Advertisement
Reviews and Perspectives Reviews in Basic and Clinical Gastroenterology and Hepatology| Volume 154, ISSUE 3, P500-514, February 01, 2018

Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs

Published:December 05, 2017DOI:https://doi.org/10.1053/j.gastro.2017.10.049
      Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the mechanisms of gastrointestinal damage induction by NSAIDs via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and inter-dependent factors. This model highlights the obstacles for the development of safer NSAIDs.

      Keywords

      Abbreviations used in this paper:

      ATP (adenosine triphosphate), COX (cyclooxygenase), NSAID (nonsteroidal anti-inflammatory drug), pKa (logarithmic transformed acid dissociation constant)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Singh G.
        • Triadafilopoulos G.
        Epidemiology of NSAID induced gastrointestinal complications.
        J Rheumatol. 1999; 56: 18-24
        • Bhala N.
        • Emberson J.
        • Merhi A.
        • et al.
        • Coxib and Traditional NSAID Trialists' (CNT) Collaboration
        Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.
        Lancet. 2013; 382: 769-779
        • Nissen S.E.
        • Yeomans N.D.
        • Solomon D.H.
        • et al.
        Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis.
        N Engl J Med. 2016; 375: 2519-2529
        • Bjarnason I.
        • Scarpignato C.
        • Takeuchi K.
        • et al.
        Determinants of the short-term gastric damage caused by NSAIDs in man.
        Aliment Pharmacol Ther. 2007; 26: 95-106
        • Geis G.S.
        • Stead H.
        • Wallemark C.B.
        • et al.
        Prevalence of mucosal lesions in the stomach and duodenum due to chronic use of NSAID in patients with rheumatoid arthritis or osteoarthritis, and interim report on prevention by misoprostol of diclofenac associated lesions.
        J Rheumatol Suppl. 1999; 28: 11-14
        • Bjarnason I.
        • Hayllar J.
        • Macpherson A.J.
        • et al.
        Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine.
        Gastroenterology. 1993; 104: 1832-1847
        • Maiden L.
        • Thjodleifsson B.
        • Theodors A.
        • et al.
        A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy.
        Gastroenterology. 2005; 128 (1172−118)
        • Vane J.R.
        Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs.
        Nature. 1971; 231: 232-235
        • Whittle B.J.
        Arachidonic acid metabolites and the gastro-intestinal toxicity of anti-inflammatory agents.
        Prostaglandins. 1981; 21: 113-118
        • Vane J.R.
        Towards a better aspirin.
        Nature. 1994; 367: 215-216
        • Whittle B.J.R.
        Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and gastrointestinal damage induced by indomethacin in the rat.
        Gastroenterology. 1981; 80: 94-98
        • Peskar B.M.
        On the synthesis of prostaglandins by human gastric mucosa and its modification by drugs.
        Biochem Biophys Acta. 1977; 487: 307-314
        • Strub K.M.
        • Muller R.K.
        Relation between ulcerogenic activity of various NSAID and their potency as inhibitors of prostaglandin synthesis in vivo.
        Agents Actions. 1979; 4: 245-254
        • Graham D.Y.
        • Agrawal N.M.
        • Roth S.H.
        Prevention of NSAID-induced gastric ulcer with misoprostol: multicenter double blind, placebo-controlled trial.
        Lancet. 1988; (ii:1277−1280)
        • Silverstein F.E.
        • Graham G.Y.
        • Senior J.R.
        • et al.
        Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatoy drugs.
        Ann Int Med. 1995; 123: 241-249
        • Roberts A.
        Cytoprotection by prostaglandins.
        Gastroenterology. 1975; 77: 761-767
        • Jiranek G.C.
        • Kimmey M.B.
        • Saunders D.R.
        • et al.
        Misoprostol reduces gastroduodenal injury from one week of aspirin: an endoscopic study.
        Gastroenterology. 1989; 96: 656-661
        • Bardhan K.D.
        • Bjarnason I.
        • Scott D.L.
        • et al.
        The prevention and healing of acute NSAID-associated gastroduodenal mucosal damage by misoprostol.
        Br J Rheumatol. 1993; 32: 990-995
        • Laine L.
        • Takeuchi K.
        • Tarnawski A.
