Abstract
Ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) causes an enteropathy. The pathogenesis involves biochemical initiation of intestinal mucosal damage due to NSAID-induced inhibition of cyclooxygenase and the topical effects of these drugs. These effects lead to increased intestinal permeability and inflammation. Luminal bile acids play a controversial role in the damage produced by these drugs. The aim of this study was to determine the role of bile in producing the enteropathy caused by indomethacin, an NSAID commonly used in toxicity studies. Sprague–Dawley rats were subjected to bile duct ligation. Twenty-four hours later, they were dosed with indomethacin. Intestinal permeability (51Cr-EDTA) and inflammation (faecal calprotectin) were measured in the animals at various time periods after the dose. Intestinal permeability was significantly higher in rats 1–6 h after dosing with indomethacin, but not at 24–29 h or day 4, when compared with corresponding values for control animals. Excretion of faecal calprotectin was elevated in the indomethacin-treated rats. The drug-treated animals showed no evidence of ulceration when they were sacrificed 29 h or a week after the dose of indomethacin. Bile acids per se did not affect intestinal permeability or faecal excretion of calprotectin, when given along with indomethacin or its vehicle. We conclude that macroscopic small bowel damage does not occur with indomethacin if bile is excluded, despite the induction of permeability and inflammation. This study highlights the importance of luminal factors, such as bile, in producing indomethacin-induced ulceration in the rat small intestine.
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Basivireddy J, Jacob M, Ramamoorthy P, Pulimood AB, Balasubramanian KA (2003) Indomethacin-induced free radical-mediated changes in the intestinal brush border membranes. Biochem Pharmacol 65:683–695
Beck WS, Schneider HT, Dietzel K, Nuernberg B, Brune K (1990) Gastrointestinal ulcerations induced by anti-inflammatory drugs in rats: physicochemical and biochemical factors involved. Arch Toxicol 64:210–217
Bjarnason I, McPherson A (1989) The changing gastrointestinal side effect profile of non-steroidal anti-inflammatory drugs. A new approach for the prevention of a new problem. Scand J Gastroenterol 24(Suppl 163):56–64
Bjarnason I, Peters TJ, Veall N (1983a) A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-EDTA absorption test. Lancet 1:323–325
Bjarnason I, O’Morain C, Levi AJ, Peters TJ (1983b) The absorption of chromium-51 labeled ethylenediaminetetraacetate in inflammatory bowel disease. Gastroenterology 85:318–322
Bjarnason I, Williams P, So A, Zanelli GD, Levi AJ, Gumpell JM, Peters TJ, Ansell B (1984) Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs. Lancet 2:1171–1174
Bjarnason I, Zanelli G, Smith T, Prouse P, Williams P, Smethurst P, Delacey G, Gumpel MJ, Levi AJ (1987) Non-steroidal anti-inflammatory drug-induced inflammation in humans. Gastroenterology 93:480–489
Bjarnason I, Smethurst P, Clark P Menzies I, Levi J, Peters T (1989a) Effect of prostaglandin on indomethacin-induced increased intestinal permeability in man. Scand J Gastroenterol 24(Suppl 164):97–103
Bjarnason I, Smethurst P, Fenn CG, Lee CE, Menzies I, Levi AJ (1989b) Misoprostol reduces indomethacin-induced changes in human small intestinal permeability. Dig Dis Sci 34:407–411
Bjarnason I, Fehilly B, Smethurst P, Menzies I, Levi AJ (1991) The importance of local versus systemic effects of non-steroidal anti-inflammatory drugs to increase intestinal permeability in man. Gut 32:275–277
Bjarnason I, Smethurst P, McPherson A, Walker F, McElnay JC, Passmore AP, Menzies IS (1992a) Glucose and citrate reduce the permeability changes caused by indomethacin in man. Gastroenterology 102:1546–1550
Bjarnason I, Fehilly B, Smethurst P, Menzies I, Levi AJ (1992b) Effects of non-steroidal anti-inflammatory drugs on permeability of the small intestine in humans. J Rheumatol 19(Suppl 36):83–84
Bjarnason I, Hayllar J, McPherson AJ, Russel AS (1993) Side effects of non-steroidal anti-inflammatory drugs on the small and large intestine in man. Gastroenterology 104:1832–1847
Brandtzaeg P, Gabrielsen TO, Dale I, Muller F, Steinbakk M, Fagerhol MK (1995) The leukocyte protein L1 (calprotectin): a putative nonspecific defence factor at epithelial surfaces. Adv Exp Med Biol 371A:201–206
Brodie DA, Cook PG, Bauer BJ, Dagle GE (1970) Indomethacin-induced intestinal lesions in the rat. Toxicol Appl Pharmacol 17:615–624
Dale I, Brandtzaeg P, Fagerhol MK, Scott H (1985) Distribution of a new myelomonocytic antigen (L-1) in human peripheral blood leukocytes. Am J Clin Pathol 84:24–34
Duggan DE, Hooke KF, Noll RM, Kwan KC (1975) Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem Pharmacol 25:1749–1754
