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Background & Aims Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used classes of drugs, with the former frequently coprescribed to reduce gastroduodenal injury caused by the latter. However, suppression of gastric acid secretion by PPIs is unlikely to provide any protection against the damage caused by NSAIDs in the more distal small intestine. Methods Rats were treated with antisecretory doses of omeprazole or lanzoprazole for 9 days, with concomitant treatment with anti-inflammatory doses of naproxen or celecoxib on the final 4 days. Small intestinal damage was blindly scored, and changes in hematocrit were measured. Changes in small intestinal microflora were evaluated by denaturing gradient gel electrophoresis and reverse-transcription polymerase chain reaction. Results Both PPIs significantly exacerbated naproxen- and celecoxib-induced intestinal ulceration and bleeding in the rat. Omeprazole treatment did not result in mucosal injury or inflammation; however, there were marked shifts in numbers and types of enteric bacteria, including a significant reduction (∼80%) of jejunal Actinobacteria and Bifidobacteria spp. Restoration of small intestinal Actinobacteria numbers through administration of selected ( Bifidobacteria enriched) commensal bacteria during treatment with omeprazole and naproxen prevented intestinal ulceration/bleeding. Colonization of germ-free mice with jejunal bacteria from PPI-treated rats increased the severity of NSAID-induced intestinal injury, as compared with mice colonized with bacteria from vehicle-treated rats. Conclusions PPIs exacerbate NSAID-induced intestinal damage at least in part because of significant shifts in enteric microbial populations. Prevention or reversal of this dysbiosis may be a viable option for reducing the incidence and severity of NSAID enteropathy.

real-time reverse transcription-polymerase chain reaction . To clarify the role of HMGB1 in healing of gastric ulcer, the mice were intraperitoneally administered mouse recombinant HMGB1 (rHMGB1), anti-HMGB1 neutralizing antibodies or nonspecific chicken IgY after the induction of ulcer.Results: At day 4 after ulcer induction, mean ulcer sizes did not differ among the 4 groups. Endothelial cells and inflammatory cells such as macrophages in the ulcerous region showed immunoreactivity for TLR2 and TLR4 and RAGE proteins. By day 9, the ulcer size in RAGE KO mice and TLR4 KO mice was 40% smaller than that in wild-type mice, while there was no difference in ulcer sizes between wild-type mice and TLR2 KO mice. Deficiency of RAGE and TLR4 markedly inhibited the increase in expression of TNF-αmRNA in ulcerous tissue. Administration of rHMGB1 delayed the healing of gastric ulcer (ulcer index: 1.39 ± 0.30 mm2 in the vehicle-treated mice and 4.52 ± 0.35 mm2 in rHMGB1-treated mice), accompanied by increase in expression of TNF-α mRNA and MPO activities in ulcerous tissue, while administration of anti-HMGB1 antibody enhanced ulcer healing by day 9 (ulcer index: 2.90 ± 0.86 mm2 in non-specific IgY-treated mice, 1.46 ± 0.80 mm2 in neutralizing antibody for HMGB1-treated mice). Conclusion: These results suggest that HMGB1 is a critical factor that delays healing of gastric ulcer not via TLR2 but via TLR4 and RAGE.

Background & Aims Hydrogen sulfide (H 2 S) is an endogenous gaseous mediator of mucosal defense with antiinflammatory effects that promote ulcer healing. The effects of H 2 S during the pathogenesis of colitis have not been established. We analyzed the contribution of H 2 S to inflammation and ulceration of the colon in a rat model of colitis. Methods Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid. The ability of the colon to synthesize H 2 S was studied over the course of the resolution of the colitis. Expression of 2 enzymes involved in the synthesis of H 2 S and the effects of inhibitors of these enzymes were examined. We also examined the effects of H 2 S donors on the resolution of colitis. Results The capacity for the colon to produce H 2 S increased markedly over the first days after induction of colitis and then declined toward control levels as the colitis was resolved. Inhibition of colonic H 2 S synthesis markedly exacerbated the colitis, resulting in significant mortality. Inhibition of H 2 S synthesis in healthy rats resulted in inflammation and mucosal injury in the small intestine and colon along with down-regulation of cyclooxygenase-2 messenger RNA expression and prostaglandin synthesis. Intracolonic administration of H 2 S donors significantly reduced the severity of colitis and reduced colonic expression of messenger RNA for the proinflammatory cytokine tumor necrosis factor α. Conclusions In rats, H 2 S modulates physiological inflammation and contributes to the resolution of colitis.