Skip to main content
SpringerLink
Log in

Role of bile in pathogenesis of indomethacin-induced enteropathy

  • Organ Toxicity and Mechanisms
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Brodie DA, Cook PG, Bauer BJ, Dagle GE (1970) Indomethacin-induced intestinal lesions in the rat. Toxicol Appl Pharmacol 17:615–624

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Duggan DE, Hooke KF, Noll RM, Kwan KC (1975) Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem Pharmacol 25:1749–1754

    Article  Google Scholar 

  • 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

    Google Scholar 

  • Fang WF, Broughton A, Jacobson ED (1977) Indomethacin-induced intestinal inflammation. Dig Dis Sci 22:187–190

    Google Scholar 

  • Fliedner SH, Cronkite EP, Robertson JS (1964) Granulopoeisis, senescence and random loss of neutrophilic granulocytes in human beings. Blood 24:404–414

    Google Scholar 

  • Jacob M, Bjarnason I, Simpson RJ (2002) Effects of indomethacin on energy metabolism in jejunal tissue in vivo. Clin Sci 102:541–546

    Article  PubMed  CAS  Google Scholar 

  • Kent TH, Cardelli RM, Stamler FW (1969) Small intestinal ulcers and intestinal flora in rats given indomethacin. Am J Pathol 54:237–245

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Satoh H, Guth PH, Grossman MI (1982) Role of food in gastrointestinal ulceration produced by indomethacin in the rat. Gastroenterology 83:210–215

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Molly Jacob was supported by a Cowburn studentship from King’s College School of Medicine.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Christian Medical College, Vellore, 632002, India

    Molly Jacob

  2. Department of Clinical Biochemistry, Guy’s, King’s, St Thomas’s Medical School, Denmark Hill Campus, Bessemer Road, London, SE5 9PJ, UK

    Russel Foster

  3. Guy’s, King’s, St Thomas’s Medical School, Denmark Hill Campus, Bessemer Road, London, SE5 9PJ, UK

    Gudmundur Sigthorsson & Ingvar Bjarnason

  4. Division of Biochemistry and Nutrition Sciences Research Division, King’s College London, Franklin Wilkins Building, 150 Stamford Street, London, SE1 8WA, UK

    Robert Simpson

Authors
  1. Molly Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Russel Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gudmundur Sigthorsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Simpson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ingvar Bjarnason
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Molly Jacob.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-006-0149-2

Keywords

Search

Navigation