        Gastric mucosal defense and cytoprotection: bench to bedside.
        Gastroenterology. 2008; 165: 41-60
        • Rostom A.
        • Muir K.
        • Dubé C.J.
        • et al.
        Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review.
        Clin Gastroenterol Hepatol. 2007; 5: 818-828
        • Wallace J.L.
        Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?.
        Physiol Rev. 2008; 88: 1547-1565
        • Whittle B.J.R.
        Unwanted effects of aspirin and related agents on the gastrointestinal tract.
        in: Vane J.R. Botting R.M. Aspirin and other Salicylates. Chapman & Hall Medical, London1992: 465-509
        • Whittle B.J.R.
        Mechanism underlying gastric mucosal damage induced by indomethacin and bile salt, and the actions of prostaglandins.
        Br J Pharmacol. 1977; 60: 455-460
        • Whittle B.J.R.
        Protective mechanisms of the gastric mucosa.
        in: Gustsavsson S. Kumar D. Graham D.Y. The Stomach. Churchill Livingstone, Edinburgh1992: 81-101
        • Wallace J.L.
        Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years.
        Gastroenterology. 1997; 112: 1000-1016
        • Wallace J.L.
        • McKnight G.W.
        The mucoid cap over superficial gastric damage in the rat. A high-pH microenvironment dissipated by nonsteroidal anti-inflammatory drugs and endothelin.
        Gastroenterology. 1990; 99: 295-304
        • Wallace J.L.
        • Caliendo G.
        • Santagada V.
        • et al.
        Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat.
        Gastroenterology. 2007; 132: 261-271
        • Asako H.
        • Kubes P.
        • Wallace J.
        • et al.
        Modulation of leukocyte adhesion in rat mesenteric venules by aspirin and salicylate.
        Gastroenterology. 1992; 103: 146-152
        • McCafferty D.M.
        • Granger D.N.
        • Wallace J.L.
        Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rat.
        Gastroenterology. 1995; 109: 1173-1180
        • Whittle B.J.R.
        • Kaufman G.L.
        • Moncada S.
        Vasoconstriction with thromboxane A2 induces ulceration of gastric mucosa.
        Nature. 1981; 292: 472-474
        • Wallace J.L.
        The 1994 Merk Frosst Award. Mechanism of nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal damage-potential for development of gastrointestinal tract safe NSAIDs.
        Can J Physiol Pharmacol. 1994; 72: 1493-1498
        • Syer S.D.
        • Blackler R.W.
        • Martin R.
        • et al.
        NSAID enteropathy and bacteria: a complicated relationship.
        J Gastroenterol. 2015; 50: 387-393
        • Ligumski M.
        • Golanska E.M.
        • Hansen D.G.
        • et al.
        Aspirin can inhibit gastric mucosal cyclo-oxigenase without causing lesions in the rat.
        Gastroenterology. 1983; 84: 756-761
        • Ligumski M.
        • Sestieri M.
        • Karmeli F.
        • et al.
        Rectal administration of nonsteroidal antiinflammatory drugs.
        Gastroenterology. 1990; 98: 1245-1249
        • Langenbach R.
        • Morham S.G.
        • Tiano H.F.
        • et al.
        Prostaglandin synthase 1 gene disruption in mice reduced arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration.
        Cell. 1995; 83: 483-492
        • Sigthorsson G.
        • Simpson R.J.
        • Walley M.
        • et al.
        COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice.
        Gastroenterology. 2002; 122: 1913-1923
        • Wallace J.L.
        • McKnight W.
        • Reuter B.K.
        • et al.
        NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2.
        Gastroenterology. 2000; 119: 706-714
        • Takeuchi K.
        • Smale S.
        • Premchand P.
        • et al.
        Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease.
        Clin Gastroenterol Hepatol. 2006; 4: 196-202
        • Morham S.G.
        • Langenbach R.
        • Loftin C.D.
        • et al.
        Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse.
        Cell. 1995; 83: 473-482
        • Sigthorsson G.
        • Crane R.
        • Simon T.
        • et al.
        COX-2 specific inhibition with rofecoxib 25 or 50 mg OD does not increase intestinal permeability: a controlled study with placebo and indomethacin 50 mg TID.
        Gut. 2000; 47: 527-532
        • Maiden L.
