Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Communication
  • Published:

Recombinant human lactoferrin ingestion attenuates indomethacin-induced enteropathy in vivo in healthy volunteers

Abstract

Objective: To determine whether recombinant human lactoferrin ingestion inhibits nonsteroidal antiinflammatory drugs (NSAID)-induced gastroenteropathy in vivo in healthy volunteers as a model for disorders associated with a rise in permeability of the stomach and the small intestine.

Design: A randomized crossover dietary intervention.

Subjects and interventions: In all, 15 healthy volunteers (age 23±1.4 y) were tested. A sucrose and a lactulose/rhamnose (L/R) permeability test was performed to assess gastroduodenal and small intestine permeability as indicator of NSAID-induced gastroenteropathy. All subjects consumed standardized meals for 2 days. On the second day at time=−24 h each subject ingested a drink containing 5 g recombinant human lactoferrin or placebo during breakfast. At t=−9 h, subjects ingested the same drink with 75 mg of the NSAID indomethacin and after an overnight fast at t=−1 h subjects consumed the drink and 50 mg indomethacin. After 1 h, at t=0, a permeability test was performed.

Results: Small intestine permeability after indomethacin and placebo was significantly higher (L/R ratio=0.036; 0.014–0.092, P<0.05) compared to the permeability observed after ingestion of indomethacin and lactoferrin (0.028; 0.015–0.056), whereas gastroduodenal permeability did not differ between the two interventions (P=0.3).

Conclusions: Oral recombinant human lactoferrin supplementation during a short-term indomethacin challenge reduced the NSAID-mediated increase in small intestinal permeability and hence may provide a nutritional tool in the treatment of hyperpermeability-associated disorders.

Sponsorship: Grant and human recombinant lactoferrin donated from Agennix Inc., Houston, TX.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  • Aguila A, Herrera AG, Morrison D, Cosgrove B, Perojo A, Montesinos I, Perez J, Sierra G, Gemmell CG & Brock JH (2001): Bacteriostatic activity of human lactoferrin against Staphylococcus aureus is a function of its iron-binding properties and is not influenced by antibiotic resistance. FEMS Immunol. Med. Microbiol. 31, 145–152.

    Article  CAS  Google Scholar 

  • Baker EN, Anderson BF, Baker HM, Haridas M, Jameson GB, Norris GE, Rumball SV & Smith CA (1991): Structure, function and flexibility of human lactoferrin. Int. J. Biol. Macromol. 13, 122–129.

    Article  CAS  Google Scholar 

  • Baldwin DA, Jenny ER & Aisen P (1984): The effect of human serum transferrin and milk lactoferrin on hydroxyl radical formation from superoxide and hydrogen peroxide. J. Biol. Chem. 259, 13391–13394.

    CAS  PubMed  Google Scholar 

  • Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K & Tomita M (1992): Identification of the bactericidal domain of lactoferrin. Biochim. Biophys. Acta 1121, 130–136.

    Article  CAS  Google Scholar 

  • Bjarnason I, Fehilly B, Smethurst P, Menzies IS & Levi AJ (1991): Importance of local versus systemic effects of nonsteroidal anti-inflammatory drugs in increasing small intestinal permeability in man. Gut 32, 275–277.

    Article  CAS  Google Scholar 

  • Bjarnason I, Hayllar J, MacPherson AJ & Russell AS (1993): Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 104, 1832–1847.

    Article  CAS  Google Scholar 

  • Bjarnason I, O'Morain C, Levi AJ & Peters TJ (1983): Absorption of 51chromium-labeled ethylenediaminetetraacetate in inflammatory bowel disease. Gastroenterology 85, 318–322.

    CAS  PubMed  Google Scholar 

  • Bjarnason I, Smethurst P, Fenn CG, Lee CE, Menzies IS & Levi AJ (1989): Misoprostol reduces indomethacin-induced changes in human small intestinal permeability. Digestive Dis. Sci. 34, 407–411.

