Digestive Diseases and Sciences

, Volume 58, Issue 6, pp 1560–1568 | Cite as

Lactulose Mediates Suppression of Dextran Sodium Sulfate-Induced Colon Inflammation by Increasing Hydrogen Production

  • Xiao Chen
  • Xiao Zhai
  • Jiazi Shi
  • Wen Wu Liu
  • Hengyi Tao
  • Xuejun Sun
  • Zhimin Kang
Original Article



Molecular hydrogen (H2) is a potent antioxidant and able to protect organs from oxidative stress injuries. Orally administered lactulose, a potent H2 inducer, is digested by colon microflora and significantly increases H2 production, indicating its potential anti-inflammatory action.


To evaluate the anti-inflammatory effects of lactulose on dextran sodium sulfate (DSS)-induced colitis in mice.


Mice were randomly assigned into seven groups, receiving regular distilled water, H2-rich saline (peritoneal injection), DSS, oral lactulose (0.1, 0.15, 0.2 ml/10 g, respectively), and lactulose (0.2 ml/10 g) + oral antibiotics. The mouse model of human ulcerative colitis was established by supplying mice with water containing DSS. The H2 breath test was used to determine the exhaled H2 concentration. Body weight, colitis score, colon length, pathological features and tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), maleic dialdehyde (MDA) and marrow peroxidase (MPO) levels in colon lesions were evaluated.


After 7 days, DSS-induced loss of body weight, increase of colitis score, shortening of colon length, pathological changes and elevated levels of TNF-α, IL-1β, MDA, and MPO in colon lesions, were significantly suppressed by oral lactulose administration and intraperitoneally injected H2-rich saline. Ingestion of antibiotics significantly compromised the anti-inflammatory effects of lactulose. The H2 breath test showed that lactulose administration significantly induced hydrogen production and that antibiotics administration could inhibit H2 production.


Lactulose can prevent the development of DSS-induced colitis and alleviate oxidative stress in the colon, as measured by MDA and MPO, probably by increasing endogenous H2 production.


Lactulose Hydrogen Ulcerative colitis Antioxidant Oxidative stress 



This work is supported by Creativity and Innovation Training Program of Second Military Medical University (ZD2010009).