        • Thjodleifsson B.
        • Seigal A.
        • et al.
        Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study.
        Clin Gastroenterol Hepatol. 2007; 5: 1040-1045
        • Somasundaram S.
        • Hayllar J.
        • Rafi S.
        • et al.
        The biochemical basis of NSAID-induced damage to the gastrointestinal tract: a review and a hypothesis.
        Scand J Gastroenterol. 1995; 30: 289-299
        • Bjarnason I.
        • Takeuchi K.
        • Bjarnason A.
        • et al.
        The G.U.T. of gut.
        Scand J Gastroenterol. 2004; 39: 807-815
        • Brune K.
        • Glatt M.
        • Graf P.
        Mechanisms of action of anti-inflammatory drugs.
        Gen Pharmacol. 1976; 7: 27-33
        • Brune K.
        • Graf P.
        • Rainsford K.D.
        Biodistribution of acidic anti-inflammatory drugs: a clue to the understanding of their effects and side-effects.
        Drug Exp Clin Res. 1977; 2: 155-168
        • Rainsford K.D.
        Structure-activity relationships of non-steroidal anti-inflammatory drugs. I. Gastric ulcerogenic activity.
        Agents Actions. 1978; 8: 587-605
        • Rainsford K.D.
        • Whitehouse M.W.
        Anti-inflammatory antipyretic salicylic acid esters, with low gastric ulcerogenic activity.
        Agents Actions. 1980; 10: 451-456
        • Varum F.J.
        • Veiga F.
        • Sousa J.S.
        • et al.
        An investigation into the role of mucus thickness on mucoadhesion in the gastrointestinal tract of pig.
        Eur J Pharm Sci. 2010; 40: 335-341
        • Lichtenberger L.M.
        • Wang Z.-M.
        • Romero J.J.
        • et al.
        Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury.
        Nat Med. 1995; 1: 154-158
        • Lichtenberger L.M.
        The hydrophobic barrier properties of gastrointestinal mucus.
        Annu Rev Physiol. 1995; 57: 565-583
        • Goddard P.J.
        • Hills B.A.
        • Lichtenberger L.M.
        Does aspirin damage canine gastric mucosa by reducing its surface hydrophobicity?.
        Am J Physiol. 1987; 252: G421-G430
        • Lugea A.
        • Antolin M.
        • Mourelle M.
        • et al.
        Deranged hydrophobic barrier of the rat gastroduodenal mucosa after parenteral nonsteroidal anti-inflammatory drugs.
        Gastroenterology. 1997; 112: 1931-1939
        • Lichtenberger L.M.
        • Zhou Y.
        • Jayaraman V.
        • et al.
        Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine.
        Biochem Biophys acta. 2012; 182: 994-1002
        • Lichtenberger L.M.
        • Ulloa C.
        • Romero J.J.
        • et al.
        Nonsteroidal anti-inflammatory drug and phospholipid prodrugs: combination therapy with antisecretory agents in rats.
        Gastroenterology. 1996; 111: 990-995
        • Lim Y.J.
        • Phan T.M.
        • Dial E.J.
        • et al.
        In vitro and in vivo protection against indomethacin-induced small intestinal injury by proton pump inhibitors, acid pump antagonists, or indomethacin-phosphatidylcholine.
        Digestion. 2012; 86: 171-177
        • Lichtenberger L.M.
        • Romero J.J.
        • Dial E.J.
        Surface phospholipids in gastric injury and protection when a selective cyclooxygenase-2 inhibitor (Coxib) is used in combination with aspirin.
        Br J Pharmacol. 2007; 150: 913-919
        • Anand B.S.
        • Romero J.J.
        • Sanduja S.K.
        • et al.
        Phospholipid association reduces the gastric mucosal toxicity of aspirin in human subjects.
        Am J Gastroenterol. 1999; 94: 1818-1822
        • Cryer B.
        • Bhatt D.L.
        • Lanza F.L.
        • et al.
        Low-dose aspirin-induced ulceration is attenuated by aspirin-phosphatidylcholine: a randomized clinical trial.
        Am J Gastroenterol. 2011; 106: 272-277
        • Lanza F.L.
        • Marathi U.K.
        • Anand B.S.
        • et al.
