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Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent
  1. T Watanabe1,
  2. K Higuchi1,
  3. A Kobata2,
  4. H Nishio2,
  5. T Tanigawa1,
  6. M Shiba1,
  7. K Tominaga1,
  8. Y Fujiwara1,
  9. N Oshitani1,
  10. T Asahara3,
  11. K Nomoto3,
  12. K Takeuchi2,
  13. T Arakawa1
  1. 1
    Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
  2. 2
    Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
  3. 3
    Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo
  1. Dr Toshio Watanabe, Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan; watanabet{at}


Background: Enterobacteria and cytokines both play roles in the pathophysiology of NSAID-induced enteropathy. Toll-like receptor (TLR) 4 recognises lipopolysaccharide (LPS), resulting in activation of an inflammatory cascade via the accessory protein MyD88.

Aims: To investigate role of TLR4 in inflammatory responses in indomethacin-induced enteropathy.

Methods: Indomethacin was administered p.o. to non-fasting rats and mice to induce small intestinal damage. The extent of such damage was evaluated by measuring the injured area stained dark blue with Evans blue. Rats were given antibiotics (ampicillin, aztreonam or vancomycin) p.o., or intraperitoneal LPS (a TLR4 ligand) or neutralising antibodies against neutrophils, tumour necrosis factor (TNF)-α, or monocyte chemotactic protein (MCP)-1. Furthermore, the intestinal ulcerogenicity of indomethacin was examined in TLR4-mutant, TLR4−/−, and MyD88−/− mice.

Results: Indomethacin induced small intestinal damage with an increase in expression of TNF-α and MCP-1 in both rats and mice. Antibodies against neutrophils, TNF-α and MCP-1 inhibited the damage by 83%, 67% and 63%, respectively, in rats. Ampicillin and aztreonam also inhibited this damage, and decreased the number of Gram-negative bacteria in the small intestinal contents of the rat. However, vancomycin, which exhibited no activity against Gram-negative bacteria, had no preventive effect against this damage. Administration of LPS 1 h after indomethacin aggravated the damage, whereas LPS pretreatment inhibited it with reduction of expression of TLR4 and cytokines. In TLR4-mutant mice, the damage and cytokine expression were markedly inhibited. TLR4−/− and MyD88−/− mice were also resistant to the damage.

Conclusions: Indomethacin may injure the small intestine through a TLR4/MyD88-dependent pathway.

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  • Funding: This study was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

  • Competing interests: None.

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