1887

Abstract

Mucositis is one of the most debilitating side effects of chemotherapy and some previous studies suggest a role for indigenous microbiota in the course of this pathology. Therefore, the aim of our study was to evaluate the differences in phenotype between germ-free (GF) and conventional (CV) mice, and the role of β-glucuronidase-producing bacteria in the development of irinotecan treatment in a murine model. After mucositis induction, CV mice showed a significant increase in all inflammatory parameters when compared to GF mice. CV animals also showed more lesions of the intestinal epithelium, coherent with their higher intestinal permeability. The conventionalization of GF animals reversed their phenotype to that found in CV mice. In addition, gnotobiotic mice monoassociated with an strain producing β-glucuronidase showed an increased permeability when compared to gnotobiotic mice monoassociated with an strain deleted for the gene encoding β-glucuronidase, but these did not show any differences in the influx of neutrophils, eosinophils or histological characteristics. Our data confirmed that components of the gut microbiota are involved in the signs of mucositis. Nevertheless, other mechanisms than this enzyme are involved in the irinotecan treatment, since the monoassociation was not able to restore the entire phenotype observed in the CV animals with irinotecan treatment in our murine model.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000149
2015-10-01
2020-01-26
Loading full text...

Full text loading...

/deliver/fulltext/micro/161/10/1950.html?itemId=/content/journal/micro/10.1099/mic.0.000149&mimeType=html&fmt=ahah