        Clinical trial: comparison of ibuprofen-phosphatidylcholine and ibuprofen on the gastrointestinal safety and analgesic efficacy in osteoarthritic patients.
        Aliment Pharmacol Ther. 2008; 28: 431-442
        • Tyler D.D.
        Respiratory enzyme systems of mitochondria.
        in: Tyler D.D. The Mitochondrian in Health and Disease. VCH Publishers, New York1992: 270-351
        • Zamzami N.
        • Susin S.A.
        • Marchetti P.
        • et al.
        Mitochondrial control of nuclear apoptosis.
        J Exp Med. 1996; 183: 1533-1544
        • Sivalingam N.
        • Basivireddy J.
        • Balasubramanian K.A.
        • et al.
        Curcumin attenuates indomethacin-induced oxidative stress and mitochondrial dysfunction.
        Arch Toxicol. 2008; 82: 471-481
        • Madara J.L.
        Tight junction dynamics: is paracellular transport regulated?.
        Cell. 1988; 53: 497-498
        • Masubuchi Y.
        • Saito H.
        • Horie T.
        Structural requirements for the hepatotoxicity of nonsteroidal anti-inflammatory drugs in isolated rat hepatocytes.
        J Pharmacol Exp Ther. 1998; 287: 208-213
        • Adams S.S.
        • Cobb R.
        A possible basis for the anti-inflammatory activity of salicylates and other non-hormonal anti-rheumatic drugs.
        Nature. 1958; 181: 773-774
        • Adams S.S.
        • Cliffe E.E.
        • Lessel B.
        • et al.
        Some biological properties of ‘ibufenac', a new anti-rheumatic drug.
        Nature. 1963; 200: 271-272
        • Glarborg-Jorgensen T.
        • Weis-Fogh U.S.
        • Neilsen H.H.
        • et al.
        Salicylate- and aspirin-induced uncoupling of oxidative phosphorylation in mitochondria isolated from the mucosal membrane of the stomach.
        Scand J Lab Invest. 1976; 36: 649-653
        • Spenny J.G.
        • Bhown M.
        Effect of prostaglandin acid on gastric mucosa II. Mucosal ATP and phosphocreatinine content and salicylic effects on mitochondrial metabolism.
        Gastroenterology. 1977; 73: 995-999
        • Somasundaram S.
        • Rafi S.
        • Hayllar J.
        • et al.
        Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID-induced injury to the rat intestine.
        Gut. 1997; 41: 344-353
        • Mahmud T.
        • Rafi S.S.
        • Scott D.L.
        • et al.
        Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation.
        Arth Rheum. 1996; 39: 1998-2003
        • Roth S.H.
        Endoscopy-controlled study of the safety of nabumetone compared with naproxen in arthritis therapy.
        Am J Med. 1987; 83: 25-30
        • Basivireddy J.
        • Vasudevan A.
        • Jacob M.
        • et al.
        Indomethacin-induced mitochondrial dysfunction and oxidative stress in villus enterocytes.
        Biochem Pharmacol. 2002; 64: 339-349
        • Mahmud T.
        • Somasundaram S.
        • Sigthorsson G.
        • et al.
        Enantiomers of flurbiprofen can distingush key pathophysiological steps of NSAID-enteropathy in the rat by steroselective inhibition of cyclooxygenase.
        Gut. 1998; 43: 775-782
        • Somasundaram S.
        • Macpherson A.J.
        • Hayllar J.
        • et al.
        Enterocyte mitochondrial damage due to NSAID in the rat.
        Gut. 1992; 33: S5
        • Somasundaram S.
        • Rafi S.
        • Jacob M.
        • et al.
        Intestinal tolerability of nitroxybutyl-flurbiprofen in rats.
        Gut. 1997; 40: 608-613
        • Krause M.M.
        • Brand M.D.
        • Krauss S.
        • et al.
        Nonsteroidal antiinflammatory drugs and a selective cyclooxygenase 2 inhibitor uncouple mitochondria in intact cells.
        Arthritis Rheum. 2003; 48: 1438-1444
        • Fornai M.
        • Antonioli L.
        • Colucci R.
        • et al.
        NSAID-induced enteropathy: are the currently available selective COX-2 inhibitors all the same?.