Fagerhol MK, Andersson KB, Naess-Andressen CF, et al (1990) Calprotectin (the L1 leukocyte protein). In: Smith VL, Dedma JR (eds) Stimulus response coupling: the role of intracellular calcium binding proteins. CRC Press Inc., Boca Raton, pp 187–210
Fang WF, Broughton A, Jacobson ED (1977) Indomethacin-induced intestinal inflammation. Dig Dis Sci 22:187–190
Fliedner SH, Cronkite EP, Robertson JS (1964) Granulopoeisis, senescence and random loss of neutrophilic granulocytes in human beings. Blood 24:404–414
Jacob M, Bjarnason I, Simpson RJ (2002) Effects of indomethacin on energy metabolism in jejunal tissue in vivo. Clin Sci 102:541–546
Kent TH, Cardelli RM, Stamler FW (1969) Small intestinal ulcers and intestinal flora in rats given indomethacin. Am J Pathol 54:237–245
Lugea A, Antolin M, Mourelle M, Garner F, Malagelada JR (1997) Deranged hydrophobic barrier of the rat gastroduodenal mucosa after parenteral nonsteroidal anti-inflammatory drugs. Gastroenterology 112:1931–1939
Mahmud T, Somasundaram S, Sigthorsson G, Simpson RJ, Rafi S, Foster R, Tavares IA, Roseth A, Hutt AJ, Jacob M, Pacy J, Scott DL, Wrigglesworth JM, Bjarnason I (1998) Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat. Gut 43:775–782
Maxton DG, Bjarnason I, Reynolds AP, Catt SD, Peters TJ, Menzies IS (1986) Lactulose, 51Cr labeled ethylenediaminetetraacetate, L-rhamnose and polyethylene glycol 400 as probe markers for assessment of in vivo human intestinal permeability. Clin Sci 71:71–80
Meling TR, Aabakken L, Roseth A, Osnes M (1996) Faecal calprotectin shedding after short-term treatment with non-steroidal anti-inflammatory drugs. Scand J Gastroenterol 31:339–344
Ohri SK, Somasundaram S, Koak Y, McPherson A, Keogh BE, Taylor KM, Menzies IS, Bjarnason I (1994) The effect of intestinal hypoperfusion during cardiopulmonary bypass surgery on saccharide permeation and intestinal permeability in man. Gastroenterology 106:318–323
Roseth AG, Fagerhol MK, Aadland E, Schjonsby H (1992) Assessment of the neutrophil dominating protein calprotectin in faeces. A methodological study. Scand J Gastroenterol 27:793–798
Satoh H, Guth PH, Grossman MI (1982) Role of food in gastrointestinal ulceration produced by indomethacin in the rat. Gastroenterology 83:210–215
Satoh H, Guth PH, Grossman MI (1983) Role of bacteria in gastric ulceration produced by indomethacin in the rat: cytoprotective action of antibiotics. Gastroenterology 84:483–489
Shah AA, Thjodleifsson B, Murray FE, Kay E, Barry M, Sigthorsson G, Gudjonsson H, Oddson E, Price AB, Fitzgerald DJ, Bjarnason I (2001) Selective inhibition in humans of COX-2 is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen. Gut 48:339–348
Sigthorsson G, Jacob M, Wrigglesworth J, Somasundaram S, Tavares I, Foster R, Roseth A, Rafi S, Mahmud T, Simpson R, Bjarnason I (1998) Comparison of indomethacin and nimesulide, a selective cyclooxygenase inhibitor, on key pathophysiological steps in the pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in the rat. Scand J Gastroenterol 33:728–735
Somasundaram S, Hayllar H, Rafi S, Wrigglesworth J, MacPherson AJ, Bjarnason I (1995) The biochemical basis of non-steroidal anti-inflammatory drug induced damage to the gastrointestinal tract: a review and a hypothesis. Scand J Gastroenterol 30:289–299
Somasundaram S, Rafi S, Hayllar J, Sigthorsson G, Jacob M, Price AB, MacPherson A, Mahmud T, Scott D, Wrigglesworth J, Bjarnason I (1997) Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID-induced injury to the rat intestine. Gut 41:344–353
Somasundaram S, Sigthorsson G, Simpson RJ, Watts J, Jacob M, Tavares IA, Rafi S, Roseth A, Foster R, Price AB, Wrigglesworth JM, Bjarnason I (2000) Uncoupling of intestinal mitochondria oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat. Aliment Pharmacol Ther 14:639–650
Tibble JA, Foster R, Sigthorsson G, Scott D, Roseth A, Bjarnason I (1999) Faecal calprotectin: a simple method for the diagnosis of NSAID-induced enteropathy. Gut 45:362–366
Wallace JL, Keenan CM, Granger DN (1990) Gastric ulceration induced by non-steroidal anti-inflammatory drugs is a neutrophil dependent process. Am J Physiol 259:G462–G467
Wax J, Clinger A, Varner P, Bass P, Winder CV (1970) Relationship of the enterohepatic cycle to ulcerogenesis in the rat small bowel with flufenamic acid. Gastroenterology 58:772–779
Yesair DW, Callahan M, Remington L, Kensler CJ (1970) Role of the enterohepatic cycle of indomethacin on its metabolism, distribution in tissues and its excretion by rats, dogs and monkeys. Biochem Pharmacol 19:1579–1590
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Molly Jacob was supported by a Cowburn studentship from King’s College School of Medicine.
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Jacob, M., Foster, R., Sigthorsson, G. et al. Role of bile in pathogenesis of indomethacin-induced enteropathy. Arch Toxicol 81, 291–298 (2007). https://doi.org/10.1007/s00204-006-0149-2
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DOI: https://doi.org/10.1007/s00204-006-0149-2