could be useful for addressing NSAID-induced small intestinal damage.

The researchers questioned whether NSAID-induced damage in the small intestine involves the gut microbiota, covering from animal research to human pathologies. An initial experimental study showed that germ-free rats were resistant to indomethacin-induced intestinal lesions. Besides this, NSAID-induced ileal ulcers in gnotobiotic rats were present in those mono-associated with Eubacterium limosum and Escherichia coli but not in those mono-associated with Bifidobacterium and Lactobacillus. These results show that composition of the intestinal microbiota is involved in NSAID-induced small intestinal damage. Specifically, first NSAIDs induce barrier dysfunction through inhibition of cyclooxygenase and subsequent deficiency of prostaglandin and mitochondrial malfunction. Then, toll-like receptor 4 (TLR4) on macrophages recognizes lipopolysaccharide (LPS) found in Gram-negative bacteria that can pass across a weakened barrier. The myeloid differentiation primary-response 88/nuclear factor-kB signalling pathway leads to the release of proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interleukin 1b (IL-1b). This proinflammatory response finally ends with neutrophil infiltration into the mucosa and submucosa of the small intestine, causing damage. However, when interpreting these results it should be keep in mind that the human small intestine harvests not too many bacteria when compared to the large intestine.

When it comes to studying the significance of dysbiosis in NSAID-induced small intestinal damage, the researchers discuss their own study, which demonstrated a possible association between small intestinal bacterial overgrowth (SIBO) and NSAID-induced small intestinal damage in chronic NSAID users. Besides this, a meta-analysis is reported that showed proton pump inhibitors -drugs that are often used for the prevention of NSAID-induced injuries to the upper GI tract- are associated with SIBO and may exacerbate NSAID-induced small intestinal damage.

Potential therapeutic candidates for NSAID-induced small intestinal damage were identified, and included probiotics and rebamipide -a mucoprotective drug that has been clinically used for treating gastritis and peptic ulcers.  Although antibiotics may be effective in preventing the NSAID-induced small intestinal damage, the authors emphasized that when used long-term they may increase the risk of development of multi-drug resistant bacteria. Probiotics were reported as an effective therapeutic option for preventing NSAID-induced small intestinal damage based on experimental data and on studies of patients taking probiotics compared to those receiving control treatment (here; here). Rebamipide may inhibit NSAID-induced small intestinal damage through modulating the composition of the gut microbiota in mice.

On the whole, gut microbiota plays a relevant role in NSAID-induced small intestinal damage pathogenesis. According to data presented, targeting it through probiotics or rebamipide could be a way to prevent NSAID-induced small intestinal damage.




Otani K, Tanigawa T, Watanabe T, et al. Microbiota plays a key role in non-steroidal anti-inflammatory drug-induced small intestinal damage. Digestion. 2017; 95(1):22-8. doi: 10.1159/000452356.