        J Pharmacol Exp Ther. 2014; 348: 86-95
        • Sigthorsson G.
        • Jacob M.
        • Wrigglesworth J.M.
        • et al.
        A comparison of indomethacin and nimesulide, a selective cyclooxygenase-2 inhibitor, on key pathophysiological steps in the pathogenesis of nsaid enteropathy in the rat.
        Scand J Gastroenterol. 1998; 33: 728-735
        • Tibble J.A.
        • Sigthorsson G.
        • Foster R.
        • et al.
        Comparison of the intestinal toxicity of celecoxib, a selective COX-2 inhibitor, and indomethacin in the experimental rat.
        Scand J Gastroenterol. 2000; 35: 802-807
        • Kawai K.
        • Shiojiri H.S.
        • Fukushima H.
        • et al.
        The inhibition of mitochondrial respiration by indomethacin, a non-steroidal anti-inflammatory agent possessing inhibitory effect on prostaglandin biosynthesis.
        Res Commun Chem Path Pharmacol. 1984; 48: 267-274
        • McDougall
        • Markham A.
        • Cameron I.
        • et al.
        The mechanism of inhibition of mitochondrial oxidative phosphorylation by the non-steroidal anti-inflammatory agent diflunisal.
        Biochem Pharmacol. 1983; 32: 2595-2598
        • Mehlman M.A.
        • Tobin R.B.
        • Sporn E.M.
        Oxidative phosphorylation and respiration by rat liver mitochondria from aspirin treated rats.
        Biochem Pharmacol. 1972; 21: 3279-3285
        • Tokumitsu Y.
        • Lee S.
        • Ui M.
        In vitro effects of nonsteroidal antiinflammatory drugs on oxidative phosphorylation in rat liver mitochondria.
        Biochem Pharmacol. 1977; 26: 2101-2106
        • Picot D.
        • Loll P.J.
        • Garavito R.M.
        The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1.
        Nature. 1994; 367: 243-249
        • Kurumbail R.G.
        • Stevens A.M.
        • Gierse J.K.
        • et al.
        Structural basis for selective inhibition of cycoloxygenase-2 by anti-inflammatory agents.
        Nature. 1996; 384: 644-648
        • Vane J.R.
        • Botting R.M.
        Formation and actions of prostaglandins and their inhibition of their synthesis.
        in: Vane J.R. Botting R.M. Therapeutic Roles of Selective COX-2 Inhibitors. William Harvey Press, Burlington Press, Foxton, Cambridge, UK2001: 1-47
        • Kurumbail R.G.
        • Kiefer J.R.
        • Marnett L.J.
        Cyclooxygenase enzymes: catalysis and inhibition.
        Curr Opin Struct Biol. 2001; 11: 752-760
        • Papapetropoulos A.
        • Foresti R.
        • Ferdinandy P.
        Pharmacology of the ‘gasotransmitters' NO, CO and H2S: translational opportunities.
        Br J Pharmacol. 2015; 172: 1395-1396
        • Martín M.J.
        • Jiménez M.D.
        • Motilva V.
        New issues about nitric oxide and its effects on the gastrointestinal tract.
        Curr Pharm Dis. 2001; 7: 881-908
        • Jansson E.A.
        • Petersson J.
        • Reinders C.
        • et al.
        Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate.
        Free Radic Biol Med. 2007; 42: 510-518
        • Lanas A.
        • Bajador E.
        • Serrano P.
        • et al.
        Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding.
        N Engl J Med. 2000; 343: 834-839
        • Fiorucci S.
        • Antonelli E.
        • Distrutti E.
        • et al.
        Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs.
        Gastroenterology. 2005; 129: 1210-1220
        • Wallace J.L.
        • Caliendo G.
        • Santagada V.
        • et al.
        Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346).
        Br J Pharmacol. 2010; 159: 1236-1246
        • Miura S.
        • Suematsu M.
        • Tanaka S.
        • et al.
        Microcirculatory disturbance in indomethacin-induced intestinal ulcer.
        Am J Physiol. 1991; 26: G213-G219
        • Davies N.M.
        • Roseth A.G.
        • Appleyard C.B.
        • et al.
        NO-naproxen versus naproxen: Ulcerogenic, analgesic and anti-inflammatory effect.
