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Intrarectal Nitric Oxide Administration Prevents Cellular Infiltration but Not Colonic Injury During Dextran Sodium Sulfate Colitis

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Abstract

Background

During inflammation in the gastrointestinal tract, the production of nitric oxide (NO) is mediated by the mucosal conversion of l-arginine. Recently, it was shown that the gut microbiota can also produce NO.

Aims

The effect of gut luminal NO on inflammatory processes of an experimental colitis mice model was investigated by administrating NO directly to the colon, mimicking microbial NO production.

Methods

Twenty-four mice received daily intrarectal treatment with a NO donor in 2 doses and 8 mice were treated with placebo. Starting 1 day later, 18 of these mice were fed ad libitum with 4% of dextran sodium sulfate (DSS) in their drinking water to induce colitis. At day 6, histopathology (both the inflammation and damage score), myeloperoxidase (MPO)-activity, colon length and colonic permeability were evaluated.

Results

Co-administration of NO during DSS exposure inhibited the induction of an increasing colonic MPO-activity. This protective effect of NO was confirmed by the histological inflammation score showing a similar trend. The colonic permeability was restored when very low levels of NO were administered to the DSS-mice. On the other hand, the colon length of the NO-treated DSS-mice was negatively correlated with the NO dose and the histological damage score was not improved.

Conclusions

Our results indicate that intrarectal administration of NO has clear anti-inflammatory effects in experimental colitis, but does not prevent colonic damage. Therefore, NO-producing microorganisms in the gut lumen should be accounted as a modulating process during colitis.

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References

  1. Moncada S. Nitric oxide: discovery and impact on clinical medicine. J R Soc Med. 1999;92:164–169.

    PubMed  CAS  Google Scholar 

  2. Herulf M, Ljung T, Hellstrom PM, Weitzberg E, Lundberg JON. Increased luminal nitric oxide in inflammatory bowel disease as shown with a novel minimally invasive method. Scand J Gastroenterol. 1998;33:164–169.

    Article  PubMed  CAS  Google Scholar 

  3. Boughton-Smith NK, Evans SM, Hawkey CJ, et al. Nitric-oxide synthase activity in ulcerative colitis and Crohn’s disease. Lancet. 1993;342:338–340.

    Article  PubMed  CAS  Google Scholar 

  4. Middleton SJ, Shorthouse M, Hunter JO. Increased nitric-oxide synthesis in ulcerative colitis. Lancet. 1993;341:465–466.

    Article  PubMed  CAS  Google Scholar 

  5. Rachmilewitz D, Stamler JS, Bachwich D, Karmeli F, Ackerman Z, Podolsky DK. Enhanced colonic nitric-oxide generation and nitric-oxide synthase activity in ulcerative colitis and Crohn’s disease. Gut. 1995;36:718–723.

    Article  PubMed  CAS  Google Scholar 

  6. Rachmilewitz D, Karmeli F, Okon E, Bursztyn M. Experimental colitis is ameliorated by inhibition of nitric-oxide synthase activity. Gut. 1995;37:247–255.

    Article  PubMed  CAS  Google Scholar 

  7. Zingarelli B, Szabo C, Salzman AL. Reduced oxidative and nitrosative damage in murine experimental colitis in the absence of inducible nitric oxide synthase. Gut. 1999;45:199–209.

    Article  PubMed  CAS  Google Scholar 

  8. Reinders CI, Jonkers D, Jansson EA, et al. Rectal nitric oxide and fecal calprotectin in inflammatory bowel disease. Scand J Gastroenterol. 2007;42:1151–1157.

    Article  PubMed  CAS  Google Scholar 

  9. Sobko T, Reinders CI, Jansson EA, Norin E, Midtvedt T, Lundberg JO. Gastrointestinal bacteria generate nitric oxide from nitrate and nitrite. Nitric Oxide-Biol Chem. 2005;13:272–278.

    Article  CAS  Google Scholar 

  10. Vermeiren J, Van de Wiele T, Verstraete W, Boeckx P, Boon N. Nitric oxide production by the human intestinal microbiota by dissimilatory nitrate reduction to ammonium. J Biomed Biotechnol. 2009:10. doi:10.1155/2009/284718.

  11. Roediger WEW. Review article: nitric oxide from dysbiotic bacterial respiration of nitrate in the pathogenesis and as a target for therapy of ulcerative colitis. Aliment Pharmacol Ther. 2008;27:531–541.

