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.

Rifaximin decreases virulence of Crohn’s disease-associated Escherichia coli and epithelial inflammatory responses

Abstract

Escherichia coli with an adherent and invasive pathotype (AIEC) is implicated in the pathogenesis of Crohn’s disease (CD). Rifaximin improves symptoms in mild-to-moderate CD. It is unclear if this outcome is due to its effects on bacteria or intestinal epithelial inflammatory responses. We examined the effects of rifaximin on the growth and virulence of CD-associated E. coli and intestinal epithelial inflammatory responses. Seven well-characterized CD-associated E. coli strains (six AIEC, one non-AIEC; four rifaximin-resistant, three sensitive) were evaluated. We assessed the effects of rifaximin on CD-associated E. coli growth, adhesion to, and invasion of epithelial cells, virulence gene expression, motility, and survival in macrophages. Additionally, we determined the effects of rifaximin on intestinal epithelial inflammatory responses. In vitro rifaximin exerted a dose-dependent effect on the growth of sensitive strains but did not affect the growth of resistant strains. Rifaximin reduced adhesion, invasion, virulence gene expression and motility of CD-associated E. coli in a manner that was independent of its antimicrobial effect. Furthermore, rifaximin reduced IL-8 secretion from pregnane X receptor-expressing T84 colonic epithelial cells. The effect of rifaximin on adhesion was largely attributable to its action on bacteria, whereas decreases in invasion and cytokine secretion were due to its effect on the epithelium. In conclusion, our results show that rifaximin interferes with multiple steps implicated in host-AIEC interactions related to CD, including adhesion to, and invasion of epithelial cells, virulence gene expression, motility, and pro-inflammatory cytokine secretion. Further study is required to determine the relationship of these effects to clinical responses in CD patients.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407.

    CAS  Article  PubMed  Google Scholar 

  2. Molodecky NA, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54.

    Article  PubMed  Google Scholar 

  3. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134:577–94.

    CAS  Article  PubMed  Google Scholar 

  4. Baumgart M, et al. Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn’s disease involving the ileum. ISME J. 2007;1:403–18.

    CAS  Article  PubMed  Google Scholar 

  5. Dogan B, Simpson KW. Microflora in Crohn’s disease: the emergence of adherent and invasive Escherichia coli. Expert Rev Clin Immunol. 2008;4:133–7.

    Article  PubMed  Google Scholar 

  6. Frank DN, et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA. 2007;104:13780–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Darfeuille-Michaud A, et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology. 2004;127:412–21.

    Article  PubMed  Google Scholar 

  8. Craven M, et al. Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn’s disease. PLoS One. 2012;7:e41594.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Dogan B, et al. Inflammation-associated adherent-invasive Escherichia coli are enriched in pathways for use of propanediol and iron and M-cell translocation. Inflamm Bowel Dis. 2014;20:1919–32.

    Article  PubMed  Google Scholar 

  10. Barnich N, Boudeau J, Claret L, Darfeuille-Michaud A. Regulatory and functional co-operation of flagella and type 1 pili in adhesive and invasive abilities of AIEC strain LF82 isolated from a patient with Crohn’s disease. Mol Microbiol. 2003;48:781–94.

    CAS  Article  PubMed  Google Scholar 

  11. DuPont HL. Biologic properties and clinical uses of rifaximin. Expert Opin Pharmacother. 2011;12:293–302.

    CAS  Article  PubMed  Google Scholar 

  12. Prantera C, et al. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology. 2012;142:473.e4

    CAS  Article  PubMed  Google Scholar 

  13. Calanni F, Renzulli C, Barbanti M, Viscomi GC. Rifaximin: beyond the traditional antibiotic activity. J Antibiot. 2014;67:667–70.

    CAS  Article  PubMed  Google Scholar 

  14. Kothary V, et al. Rifaximin resistance in Escherichia coli associated with inflammatory bowel disease correlates with prior rifaximin use, mutations in rpoB, and activity of Phe-Arg-β-naphthylamide-inhibitable efflux pumps. Antimicrob Agents Chemother. 2013;57:811–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Soldi S, et al. Modulation of the gut microbiota composition by rifaximin in non-constipated irritable bowel syndrome patients: a molecular approach. Clin Exp Gastroenterol. 2015;8:309–25.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Brigidi P, Swennen E, Rizzello F, Bozzolasco M, Matteuzzi D. Effects of rifaximin administration on the intestinal microbiota in patients with ulcerative colitis. J Chemother. 2002;14:290–5.

    CAS  Article  PubMed  Google Scholar 

  17. Huang DB, DuPont HL. Rifaximin-a novel antimicrobial for enteric infections. J Infect. 2005;50:97–106.

    Article  PubMed  Google Scholar 

  18. Jiang ZD, Ke S, Dupont HL. Rifaximin-induced alteration of virulence of diarrhoea-producing Escherichia coli and Shigella sonnei. Int J Antimicrob Agents. 2010;35:278–81.

    CAS  Article  PubMed  Google Scholar 

  19. Debbia EA, Maioli E, Roveta S, Marchese A. Effects of rifaximin on bacterial virulence mechanisms at supra- and sub-inhibitory concentrations. J Chemother. 2008;20:186–94.