    Article  CAS  Google Scholar 

  • Bjarnason I, Williams P, Smethurst P, Peters TJ & Levi AJ (1986): Effect of nonsteroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut 27, 1292–1297.

    Article  CAS  Google Scholar 

  • Britigan BE, Serody JS & Cohen MS (1994): The role of lactoferrin as an anti-inflammatory molecule. Adv. Exp. Med. Biol. 357, 143–156.

    Article  CAS  Google Scholar 

  • Brock J (1995): Lactoferrin: a multifunctional immunoregulatory protein? Immunol. Today 16, 417–419.

    Article  CAS  Google Scholar 

  • Carafoli E (1987): Intracellular calcium homeostasis. Annu. Rev. Biochem. 56, 395–433.

    Article  CAS  Google Scholar 

  • Crouch SP, Slater KJ & Fletcher J (1992): Regulation of cytokine release from mononuclear cells by the iron- binding protein lactoferrin. Blood 80, 235–240.

    CAS  PubMed  Google Scholar 

  • Crowe SE & Perdue MH (1992): Gastrointestinal food hypersensitivity: basic mechanisms of pathophysiology. Gastroenterology 103, 1075–1095.

    Article  CAS  Google Scholar 

  • Davidson LA & Lonnerdal B (1989): Fe-saturation and proteolysis of human lactoferrin: effect on brush-border receptor-mediated uptake of Fe and Mn. Am. J. Physiol. 257(Pt 1), G930–G934.

    CAS  PubMed  Google Scholar 

  • Davidson LA & Lonnerdal B (1986): Isolation and characterization of rhesus monkey milk lactoferrin. Pediatr. Res. 20, 197–201.

    Article  CAS  Google Scholar 

  • Davidson LA & Lonnerdal B (1988): Specific binding of lactoferrin to brush-border membrane: ontogeny and effect of glycan chain. Am. J. Physiol. 254(Pt 1), G580–G585.

    CAS  PubMed  Google Scholar 

  • Ferry DM, Butt TJ, Broom MF, Hunter J & Chadwick VS (1989): Bacterial chemotactic oligopeptides and the intestinal mucosal barrier. Gastroenterology 97, 61–67.

    Article  CAS  Google Scholar 

  • Gutteridge JM, Paterson SK, Segal AW & Halliwell B (1981): Inhibition of Lipid Peroxidation by the Iron-Binding Protein Lactoferrin. Biochem. J. 199, 259–261.

    Article  CAS  Google Scholar 

  • Hawkey CJ & Rampton DS (1985): Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology 89, 1162–1188.

    Article  CAS  Google Scholar 

  • Ikeda M, Nozaki A, Sugiyama K, Tanaka T, Naganuma A, Tanaka K, Sekihara H, Shimotohno K, Saito M & Kato N (2000): Characterization of antiviral activity of lactoferrin against hepatitis C virus infection in human cultured cells. Virus Res. 66, 51–63.

    Article  CAS  Google Scholar 

  • Isolauri E, Juntunen M, Wiren S, Vuorinen P & Koivula T (1989): Intestinal permeability changes in acute gastroenteritis: effects of clinical factors and nutritional management. J. Pediatr. Gastroenterol. Nutr. 8, 466–473.

    Article  CAS  Google Scholar 

  • Iyer S & Lonnerdal B (1993): Lactoferrin, lactoferrin receptors and iron metabolism. Eur. J. Clin. Nutr. 47, 232–241.

    CAS  PubMed  Google Scholar 

  • Kawakami H & Lonnerdal B (1991): Isolation and function of a receptor for human lactoferrin in human fetal intestinal brush-border membranes. Am. J. Physiol. 261(Pt 1), G841–G846.

    CAS  PubMed  Google Scholar 

  • Kuhara T, Iigo M, Itoh T, Ushida Y, Sekine K, Terada N, Okamura H & Tsuda H (2000): Orally administered lactoferrin exerts an antimetastatic effect and enhances production of IL-18 in the intestinal epithelium. Nutr. Cancer 38, 192–199.