Conflict of interest



  1. 1.
    Grisham MB, Granger DN. Neutrophil-mediated mucosal injury. Role of reactive oxygen metabolites. Dig Dis Sci. 1988;33:6S–15S.PubMedCrossRefGoogle Scholar
  2. 2.
    Suematsu M, Suzuki M, Kitahora T, et al. Increased respiratory burst of leukocytes in inflammatory bowel diseases—the analysis of free radical generation by using chemiluminescence probe. J Clin Lab Immunol. 1987;24:125–128.PubMedGoogle Scholar
  3. 3.
    Karp SM, Koch TR. Oxidative stress and antioxidants in inflammatory bowel disease. Dis Mon. 2006;52:199–207.PubMedCrossRefGoogle Scholar
  4. 4.
    Keshavarzian A, Morgan G, Sedghi S, Gordon JH, Doria M. Role of reactive oxygen metabolites in experimental colitis. Gut. 1990;31:786–790.PubMedCrossRefGoogle Scholar
  5. 5.
    Neilly PJ, Gardiner KR, Rowlands BJ. Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity. Gut. 1996;38:475.PubMedCrossRefGoogle Scholar
  6. 6.
    Buffinton GD, Doe WF. Depleted mucosal antioxidant defences in inflammatory bowel disease. Free Radic Biol Med. 1995;19:911–918.PubMedCrossRefGoogle Scholar
  7. 7.
    Oz HS, Chen TS, McClain CJ, de Villiers WJ. Antioxidants as novel therapy in a murine model of colitis. J Nutr Biochem. 2005;16:297–304.PubMedCrossRefGoogle Scholar
  8. 8.
    Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–694.PubMedCrossRefGoogle Scholar
  9. 9.
    Huang CS, Kawamura T, Toyoda Y, Nakao A. Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res. 2010;44:971–982.PubMedCrossRefGoogle Scholar
  10. 10.
    Dieleman LA, Palmen MJ, Akol H, et al. Chronic experimental colitis induced by dextran sulphate sodium (dss) is characterized by th1 and th2 cytokines. Clin Exp Immunol. 1998;114:385–391.PubMedCrossRefGoogle Scholar
  11. 11.
    Kajiya M, Silva MJ, Sato K, Ouhara K, Kawai T. Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochem Biophys Res Commun. 2009;386:11–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Florent C, Flourie B, Leblond A, Rautureau M, Bernier JJ, Rambaud JC. Influence of chronic lactulose ingestion on the colonic metabolism of lactulose in man (an in vivo study). J Clin Invest. 1985;75:608–613.PubMedCrossRefGoogle Scholar
  13. 13.
    Kim YJ, Kim EH, Hahm KB. Oxidative stress in inflammation-based gastrointestinal tract diseases: challenges and opportunities. J Gastroenterol Hepatol. 2012;27:1004–1010.PubMedCrossRefGoogle Scholar
  14. 14.
    Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Gut. 1963;4:299–315.PubMedCrossRefGoogle Scholar
  15. 15.
    Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–535.PubMedCrossRefGoogle Scholar
  16. 16.
    Damiani CR, Benetton CA, Stoffel C, et al. Oxidative stress and metabolism in animal model of colitis induced by dextran sulfate sodium. J Gastroenterol Hepatol. 2007;22:1846–1851.PubMedCrossRefGoogle Scholar
  17. 17.
    Seril DN, Liao J, Yang GY, Yang CS. Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis. 2003;24:353–362.PubMedCrossRefGoogle Scholar
  18. 18.
    Hayashida K, Sano M, Ohsawa I, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia–reperfusion injury. Biochem Biophys Res Commun. 2008;373:30–35.PubMedCrossRefGoogle Scholar
  19. 19.
    Fukuda K, Asoh S, Ishikawa M, Yamamoto Y, Ohsawa I, Ohta S. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun. 2007;361:670–674.PubMedCrossRefGoogle Scholar
  20. 20.
    Buchholz BM, Kaczorowski DJ, Sugimoto R, et al. Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am J Transplant. 2008;8:2015–2024.PubMedCrossRefGoogle Scholar
  21. 21.
    Gharib B, Hanna S, Abdallahi OM, Lepidi H, Gardette B, De Reggi M. Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. C R Acad Sci III. 2001;324:719–724.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen H, Sun YP, Li Y, et al. Hydrogen-rich saline ameliorates the severity of l-arginine-induced acute pancreatitis in rats. Biochem Biophys Res Commun. 2010;393:308–313.PubMedCrossRefGoogle Scholar
  23. 23.
    Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol. 2001;96:1968–1976.PubMedCrossRefGoogle Scholar
  24. 24.
    Voskuijl W, de Lorijn F, Verwijs W, et al. Peg 3350 (transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial. Gut. 2004;53:1590–1594.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen X, Zuo Q, Hai Y, Sun XJ. Lactulose: an indirect antioxidant ameliorating inflammatory bowel disease by increasing hydrogen production. Med Hypotheses. 2011;76:325–327.PubMedCrossRefGoogle Scholar
  26. 26.
    Rhodes JM, Middleton P, Jewell DP. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scand J Gastroenterol. 1979;14:333–336.PubMedCrossRefGoogle Scholar
  27. 27.
    Sen S, Dear KL, King TS, Elia M, Hunter JO. Evaluation of hydrogen excretion after lactulose administration as a screening test for causes of irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2002;14:753–756.PubMedCrossRefGoogle Scholar
  28. 28.
    Hentschel U, Dobrindt U, Steinert M. Commensal bacteria make a difference. Trends Microbiol. 2003;11:148–150.PubMedCrossRefGoogle Scholar
  29. 29.
    Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292:1115–1118.PubMedCrossRefGoogle Scholar
  30. 30.
    Panesar PS, Kumari S. Lactulose: production, purification and potential applications. Biotechnol Adv. 2011;29:940–948.PubMedCrossRefGoogle Scholar
  31. 31.
    Looijer-van Langen MA, Dieleman LA. Prebiotics in chronic intestinal inflammation. Inflamm Bowel Dis. 2009;15:454–462.PubMedCrossRefGoogle Scholar
  32. 32.
    Kajiya M, Sato K, Silva MJ, et al. Hydrogen from intestinal bacteria is protective for concanavalin a-induced hepatitis. Biochem Biophys Res Commun. 2009;386:316–321.PubMedCrossRefGoogle Scholar
  33. 33.
    Huchzermeyer H, Schumann C. Lactulose—a multifaceted substance. Z Gastroenterol. 1997;35:945–955.PubMedGoogle Scholar
  34. 34.
    Hoffmann K, Mossell DAA, Korus W, van de Kamer JH. Investigations on the mode of action of lactulose in the human intestine. Klin Wochenschr. 1964;42:126–130.PubMedCrossRefGoogle Scholar
  35. 35.
    Schumann C. Medical, nutritional and technological properties of lactulose. An update. Eur J Nutr. 2002;41:I17–I25.PubMedCrossRefGoogle Scholar
  36. 36.
    Xie K, Yu Y, Zhang Z, et al. Hydrogen gas improves survival rate and organ damage in zymosan-induced generalized inflammation model. Shock. 2010;34:495–501.PubMedCrossRefGoogle Scholar
  37. 37.
    Seyan AS, Hughes RD, Shawcross DL. Changing face of hepatic encephalopathy: role of inflammation and oxidative stress. World J Gastroenterol. 2010;16:3347–3357.PubMedCrossRefGoogle Scholar
  38. 38.
    Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology. 2010;51:1062–1069.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Graduate Management Unit, Shanghai Changhai HospitalSecond Military Medical UniversityShanghaiPeople’s Republic of China
  2. 2.Graduate Management UnitSecond Military Medical UniversityShanghaiPeople’s Republic of China
  3. 3.Department of Diving Medicine, Faculty of Naval MedicineSecond Military Medical UniversityShanghaiPeople’s Republic of China

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