    CAS  Article  PubMed  Google Scholar 

  20. Brown EL, Xue Q, Jiang ZD, Xu Y, Dupont HL. Pretreatment of epithelial cells with rifaximin alters bacterial attachment and internalization profiles. Antimicrob Agents Chemother. 2010;54:388–96.

    CAS  Article  PubMed  Google Scholar 

  21. Barnich N, Bringer MA, Claret L, Darfeuille-Michaud A. Involvement of lipoprotein NlpI in the virulence of adherent invasive Escherichia coli strain LF82 isolated from a patient with Crohn’s disease. Infect Immun. 2004;72:2484–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Bringer MA, Barnich N, Glasser AL, Bardot O, Darfeuille-Michaud A. HtrA stress protein is involved in intramacrophagic replication of adherent and invasive Escherichia coli strain LF82 isolated from a patient with Crohn’s disease. Infect Immun. 2005;73:712–21.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Bringer MA, Rolhion N, Glasser AL, Darfeuille-Michaud A. The oxidoreductase DsbA plays a key role in the ability of the Crohn’s disease-associated adherent-invasive Escherichia coli strain LF82 to resist macrophage killing. J Bacteriol. 2007;189:4860–71.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Rolhion N, Barnich N, Claret L, Darfeuille-Michaud A. Strong decrease in invasive ability and outer membrane vesicle release in Crohn’s disease-associated adherent-invasive Escherichia coli strain LF82 with the yfgL gene deleted. J Bacteriol. 2005;187:2286–96.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Rolhion N, Carvalho FA, Darfeuille-Michaud A. OmpC and the sigma(E) regulatory pathway are involved in adhesion and invasion of the Crohn’s disease-associated Escherichia coli strain LF82. Mol Microbiol. 2007;63:1684–700.

    CAS  Article  PubMed  Google Scholar 

  26. Jiang ZD, Ke S, Palazzini E, Riopel L, Dupont H. In vitro activity and fecal concentration of rifaximin after oral administration. Antimicrob Agents Chemother. 2000;44:2205–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Nitzan O, Elias M, Peretz A, Saliba W. Role of antibiotics for treatment of inflammatory bowel disease. World J Gastroenterol. 2016;22:1078–87.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Dogan B, et al. Multidrug resistance is common in Escherichia coli associated with ileal Crohn’s disease. Inflamm Bowel Dis. 2013;19:141–50.

    Article  PubMed  Google Scholar 

  29. Carvalho FA, et al. Crohn’s disease-associated Escherichia coli LF82 aggravates colitis in injured mouse colon via signaling by flagellin. Inflamm Bowel Dis. 2008;14:1051–60.

    Article  PubMed  Google Scholar 

  30. Barnich N, et al. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. J Clin Invest. 2007;117:1566–74.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Schrodt C, McHugh EE, Gawinowicz MA, Dupont HL, Brown EL. Rifaximin-mediated changes to the epithelial cell proteome: 2-D gel analysis. PLoS One. 2013;8:e68550.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Simpson KW, et al. Adherent and invasive Escherichia coli is associated with granulomatous colitis in Boxer dogs. Infect Immun. 2006;74:4778–92.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Martinez-Medina M, Garcia-Gil LJ. Escherichia coli in chronic inflammatory bowel diseases: An update on adherent invasive Escherichia coli pathogenicity. World J Gastrointest Pathophysiol. 2014;5:213–27.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ma X, et al. Rifaximin is a gut-specific human pregnane X receptor activator. J Pharmacol Exp Ther. 2007;322:391–8.

    CAS  Article  PubMed  Google Scholar 

  35. Cheng J, Shah YM, Gonzalez FJ. Pregnane X receptor as a target for treatment of inflammatory bowel disorders. Trends Pharmacol Sci. 2012;33:323–30.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Dring MM, et al. The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease. Gastroenterology. 2006;130:341–8.

    CAS  Article  PubMed  Google Scholar 

  37. Haslam IS, Jones K, Coleman T, Simmons NL. Rifampin and digoxin induction of MDR1 expression and function in human intestinal (T84) epithelial cells. Br J Pharmacol. 2008;154:246–55.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Habano W, et al. Involvement of promoter methylation in the regulation of Pregnane X receptor in colon cancer cells. BMC Cancer. 2011;11:81.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Langmann T, et al. Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology. 2004;127:26–40.

    CAS  Article  PubMed  Google Scholar 

  40. Glasser AL, et al. Adherent invasive Escherichia coli strains from patients with Crohn’s disease survive and replicate within macrophages without inducing host cell death. Infect Immun. 2001;69:5529–37.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Bringer MA, Billard E, Glasser AL, Colombel JF, Darfeuille-Michaud A. Replication of Crohn’s disease-associated AIEC within macrophages is dependent on TNF-alpha secretion. Lab Invest. 2012;92:411–9.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Alfa Wassermann (Bologna, Italy). We thank the International Postdoctoral Exchange Fellowship Program of China for supporting JF.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Belgin Dogan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dogan, B., Fu, J., Zhang, S. et al. Rifaximin decreases virulence of Crohn’s disease-associated Escherichia coli and epithelial inflammatory responses. J Antibiot 71, 485–494 (2018). https://doi.org/10.1038/s41429-017-0022-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-017-0022-y

Further reading

Search

Quick links