    Article  PubMed  CAS  Google Scholar 

  12. Vermeiren J, Van de Wiele T, Van Nieuwenhuyse G, Boeckx P, Verstraete W, Boon N. Sulfide- and nitrite- dependent nitric oxide production in the intestinal tract. Microbial Biotechnol. 2012. doi:10.1111/j.1751-7915.2011.00320.x.

  13. Van der Sluis M, De Koning BAE, De Bruijn A, et al. Muc2-deficient mice spontaneously develop colitis, indicating that muc2 is critical for colonic protection. Gastroenterology. 2006;131:117–129.

    Article  PubMed  Google Scholar 

  14. Hindryckx P, Waeytens A, Laukens D, et al. Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury. Lab Invest. 2010;90:566–576.

    Article  PubMed  CAS  Google Scholar 

  15. Napolitano LM, Koruda MJ, Meyer AA, Baker CC. The impact of femur fracture with associated soft tissue injury on immune function and intestinal permeability. Shock. 1996;5:202–207.

    Article  PubMed  CAS  Google Scholar 

  16. Lamine F, Eutamene H, Fioramonti J, Bueno L, Theodorou V. Colonic responses to Lactobacillus farciminis treatment in trinitrobenzene sulphonic acid-induced colitis in rats. Scand J Gastroenterol. 2004;39:1250–1258.

    Article  PubMed  CAS  Google Scholar 

  17. Lamine F, Fioramonti J, Bueno L, et al. Nitric oxide released by Lactobacillus farciminis improves TNBS-induced colitis in rats. Scand J Gastroenterol. 2004;39:37–45.

    Article  PubMed  CAS  Google Scholar 

  18. Wallace JL, Vergnolle N, Muscara MN, et al. Enhanced anti-inflammatory effects of a nitric oxide-releasing derivative of mesalamine in rats. Gastroenterology. 1999;117:557–566.

    Article  PubMed  CAS  Google Scholar 

  19. Wolf G, Arendt EK, Pfahler U, Hammes WP. Heme-dependent and heme-independent nitrite reduction by lactic-acid bacteria results in different N-containing products. Int J Food Microbiol. 1990;10:323–329.

    Article  PubMed  CAS  Google Scholar 

  20. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–241.

    Article  PubMed  CAS  Google Scholar 

  21. Salzman AL, Menconi MJ, Unno N, et al. Nitric-oxide dilates tight junctions and depletes ATP in cultured Caco-2bbe intestinal epithelial monolayers. Am J Physiol-Gastroint Liver Physiol. 1995;31:G361–G373.

    Google Scholar 

  22. Yamamoto A, Tatsumi H, Maruyama M, Uchiyama T, Okada N, Fujita T. Modulation of intestinal permeability by nitric oxide donors: Implications in intestinal delivery of poorly absorbable drugs. J Pharmacol Exp Ther. 2001;296:84–90.

    PubMed  CAS  Google Scholar 

  23. Resta-Lenert S, Barrett KE. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut. 2003;52:988–997.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We like to thank Varvara Tsilia for her help in sacrificing the mice. This work was supported by a Concerted Research Action of the Flemish Community (GOA) (BOF07/GOA/002).

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Authors and Affiliations

  1. Faculty of Bioscience Engineering, Laboratory of Microbial Ecology and Technology (LabMET), Ghent University, Coupure Links 653, 9000, Ghent, Belgium

    Joan Vermeiren, Glynn Van Nieuwenhuyse, Nico Boon & Tom Van de Wiele

  2. Department of Gastroenterology, Ghent University, De Pintelaan 185, 3K12IE, 9000, Ghent, Belgium

    Pieter Hindryckx, Debby Laukens & Martine De Vos

Authors
  1. Joan Vermeiren
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  2. Pieter Hindryckx
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  3. Glynn Van Nieuwenhuyse
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  4. Debby Laukens
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  5. Martine De Vos
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  6. Nico Boon
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  7. Tom Van de Wiele
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Correspondence to Tom Van de Wiele.

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Vermeiren, J., Hindryckx, P., Van Nieuwenhuyse, G. et al. Intrarectal Nitric Oxide Administration Prevents Cellular Infiltration but Not Colonic Injury During Dextran Sodium Sulfate Colitis. Dig Dis Sci 57, 1832–1837 (2012). https://doi.org/10.1007/s10620-012-2105-8

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  • DOI: https://doi.org/10.1007/s10620-012-2105-8

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