        Aliment Pharmacol Ther. 1997; 11: 69-79
        • Fiorucci S.
        • Santucci L.
        • Gresele P.
        • et al.
        Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study.
        Gastroenterology. 2003; 124: 600-607
        • Hawkey C.J.
        • Jones J.I.
        • Atherton C.T.
        • et al.
        Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans.
        Gut. 2003; 52: 1537-1542
        • Lohmander L.S.
        • McKeith D.
        • Svensson O.
        • et al.
        A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis.
        Ann Rheum Dis. 2005; 64: 449-456
        • Wallace J.L.
        • Elliott S.N.
        • Del Soldato P.
        • et al.
        Gastrointestinal-sparing anti-inflammatory drugs: the development of nitric oxide-releasing NSAIDs.
        Drug DR. 1997; 42: 144-149
        • Zanardo R.C.
        • Brancaleone V.
        • Distrutti E.
        • et al.
        Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation.
        FASEB J. 2006; 20: 2118-2120
        • Anthony A.
        • Dhillon A.P.
        • Nygard G.
        • et al.
        Early histological features of small intestinal injury induced by indomethacin.
        Aliment Pharmacol Ther. 1993; 7: 29-40
        • Anthony A.
        • Pounder R.E.
        • Dhillon A.P.
        • et al.
        Vascular anatomy defines sites of indomethacin induced jejunal ulceration along the mesenteric margin.
        Gut. 1997; 41: 763-770
        • Kelly D.
        • Piasecki C.
        • Anthony A.
        • et al.
        Early indomethacin lesions in rat jejunum: reduced focal blood flow and shortening of villi preceed ulceration.
        Gut. 1998; 42: 366-373
        • Nygard G.
        • Anthony A.
        • Piasecki C.
        • et al.
        Acute indomethacin-induced jejunal injury in the rat: Early morphological and biochemical changes.
        Gastroenterology. 1994; 106: 567-575
        • Weiss G.J.
        Tissue destruction by neutrophils.
        N Engl J Med. 1989; 320: 365-376
        • Wilkinson P.C.
        Leucocyte locomotion: determinants of locomotor capacity, chemotaxis and chemokinesis.
        in: Peters T.J. The Cell Biology of Inflammation in the Gastrointestinal Tract. Corners Publication, Hull, UK1990: 15-27
        • Scheiman J.M.
        • Yeomans N.D.
        • Talley N.J.
        • et al.
        Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors.
        Am J Gastroenterol. 2006; 101: 701-710
        • Yeomans N.D.
        • Tulassay Z.
        • Juhász L.
        • et al.
        A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group.
        N Engl J Med. 1998; 338: 719-726
        • Taha A.S.
        • HN
        • Hawkey C.J.
        • Swannell A.J.
        • et al.
        Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs.
        N Engl J Med. 1996; 334: 1435-1439
        • Quinn C.M.
        • Bjarnason I.
        • Price A.B.
        Gastritis in patients on non-steroidal anti-inflammatory drugs.
        Histopathology. 1993; 23: 341-348
        • Konturek J.W.
        • Dembinski A.
        • Konturek S.J.
        • et al.
        Infection of Helicobacter pylori in gastric adaptation to continued administration of aspirin in humans.
        Gastroenterology. 1998; 114: 245-255
        • White J.R.
        • Winter J.A.
        • Robinson K.
        Differential inflammatory response to Helicobacter pylori infection: etiology and clinical outcomes.
        J Inflamm Res. 2015; 8: 137-147
        • Datta De D.
        • Roychoudhury S.
        To be or not to be: the host genetic factor and beyond in Helicobacter pylori mediated gastro-duodenal diseases.
        World J Gastroenterol. 2015; 21: 2883-2895
        • Lanas A.
        • Chan F.K.
        Peptic ulcer disease.
        Lancet. 2017; 390: 613-624
        • Iijima K.
        • Ara N.
        • Abe Y.
        • et al.
        Biphasic effects of H. pylori infection on low-dose aspirin-induced gastropathy depending on the gastric acid secretion level.
        J Gastroenterol. 2012; 47: 1291-1297
        • Huang J.Q.
        • Sridhar S.
        • Hunt R.H.
        Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis.
        Lancet. 2002; 359: 14-22
        • Duggan D.E.