References

  1. Alimonti A., Satta F., Pavese I., Burattini E., Zoffoli V., Vecchione A.. 2003; Prevention of irinotecan plus 5-fluorouracil/leucovorin-induced diarrhoea by oral administration of neomycin plus bacitracin in first-line treatment of advanced colorectal cancer. Ann Oncol14:805–806 [CrossRef][PubMed]
    [Google Scholar]
  2. Arantes R.M., Nogueira A.M.. 1997; Distribution of enteroglucagon- and peptide YY-immunoreactive cells in the intestinal mucosa of germ-free and conventional mice. Cell Tissue Res290:61–69 [CrossRef][PubMed]
    [Google Scholar]
  3. Bansal T., Awasthi A., Jaggi M., Khar R.K., Talegaonkar S.. 2008; Development and validation of reversed phase liquid chromatographic method utilizing ultraviolet detection for quantification of irinotecan (CPT-11) and its active metabolite, SN-38, in rat plasma and bile samples: application to pharmacokinetic studies. Talanta76:1015–1021 [CrossRef][PubMed]
    [Google Scholar]
  4. Bates J.M., Akerlund J., Mittge E., Guillemin K.. 2007; Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. Cell Host Microbe2:371–382 [CrossRef][PubMed]
    [Google Scholar]
  5. Beaud D., Tailliez P., Anba-Mondoloni J.. 2005; Genetic characterization of the β-glucuronidase enzyme from a human intestinal bacterium, Ruminococcus gnavus . Microbiology151:2323–2330 [CrossRef][PubMed]
    [Google Scholar]
  6. Brandi G., Dabard J., Raibaud P., Di Battista M., Bridonneau C., Pisi A.M., Morselli Labate A.M., Pantaleo M.A., De Vivo A., Biasco G.. 2006; Intestinal microflora and digestive toxicity of irinotecan in mice. Clin Cancer Res12:1299–1307 [CrossRef][PubMed]
    [Google Scholar]
  7. Cawley E.P., McManus J.F.A., Lupton C.H. Jr, Wheeler C.E.. 1956; An examination of skin from patients with collagen disease utilizing the combined Alcian blue-periodic acid Schiff stain. J Invest Dermatol27:389–394 [CrossRef][PubMed]
    [Google Scholar]
  8. Dekaney C.M., Gulati A.S., Garrison A.P., Helmrath M.A., Henning S.J.. 2009; Regeneration of intestinal stem/progenitor cells following doxorubicin treatment of mice. Am J Physiol Gastrointest Liver Physiol297:G461–G470 [CrossRef][PubMed]
    [Google Scholar]
  9. Elian S.D., Souza E.L., Vieira A.T., Teixeira M.M., Arantes R.M., Nicoli J.R., Martins F.S.. 2015; Bifidobacterium longum subsp. infantis BB-02 attenuates acute murine experimental model of inflammatory bowel disease. Benef Microbes6:277–286 [CrossRef][PubMed]
    [Google Scholar]
  10. Fagundes C.T., Amaral F.A., Vieira A.T., Soares A.C., Pinho V., Nicoli J.R., Vieira L.Q., Teixeira M.M., Souza D.G.. 2012; Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice. J Immunol188:1411–1420 [CrossRef][PubMed]
    [Google Scholar]
  11. Fijlstra M., Rings E.H., Verkade H.J., van Dijk T.H., Kamps W.A., Tissing W.J.. 2011; Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model. Am J Physiol Gastrointest Liver Physiol300:G283–G291 [CrossRef][PubMed]
    [Google Scholar]
  12. Fittkau M., Voigt W., Holzhausen H.J., Schmoll H.J.. 2004; Saccharic acid 1.4-lactone protects against CPT-11-induced mucosa damage in rats. J Cancer Res Clin Oncol130:388–394 [CrossRef][PubMed]
    [Google Scholar]
  13. Fournier B.M., Parkos C.A.. 2012; The role of neutrophils during intestinal inflammation. Mucosal Immunol5:354–366 [CrossRef][PubMed]
    [Google Scholar]
  14. Hapfelmeier S., Lawson M.A., Slack E., Kirundi J.K., Stoel M., Heikenwalder M., Cahenzli J., Velykoredko Y., Balmer M.L., other authors. 2010; Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science328:1705–1709 [CrossRef][PubMed]
    [Google Scholar]
  15. Ikuno N., Soda H., Watanabe M., Oka M.. 1995; Irinotecan (CPT-11) and characteristic mucosal changes in the mouse ileum and cecum. J Natl Cancer Inst87:1876–1883 [CrossRef][PubMed]
    [Google Scholar]
  16. Kurita A., Kado S., Matsumoto T., Asakawa N., Kaneda N., Kato I., Uchida K., Onoue M., Yokokura T.. 2011; Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of β-glucuronidase activity in intestinal lumen. Cancer Chemother Pharmacol67:201–213 [CrossRef][PubMed]
    [Google Scholar]
  17. Lalla R.V., Bowen J., Barasch A., Elting L., Epstein J., Keefe D.M., McGuire D.B., Migliorati C., Nicolatou-Galitis O., other authors. 2014; MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer120:1453–1461[PubMed][CrossRef]
    [Google Scholar]
  18. Lee C.S., Ryan E.J., Doherty G.A.. 2014; Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: the role of inflammation. World J Gastroenterol20:3751–3761 [CrossRef][PubMed]
    [Google Scholar]
  19. Leitão R.F., Ribeiro R.A., Bellaguarda E.A., Macedo F.D., Silva L.R., Oriá R.B., Vale M.L., Cunha F.Q., Brito G.A.. 2007; Role of nitric oxide on pathogenesis of 5-fluorouracil induced experimental oral mucositis in hamster. Cancer Chemother Pharmacol59:603–612 [CrossRef][PubMed]
    [Google Scholar]
  20. Lima V., Brito G.A., Cunha F.Q., Rebouças C.G., Falcão B.A., Augusto R.F., Souza M.L., Leitão B.T., Ribeiro R.A.. 2005; Effects of the tumour necrosis factor-α inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters. Eur J Oral Sci113:210–217 [CrossRef][PubMed]
    [Google Scholar]
  21. Lin X.B., Farhangfar A., Valcheva R., Sawyer M.B., Dieleman L., Schieber A., Gänzle M.G., Baracos V.. 2014; The role of intestinal microbiota in development of irinotecan toxicity and in toxicity reduction through dietary fibres in rats. PLoS One9:e83644 [CrossRef][PubMed]
    [Google Scholar]
