Journal of Gastroenterology

, Volume 49, Issue 5, pp 806–813 | Cite as

Oral nanotherapeutics: effect of redox nanoparticle on microflora in mice with dextran sodium sulfate-induced colitis

  • Long Binh Vong
  • Toru Yoshitomi
  • Kazuya Morikawa
  • Shinji Saito
  • Hirofumi Matsui
  • Yukio NagasakiEmail author
Original Article—Alimentary Tract



Patients with ulcerative colitis (UC) exhibit overproduction of reactive oxygen species (ROS) and imbalance of colonic microflora. We previously developed a novel redox nanoparticle (RNPO), which effectively scavenged ROS in the inflamed mucosa of mice with dextran sodium sulfate (DSS)-induced colitis after oral administration. The objective of this study was to examine whether the orally administered RNPO changed the colonic microflora in healthy mice and those with colitis.


RNPO was synthesized by self-assembly of an amphiphilic block copolymer that contains stable nitroxide radicals in hydrophobic side chain via ether linkage. Colitis was induced in mice by supplementing DSS in drinking water for 7 days, and RNPO was orally administered daily during DSS treatment. The alterations of fecal microflora during treatment of DSS and RNPO were investigated using microbiological assays.


We investigated that RNPO did not result in significant changes to the fecal microflora in healthy mice. Although total aerobic and anaerobic bacteria were not significantly different between experimental groups, a remarkable increase in commensal bacteria (Escherichia coli and Staphylococcus sp.) was observed in mice with DSS-induced colitis. Interestingly, orally administered RNPO remarkably reduced the rate of increase of these commensal bacteria in mice with colitis.


On the basis of the obtained results, it was confirmed that the oral administration of RNPO did not change any composition of bacteria in feces, which strongly suggests a protective effect of RNPO on healthy environments in intestinal microflora. RNPO may become an effective and safe medication for treatment of UC.


Ulcerative colitis Colonic microflora Reactive oxygen species Redox nanoparticle Inflammation 



A portion of this work was supported by a Grant-in-Aid for Scientific Research A (No. 21240050) and the World Premier International Research Center Initiative (WPI Initiative) on Materials Nanoarchitronics of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.

Conflict of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity having a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript, apart from those disclosed. The authors declare that they have no conflicts of interest with this work.


