title: Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis.
abstract: OBJECTIVE
  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.
authors: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. jwalla@mcmaster.ca
authors: John L
authors: JL
authors: Wallace
authors: Stephanie
authors: S
authors: Syer
authors: Emmanuel
authors: E
authors: Denou
authors: Giada
authors: G
authors: de Palma
authors: Linda
authors: L
authors: Vong
authors: Webb
authors: W
authors: McKnight
authors: Jennifer
authors: J
authors: Jury
authors: Manlio
authors: M
authors: Bolla
authors: Premysl
authors: P
authors: Bercik
authors: Stephen M
authors: SM
authors: Collins
authors: Elena
authors: E
authors: Verdu
authors: Ennio
authors: E
authors: Ongini
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000633:toxicity; D039903:Actinobacteria / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000633:toxicity*; D001644:Bifidobacterium / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D000068579:Celecoxib; D003106:Colon / Q000187:drug effects / Q000382:microbiology; D058645:Denaturing Gradient Gel Electrophoresis; D004195:Disease Models, Animal; D004347:Drug Interactions; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D006400:Hematocrit; D007583:Jejunum / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D064747:Lansoprazole; D008297:Male; D009288:Naproxen / Q000633:toxicity; D009853:Omeprazole / Q000633:toxicity; D010437:Peptic Ulcer / Q000139:chemically induced* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D019936:Probiotics / Q000494:pharmacology; D054328:Proton Pump Inhibitors / Q000633:toxicity*; D011720:Pyrazoles / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000633:toxicity; D013997:Time Factors
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000894:Anti-Inflammatory Agents, Non-Steroidal; D054328:Proton Pump Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D064747:Lansoprazole; D009288:Naproxen; D000068579:Celecoxib; D009853:Omeprazole