Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Gastroenterology. 2011 Oct;141(4):1314-22, 1322.e1-5. doi: 10.1053/j.gastro.2011.06.075. Epub 2011 Jul 13.
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.
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.
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.
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.
质子泵抑制剂（PPIs）和非甾体抗炎药（NSAIDs）是最常用的两类药物，前者常被联合应用以减少后者引起的胃十二指肠损伤。然而，PPIs 抑制胃酸分泌可能无法为 NSAIDs 在更远端小肠引起的损伤提供任何保护。
大鼠接受抗分泌剂量的奥美拉唑或兰索拉唑治疗 9 天，在最后 4 天同时接受抗炎剂量的萘普生或塞来昔布治疗。盲法评估小肠损伤程度，并测量红细胞比容变化。通过变性梯度凝胶电泳和逆转录聚合酶链反应评估小肠微生物群的变化。
两种 PPI 均显著加重了萘普生和塞来昔布诱导的大鼠小肠溃疡和出血。奥美拉唑治疗并未导致黏膜损伤或炎症；然而，肠道细菌的数量和类型发生了明显变化，包括肠 Actinobacteria 和双歧杆菌属数量显著减少（约 80%）。在奥美拉唑和萘普生治疗期间给予选定的（富含双歧杆菌的）共生菌以恢复小肠 Actinobacteria 数量可预防小肠溃疡/出血。用来自 PPI 处理大鼠的空肠细菌定植无菌小鼠增加了 NSAID 诱导的小肠损伤的严重程度，与用来自 vehicle 处理大鼠的细菌定植的小鼠相比。
PPIs 至少部分加重 NSAID 诱导的肠道损伤是由于肠道微生物群的显著变化。预防或逆转这种肠道菌群失调可能是减少 NSAID 肠病发生率和严重程度的可行选择。