        • Hooke K.F.
        • Noll R.M.
        • et al.
        Enterohepatic circulation of indomethacin and its role in intestinal irritation.
        Biochem Pharmacol. 1975; 25: 1749-1754
        • Beck W.S.
        • Schneider H.T.
        • Dietzel K.
        • et al.
        Gastrointestinal ulcerations induced by anti-inlammatory drugs in rats: physicochemical and biochemical factors involved.
        Arch Toxicol. 1990; 64: 210-216
        • Wax J.
        • Clinger W.A.
        • Varner P.
        • et al.
        Relationship of the enterohepatic cycle to ulcerogenesis in the rat small bowel with flufenamic acid.
        Gastroenterology. 1970; 58: 772-780
        • Brodie D.A.
        • Cook P.G.
        • Bauer B.J.
        • et al.
        Indomethacin-induced intestinal lesions in the rat.
        Toxicol Appl Pharmacol. 1970; 17: 615-624
        • Melrange R.
        • Gentry C.
        • O'Connell C.
        • et al.
        Antiinflammatory and gastrointestinal effects of nabumetone or its active metabolite, 6-methoxy-6-naphthylacetic acid (6MNA).
        Digest Dis Sci. 1992; 37: 1847-1852
        • Semple P.F.
        • Russell R.I.
        Role of bile acids in the pathogenesis of aspirin-induced gastric mucosal hemorrhage in rats.
        Gastroenterology. 1975; 68: 67-70
        • Zhou Y.
        • Dial E.J.
        • Doyen R.
        • et al.
        Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs.
        Am J Physiol Gastrointest Liver Physiol. 2010; 298: G722-G731
        • Barrios J.M.
        • Lichtenberger L.M.
        Role of biliary phosphatidylcholine in bile acid protection and NSAID injury of the ileal mucosa in rats.
        Gastroenterology. 2000; 118: 1179-1186
        • Dial E.J.
        • Darling R.L.
        • Lichtenberger L.M.
        Importance of biliary excretion of indomethacin in gas-trointestinal and hepatic injury.
        Gastroenterol Hepatol. 2008; 23: 384-389
        • Distrutti E.
        • Santucci L.
        • Cipriani S.
        • et al.
        Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa.
        J Gastroenterol. 2015; 50: 707-719
        • Pavlidis P.
        • Powell N.
        • Vincent R.P.
        • et al.
        Systematic review: bile acids and intestinal inflammation-luminal aggressors or regulators of mucosal defence?.
        Aliment Pharmacol Ther. 2015; 42: 802-817
        • Uchida A.
        • Yamada T.
        • Hayakawa T.
        • et al.
        Taurochenodeoxycholic acid ameliorates and ursodeoxycholic acid exacerbates small intestinal inflammation.
        Am J Physiol. 1997; 272: G1249-G1257
        • Lloyd-Still J.D.
        • Beno D.W.
        • Uhing M.R.
        • et al.
        Ursodeoxycholic acid ameliorates ibuprofen-induced enteropathy in the rat.
        J Pediatr Gastroenterol Nutr. 2001; 32: 270-273
        • Jacob M.
        • Foster R.
        • Sigthorsson G.
        • et al.
        Role of bile in pathogenesis of indomethacin-induced enteropathy.
        Arch Toxicol. 2007; 81: 291-298
        • Seitz S.
        • Boelsterli U.A.
        Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats.
        Gastroenterology. 1998; 115: 1476-1482
        • Boelsterli U.A.
        • Ramirez-Alcantara V.
        NSAID acyl glucuronides and enteropathy.
        Curr Drug Metab. 2011; 12: 245-252
        • LoGuidice A.
        • Wallace B.D.
        • Bendel L.
        • et al.
        Pharmacologic targeting of bacterial β-glucuronidase alleviates nonsteroidal anti-inflammatory drug-induced enteropathy in mice.
        J Pharmacol Exp Ther. 2012; 341: 447-454
        • Saitta K.S.
        • Zhang C.
        • Lee K.K.
        • et al.
        Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics.
        Xenobiotica. 2014; 44: 28-35
        • Wallace J.L.
        • Syer S.
        • Denou E.
        • et al.
        Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis.
        Gastroenterology. 2011; 141: 1314-1322
        • Schneider H.T.