  22. Maioli T.U., de Melo Silva B., Dias M.N., Paiva N.C., Cardoso V.N., Fernandes S.O., Carneiro C.M., Dos Santos Martins F., de Vasconcelos Generoso S.. 2014; Pretreatment with Saccharomyces boulardii does not prevent the experimental mucositis in Swiss mice. J Negat Results Biomed13:6 [CrossRef][PubMed]
    [Google Scholar]
  23. Marteau P., Chaput U.. 2011; Bacteria as trigger for chronic gastrointestinal disorders. Dig Dis29:166–171 [CrossRef][PubMed]
    [Google Scholar]
  24. Martins F.S., Silva A.A., Vieira A.T., Barbosa F.H., Arantes R.M., Teixeira M.M., Nicoli J.R.. 2009; Comparative study of Bifidobacterium animalis, Escherichia coli, Lactobacillus casei and Saccharomyces boulardii probiotic properties. Arch Microbiol191:623–630 [CrossRef][PubMed]
    [Google Scholar]
  25. McLaughlin M.M., Dacquisto M.P., Jacobus D.P., Horowitz R.E.. 1964; Effects of the germfree state on responses of mice to whole-body irradiation. Radiat Res23:333–349 [CrossRef][PubMed]
    [Google Scholar]
  26. Pabst O.. 2012; New concepts in the generation and functions of IgA. Nat Rev Immunol12:821–832 [CrossRef][PubMed]
    [Google Scholar]
  27. Ramos M.G., Bambirra E.A., Cara D.C., Vieira E.C., Alvarez-Leite J.I.. 1997; Oral administration of short-chain fatty acids reduces the intestinal mucositis caused by treatment with Ara-C in mice fed commercial or elemental diets. Nutr Cancer28:212–217 [CrossRef][PubMed]
    [Google Scholar]
  28. Sommer F., Bäckhed F.. 2013; The gut microbiota – masters of host development and physiology. Nat Rev Microbiol11:227–238 [CrossRef][PubMed]
    [Google Scholar]
  29. Sonis S.T.. 2004; A biological approach to mucositis. J Support Oncol2:21–32
    [Google Scholar]
  30. Souza D.G., Vieira A.T., Soares A.C., Pinho V., Nicoli J.R., Vieira L.Q., Teixeira M.M.. 2004; The essential role of the intestinal microbiota in facilitating acute inflammatory responses. J Immunol173:4137–4146 [CrossRef][PubMed]
    [Google Scholar]
  31. Souza D.G., Fagundes C.T., Amaral F.A., Cisalpino D., Sousa L.P., Vieira A.T., Pinho V., Nicoli J.R., Vieira L.Q., other authors. 2007; The required role of endogenously produced lipoxin A4 and annexin-1 for the production of IL-10 and inflammatory hyporesponsiveness in mice. J Immunol179:8533–8543 [CrossRef][PubMed]
    [Google Scholar]
  32. Sparreboom A., de Jonge M.J., de Bruijn P., Brouwer E., Nooter K., Loos W.J., van Alphen R.J., Mathijssen R.H., Stoter G., Verweij J.. 1998; Irinotecan (CPT-11) metabolism and disposition in cancer patients. Clin Cancer Res4:2747–2754[PubMed]
    [Google Scholar]
  33. Stringer A.M., Gibson R.J., Logan R.M., Bowen J.M., Yeoh A.S., Burns J., Keefe D.M.. 2007; Chemotherapy-induced diarrhea is associated with changes in the luminal environment in the DA rat. Exp Biol Med (Maywood)232:96–106[PubMed]
    [Google Scholar]
  34. Stringer A.M., Gibson R.J., Logan R.M., Bowen J.M., Yeoh A.S., Laurence J., Keefe D.M.. 2009a; Irinotecan-induced mucositis is associated with changes in intestinal mucins. Cancer Chemother Pharmacol64:123–132 [CrossRef][PubMed]
    [Google Scholar]
  35. Stringer A.M., Gibson R.J., Bowen J.M., Logan R.M., Ashton K., Yeoh A.S., Al-Dasooqi N., Keefe D.M.. 2009b; Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol90:489–499 [CrossRef][PubMed]
    [Google Scholar]
  36. Takakura A., Kurita A., Asahara T., Yokoba M., Yamamoto M., Ryuge S., Igawa S., Yasuzawa Y., Sasaki J., other authors. 2012; Rapid deconjugation of SN-38 glucuronide and adsorption of released free SN-38 by intestinal microorganisms in rat. Oncol Lett3:520–524[PubMed]
    [Google Scholar]
  37. Takasuna K., Hagiwara T., Hirohashi M., Kato M., Nomura M., Nagai E., Yokoi T., Kamataki T.. 1996; Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res56:3752–3757[PubMed]
    [Google Scholar]
  38. van Vliet M.J., Tissing W.J., Dun C.A., Meessen N.E., Kamps W.A., de Bont E.S., Harmsen H.J.. 2009; Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis49:262–270 [CrossRef][PubMed]
    [Google Scholar]
  39. van Vliet M.J., Harmsen H.J., de Bont E.S., Tissing W.J.. 2010; The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog6:e1000879 [CrossRef][PubMed]
    [Google Scholar]
  40. Vanhoefer U., Harstrick A., Achterrath W., Cao S., Seeber S., Rustum Y.M.. 2001; Irinotecan in the treatment of colorectal cancer: clinical overview. J Clin Oncol19:1501–1518[PubMed]
    [Google Scholar]
  41. Vieira A.T., Fagundes C.T., Alessandri A.L., Castor M.G., Guabiraba R., Borges V.O., Silveira K.D., Vieira E.L., Gonçalves J.L., other authors. 2009; Treatment with a novel chemokine-binding protein or eosinophil lineage-ablation protects mice from experimental colitis. Am J Pathol175:2382–2391 [CrossRef][PubMed]
    [Google Scholar]
  42. Voigt W., Matsui S., Yin M.B., Burhans W.C., Minderman H., Rustum Y.M.. 1998; Topoisomerase-I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis. Anticancer Res18:3499–3505[PubMed]
    [Google Scholar]
  43. Wallace B.D., Wang H., Lane K.T., Scott J.E., Orans J., Koo J.S., Venkatesh M., Jobin C., Yeh L.A., other authors. 2010; Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science330:831–835 [CrossRef][PubMed]
    [Google Scholar]
  44. Xavier R.J., Podolsky D.K.. 2007; Unravelling the pathogenesis of inflammatory bowel disease. Nature448:427–434 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000149
Loading
/content/journal/micro/10.1099/mic.0.000149
Loading

Data & Media loading...

Supplements

Supplementary Data

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error