    Article  CAS  Google Scholar 

  • Lambert GP, Broussard LJ, Mason BL, Mauermann WJ & Gisolfi CV (2001): Gastrointestinal permeability during exercise: effects of aspirin and energy-containing beverages. J. Appl. Physiol. 90, 2075–2080.

    Article  CAS  Google Scholar 

  • Legrand D, Mazurier J, Elass A, Rochard E, Vergoten G, Maes P, Montreuil J & Spik G (1992): Molecular interactions between human lactotransferrin and the phytohemagglutinin-activated human lymphocyte lactotransferrin receptor lie in two loop-containing regions of the N-terminal domain I of human lactotransferrin. Biochemistry 31, 9243–9251.

    Article  CAS  Google Scholar 

  • Levay PF & Viljoen M (1995): Lactoferrin: a general review. Haemotologica 80, 252–267.

    CAS  Google Scholar 

  • May GR, Sutherland LR & Meddings JB (1993): Is small intestinal permeability really increased in relatives of patients with Crohn's disease? Gastroenterology 104, 1627–1632.

    Article  CAS  Google Scholar 

  • Mazurier J, Montreuil J & Spik G (1985): Visualization of lactotransferrin brush-border receptors by ligand-blotting. Biochim. Biophys. Acta 821, 453–460.

    Article  CAS  Google Scholar 

  • McAbee DD & Esbensen K (1991): Binding and endocytosis of apo- and holo-lactoferrin by isolated rat hepatocytes. J. Biol. Chem. 266(35), 23624–23631.

    CAS  PubMed  Google Scholar 

  • Meddings JB (1997): Review article: Intestinal permeability in Crohn's disease. Aliment Pharmacol. Ther. 11(Suppl 3), 47–53. (Discussion 53-6).

    PubMed  Google Scholar 

  • Meddings JB, Sutherland LR, Byles NI & Wallace JL (1993): Sucrose: a novel permeability marker for gastroduodenal disease. Gastroenterology 104, 1619–1626.

    Article  CAS  Google Scholar 

  • Miller MJ, Zhang XJ, Gu XA & Clark DA (1991): Acute intestinal injury induced by acetic acid and casein: prevention by intra-luminal misoprostol. Gastroenterology 101, 22–30.

    Article  CAS  Google Scholar 

  • Murphy ME, Kariwa H, Mizutani T, Yoshimatsu K, Arikawa J & Takashima I (2000): In vitro antiviral activity of lactoferrin and ribavirin upon hantavirus. Arch. Virol. 145, 1571–1582.

    Article  CAS  Google Scholar 

  • Nibbering PH, Ravensbergen E, Welling MM, van Berkel LA, van Berkel PH, Pauwels EK & Nuijens JH (2001): Human lactoferrin and peptides derived from its N terminus are highly effective against infections with antibiotic-resistant bacteria. Infect. Immun. 69, 1469–1476.

    Article  CAS  Google Scholar 

  • Nuijens JH, van Berkel PH & Schanbacher FL (1996): Structure and biological actions of lactoferrin. J. Mammary. Gland. Biol. Neo-plasia. 1, 285–295.

    Article  CAS  Google Scholar 

  • Playford RJ, MacDonald CE, Calnan DP, Floyd DN, Podas T, Johnson W, Wicks AC, Bashir O & Marchbank T (2001): Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability. Clin. Sci. (London) 100, 627–633.

    Article  CAS  Google Scholar 

  • Rooyakkers DR, van Eijk HM & Deutz NE (1996): Simple and sensitive multi-sugar-probe gut permeability test by high-performance liquid chromatography with fluorescence labelling. J. Chromatogr. A 730, 99–105.