  1. 1.
    Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Edward VL. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–17.CrossRefGoogle Scholar
  3. 3.
    Simmonds NJ, Rampton DS. Inflammatory bowel disease: a radical view. Gut. 1993;34:865–8.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Babbs CF. Oxygen radicals in ulcerative colitis. Free Radic Biol Med. 1992;13:169–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Gionchetti P, Rizzello F, Lammers KM, Morselli C, Sollazzi L, Davies S, et al. Antibiotics and probiotics in treatment of inflammatory bowel disease. World J Gastroenterol. 2006;12:3306–13.PubMedGoogle Scholar
  6. 6.
    Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nat Rev. 2011;44:307–17.Google Scholar
  7. 7.
    Sartor RB. The influence of normal microbial flora on the development of chronic inflammation. Res Immunol. 1997;148:567–76.PubMedCrossRefGoogle Scholar
  8. 8.
    Strauch UG, Obermeier F, Grunwald N, Gürster S, Dunger N, Schultz M, et al. Influence of intestinal bacteria on induction of regulatory T cells: lessons from a transfer model of colitis. Gut. 2005;54:1546–52.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Gibson GR, Roberfroid M. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;125:1401–12.PubMedGoogle Scholar
  10. 10.
    Sasaki M, Klapproth J. The role of bacteria in the pathogenesis of ulcerative colitis. J Signal Transduct. 2012; doi:  10.1155/2012/704953.
  11. 11.
    Araki Y, Andoh A, Tsujikawa T, Fujiyama Y, Bamba T. Alterations in intestinal microflora, faecal bile acids and short chain fatty acids in dextran sulphate sodium-induced experimental acute colitis in rats. Eur J Gastroenterol Hepatol. 2011;13:107–12.CrossRefGoogle Scholar
  12. 12.
    Vong LB, Tomita T, Yoshitomi T, Matsui H, Nagasaki Y. An orally administered redox nanoparticle that accumulates in the colonic mucosa and reduces colitis in mice. Gastroenterology. 2012;143:1027–36.e3.PubMedGoogle Scholar
  13. 13.
    Yoshitomi T, Miyamoto D, Nagasaki Y. Design of core-shell-type nanoparticles carrying stable radicals in the core. Biomacromolecules. 2009;10:596–601.PubMedCrossRefGoogle Scholar
  14. 14.
    Yoshitomi T, Nagasaki Y. Nitroxyl radical-containing nanoparticles for novel nanomedicine against oxidative stress injury. Nanomedicine. 2011;6:509–18.PubMedCrossRefGoogle Scholar
  15. 15.
    Solomon L, Mansor S, Mallon P, Donnelly E, Hoper M, Loughrey M, et al. The dextran sulphate sodium (DSS) model of colitis: an overview. Comp Clin Pathol. 2010;19:235–9.CrossRefGoogle Scholar
  16. 16.
    Van der Waaij LA, Harmsen HJ, Madjipour M, Kroese FG, Zwiers M, van Dullemen HM, et al. Bacterial population analysis of human colon and terminal ileum biopsies with 16S rRNA-based fluorescent probes: commensal bacteria live in suspension and have no direct contact with epithelial cells. Inflamm Bowel Dis. 2005;10:865–71.CrossRefGoogle Scholar
  17. 17.
    Xia Y, Chen HQ, Zhang M, Jiang YQ, Hang XM, Qin HL. Effect of Lactobacillus plantarum LP-Only on gut flora and colitis in interleukin-10 knockout mice. J Gastroenterol Hepatol. 2011;26:405–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Vereecke L, Sze M, Mc Guire C, Rogiers B, Chu Y, Schmidt-Supprian M, et al. Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor-induced toxicity and experimental colitis. J Exp Med. 2010;207:1513–23.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Friend DR, Sellin J. Drug delivery in advancing the treatment of inflammatory bowel disease. Adv Drug Deliv Rev. 2005;57:215–6.CrossRefGoogle Scholar
  20. 20.
    Hanauer SB. Medical therapy for ulcerative colitis 2004. Gastroenterology. 2004;126:1582–92.PubMedCrossRefGoogle Scholar
  21. 21.
    Swidsinski A, Loening-Baucke V, Bengmark S, Lochs H, Dörffel Y. Azathioprine and mesalazine-induced effects on the mucosal flora in patients with IBD colitis. Inflamm Bowel Dis. 2007;1:51–6.CrossRefGoogle Scholar
  22. 22.
    West B, Lendrum R, Hill MJ, Walker G. Effects of sulphasalazine (Salazopyrin) on faecal flora in patients with inflammatory bowel disease. Gut. 1974;15:960–5.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Singh K, Chaturvedi R, Barry DP, Coburn LA, Asim M, Lewis ND, et al. The apolipoprotein E-mimetic peptide COG112 inhibits NF-kappaB signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis. J Biol Chem. 2011;286:3839–50.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Otsuka H, Nagasaki Y, Kataoka K. PEGylated nanoparticles for biological and pharmaceutical applications. Adv Drug Deliv Rev. 2003;55:403–19.PubMedCrossRefGoogle Scholar
  25. 25.
    Resta-Lenert S, Barrett KE. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut. 2003;52:988–97.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Kotlowski R, Bernstein CN, Sepehri S, Krause DO. High prevalence of Escherichia coli belonging to the B2 + D phylogenetic group in inflammatory bowel disease. Gut. 2007;56:669–75.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Lu J, Wang A, Ansari S, Hershberg RM, McKay DM. Colonic bacterial superantigens evoke an inflammatory response and exaggerate disease in mice recovering from colitis. Gastroenterology. 2003;125:1785–95.PubMedCrossRefGoogle Scholar
  28. 28.
    Vesterlund S, Karp M, Salminen S, Ouwehand AC. Staphylococcus aureus adheres to human intestinal mucus but can be displaced by certain lactic acid bacteria. Microbiology. 2006;152:1819–26.PubMedCrossRefGoogle Scholar
  29. 29.
    Takaishi H, Matsuki T, Nakazawa A, Takada T, Kado S, Asahara T, et al. Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. Int J Med Microbiol. 2008;298:463–72.PubMedCrossRefGoogle Scholar
  30. 30.
    Abraham C, Medzhitov R. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology. 2011;140:1729–37.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Hans W, Schölmerich J, Gross V, Falk W. The role of the resident intestinal flora in acute and chronic dextran sulfate sodium-induced colitis in mice. Eur J Gastroenterol Hepatol. 2000;12:267–73.PubMedCrossRefGoogle Scholar
  32. 32.
    Johansson ME, Gustafsson JK, Sjöberg KE, Petersson J, Holm L, Sjövall H, et al. Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. PLoS ONE. 2010;5:e12238.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Zhou FX, Chen L, Liu XW, Ouyang CH, Wu XP, Wang XH, et al. Lactobacillus crispatus M206119 exacerbates murine DSS-colitis by interfering with inflammatory responses. World J Gastroenterol. 2012;18:2344–56.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Ganz T, Weiss J. Antimicrobial peptides of phagocytes and epithelia. Semin Hematol. 1997;34:343–54.PubMedGoogle Scholar
  35. 35.
    Pavlick KP, Laroux FS, Fuseler J, Wolf RE, Gray L, Hoffman J, et al. Role of reactive metabolites of oxygen and nitrogen in inflammatory bowel disease. Free Radic Biol Med. 2002;33:311–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Roessner A, Kuester D, Malfertheiner P, Schneider-Stock R. Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol Res Pract. 2008;204:511–24.PubMedCrossRefGoogle Scholar
  37. 37.
    Keshavarzian A, Fusunyan RD, Jacyno M, Winship D, MacDermott RP, Sanderson IR. Increased interleukin-8 (IL-8) in rectal dialysate from patients with ulcerative colitis: evidence for a biological role for IL-8 in inflammation of the colon. Am J Gastroenterol. 1999;94:04–12.Google Scholar
  38. 38.
    Brownlee IA, Knight J, Dettmar PW, Pearson JP. Action of reactive oxygen species on colonic mucus secretions. Free Radic Biol Med. 2007;43:800–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Long Binh Vong
    • 1
  • Toru Yoshitomi
    • 1
  • Kazuya Morikawa
    • 2
  • Shinji Saito
    • 2
  • Hirofumi Matsui
    • 3
    • 4
  • Yukio Nagasaki
    • 1
    • 3
    • 5
    Email author
  1. 1.Department of Materials Science, Graduate School of Pure and Applied SciencesUniversity of TsukubaTsukubaJapan
  2. 2.Department of Microbiology, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  3. 3.Master’s School of Medical Sciences, Graduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
  4. 4.Division of Gastroenterology, Graduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
  5. 5.Satellite Laboratory, International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS)University of TsukubaTsukubaJapan

Personalised recommendations