        • Nuernberg B.
        • Dietzel K.
        • et al.
        Biliary elimination of non-steroidal anti-inflammatory drugs in patients.
        Br J Clin Pharmacol. 1990; 29: 127-131
        • Tibble J.
        • Sigthorsson G.
        • Foster R.
        • et al.
        Faecal calprotectin: a simple method for the diagnosis of NSAID-induced enteropathy.
        Gut. 1999; 45: 362-366
        • Brune K.
        • Dietzel K.
        • Nurnberg B.
        • et al.
        Recent insight into the mechanism of gastroinestinal tract ulceration.
        Scand J Rheumatol. 1987; 9: 135-140
        • Ishihara Y.
        • Okabe S.
        Effects of cholestyramine and synthetic hydrotalcite on acute gastric or intestinal lesion formation in rats and dogs.
        Dig Dis Sci. 1981; 26: 553-560
        • Kent T.H.
        • Cardeli R.M.
        • Stanler F.U.
        Small intestinal ulcers and intestinal flora in rats given indomethacin.
        Am J Pathol. 1969; 54: 237-245
        • Basivireddy J.
        • Jacob M.
        • Ramamoorthy P.
        • et al.
        Alterations in the intestinal glycocalyx and bacterial flora in response to oral indomethacin.
        Int J Biochem Cell Biol. 2005; 37: 2321-2332
        • Watanabe T.
        • Higuchi K.
        • Kobata A.
        • et al.
        Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent.
        Gut. 2008; 57: 181-187
        • Scarpignato C.
        NSAID-induced intestinal damage: are luminal bacteria the therapeutic target?.
        Gut. 2008; 57: 145-148
        • Wallace J.L.
        • Kennan C.M.
        • Granger D.N.
        Gastric ulceration induced by nonsteroidal antiinflammatory drugs is a neutrophil dependent process.
        Am J Physiol. 1990; 259: G462-G467
        • Scarpignato C.
        • Dolak W.
        • Lanas A.
        • et al.
        Rifaximin reduces number and severity of intestinal lesions associated with use of non-steroidal anti-inflammatory drugs in humans.
        Gastroenterology. 2017; 152: 980-982.e3
        • Bjarnason I.
        • Hayllar J.
        • Smethurst P.
        • et al.
        Metronidazole reduces inflammation and blood loss in NSAID enteropathy.
        Gut. 1992; 33: 1204-1208
        • Montalto M.
        • Gallo A.
        • Curigliano V.
        • et al.
        Clinical trial: the effects of a probiotic mixture on non-steroidal anti-inflammatory drug enteropathy—a randomized, double-blind, cross-over, placebo-controlled study.
        Aliment Pharmacol Ther. 2010; 32: 209-214
        • Endo H.
        • Higurashi T.
        • Hosono K.
        • et al.
        Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study.
        J Gastroenterol. 2011; 46: 894-905
        • Sigthorsson G.
        • Tibble J.
        • Hayllar J.
        • et al.
        Intestinal permeability and inflammation in patients on NSAIDs.
        Gut. 1998; 43: 506-511
        • Moore A.
        • Bjarnason I.
        • Cryer B.
        • et al.
        Evidence for endoscopic ulcers as meaningful surrogate endpoint for clinically significant upper gastrointestinal harm.
        Clin Gastroenterol Hepatol. 2009; 7: 1156-1163
        • Bjarnason I.
        • Zanelli G.
        • Prouse P.
        • et al.
        Blood and protein loss via small intestinal inflammation induced by nonsteroidal anti-inflammatory drugs.
        Lancet. 1987; 2: 711-714
        • Chan F.K.
        • Lanas A.
        • Scheiman J.
        • et al.
        Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial.
        Lancet. 2010; 376: 173-179
        • Allison M.C.
        • Howatson A.G.
        • Torrance C.J.
        • et al.
        Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs.
        N Engl J Med. 1992; 327: 749-754
        • Somasundaram S.
        • Sigthorsson G.
        • Price A.B.
        • et al.
        The relative importance of inhibition of cyclooxygenase and uncoupling of oxidative phosphorylation in the gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs.
        Aliment Pharmacol Ther. 2000; 14: 639-650

      Linked Article