    Article  CAS  Google Scholar 

  • Shinoda I, Takase M, Fukuwatari Y, Shimamura S, Koller M & Konig W (1996): Effects of lactoferrin and lactoferricin on the release of interleukin 8 from human polymorphonuclear leukocytes. Biosci. Biotechnol. Biochem. 60, 521–523.

    Article  CAS  Google Scholar 

  • Smecuol E, Bai JC, Vazquez H, Kogan Z, Cabanne A, Niveloni S, Pedreira S, Boerr L, Maurino E & Meddings JB (1997): Gastrointestinal permeability in celiac disease. Gastroenterology 112, 1129–1136.

    Article  CAS  Google Scholar 

  • Soderholm JD & Perdue MH (2001): Stress and gastrointestinal tract. II. Stress and intestinal barrier function. Am. J. Physiol. Gastrointest. Liver. Physiol. 280, G7–G13.

    Article  CAS  Google Scholar 

  • Somasundaram S, Hayllar H, Rafi S, Wrigglesworth JM, Macpherson AJ & Bjarnason I (1995): The biochemical basis of nonsteroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scand. J. Gastroenterol. 30, 289–299.

    Article  CAS  Google Scholar 

  • Somasundaram S, Rafi S, Hayllar J, Sigthorsson G, Jacob M, Price AB, Macpherson A, Mahmod T, Scott D, Wrigglesworth JM & 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  CAS  Google Scholar 

  • Swart PJ, Kuipers EM, Smit C, Van Der Strate BW, Harmsen MC & Meijer DK (1998): Lactoferrin. Antiviral activity of lactoferrin. Adv. Exp. Med. Biol. 443, 205–213.

    Article  CAS  Google Scholar 

  • Troost FJ, Steijns J, Saris WH & Brummer RJ (2001): Gastric digestion of bovine lactoferrin in vivo in adults. J. Nutr. 131, 2101–2104.

    Article  CAS  Google Scholar 

  • van Nieuwenhoven MA, Geerling BJ, Deutz NE, Brouns F & Brummer R J (1999): The sensitivity of the lactulose/rhamnose gut permeability test. Eur. J. Clin. Invest. 29, 160–165.

    Article  CAS  Google Scholar 

  • Wallace JL (1993): Gastric ulceration: critical events at the neutrophil–endothelium interface. Can. J. Physiol. Pharmacol. 71, 98–102.

    Article  CAS  Google Scholar 

  • Wyatt J, Vogelsang H, Hubl W, Waldhoer T & Lochs H (1993): Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet 341, 1437–1439.

    Article  CAS  Google Scholar 

  • Zagulski T, Jarzabek Z, Zagulska A & Zimecki M (1998): The main systemic, highly effective, and quickly acting antimicrobial mechanisms generated by lactoferrin in mammals in vivo. Activity in health and disease. Adv. Exp. Med. Biol. 443, 247–250.

    Article  CAS  Google Scholar 

  • Zimecki M, Spiegel K, Wlaszczyk A, Kubler A & Kruzel M L (1999): Lactoferrin increases the output of neutrophil precursors and attenuates the spontaneous production of TNF-alpha and IL-6 by peripheral blood cells. Arch. Immunol. Ther. Exp. 47, 113–118.

    CAS  Google Scholar 

  • Zimecki M, Wlaszczyk A, Cheneau P, Brunel A S, Mazurier J, Spik G & Kubler A (1998): Immunoregulatory effects of a nutritional preparation containing bovine lactoferrin taken orally by healthy individuals. Arch. Immunol. Ther. Exp. 46, 231–240.

    CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr. Fred Browns and Dr. Dominique Goovaer's (Cerestar, Belgium) for carrying out the sucrose analyses.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F J Troost.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Troost, F., Saris, W. & Brummer, RJ. Recombinant human lactoferrin ingestion attenuates indomethacin-induced enteropathy in vivo in healthy volunteers. Eur J Clin Nutr 57, 1579–1585 (2003). https://doi.org/10.1038/sj.ejcn.1601727

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ejcn.1601727

Keywords

This article is cited by

Search

Quick links