Digestive Diseases and Sciences

, 56:2575

Acute and Chronic Histological Changes of the Small Bowel Secondary to C. jejuni Infection in a Rat Model for Post-Infectious IBS

  • Walter Morales
  • Mark Pimentel
  • Laura Hwang
  • David Kunkel
  • Venkata Pokkunuri
  • Benjamin Basseri
  • Kimberly Low
  • Hanlin Wang
  • Jeffrey L. Conklin
  • Christopher Chang
Original Article

Abstract

Background

Campylobacter jejuni has been implicated in the pathogenesis of post-infectious irritable bowel syndrome (PI-IBS) in humans, effects which may be because of cytolethal distending toxin (CDT). In this study, we characterized both acute and chronic-phase histological changes of the small bowel in rats exposed to wild-type C. jejuni 81-176, or a strain that does not produce CDT, by using a validated rat model of PI-IBS.

Methods

Sprague–Dawley rats were given 1.0 × 108 CFU of either wild-type C. jejuni 81-176 (C+, PI/C+) or the CDT-negative strain (CDT−), or vehicle alone (Control). Acute-phase rats (C+, CDT−) were euthanized on days 2, 4, 8, 16, and 32. Chronic-phase rats (PI/C+, Control) were euthanized 3 months after clearing the initial infection. Segments of duodenum, jejunum, and ileum were resected and the contents plated for C. jejuni culture, and tissue sections were stained for histology.

Results

We observed preferential infection of the ileum and jejunum by Campylobacter jejuni. Compared with controls, epithelial cell basal membrane ballooning, villous tip disruption, and reduced villous-to-crypt ratios were observed for both C+ and CDT− rats. Villous widening, the only result significantly different in C+ vs. CDT− rats, was greatest at day 4 (134.1 ± 21.12 μm vs. 109.9 ± 10.6 μm for CDT−, P < 0.01). Little or no cellular inflammatory changes were seen during acute C. jejuni infection. Three months after clearing the initial infection, no histological changes remained.

Conclusion

Significant histological changes, with the absence of inflammatory cells, are seen in the duodenum, jejunum, and ileum of rats during acute infection with C. jejuni. These changes occurred irrespective of the presence or absence of the CDT toxin.

Keywords

Campylobacter jejuni Irritable bowel syndrome Cytolethal distending toxin Small bowel 

References

  1. 1.
    Bommelaer G, Poynard T, Le Pen C, et al. Prevalence of irritable bowel syndrome (ibs) and variability of diagnostic criteria. Gastroenterol Clin Biol. 2004;28:554–561.PubMedCrossRefGoogle Scholar
  2. 2.
    El-Serag HB. Impact of irritable bowel syndrome: prevalence and effect on health-related quality of life. Rev Gastroenterol Disord. 2003;3:S3–11.PubMedGoogle Scholar
  3. 3.
    Agreus L, Svardsudd K, Nyren O, Tibblin G. Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time. Gastroenterology. 1995;109:671–680.PubMedCrossRefGoogle Scholar
  4. 4.
    Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowel syndrome: postal survey of patients. BMJ. 1997;314:779–782.PubMedGoogle Scholar
  5. 5.
    Parry SD, Stansfield R, Jelley D, et al. Is irritable bowel syndrome more common in patients presenting with bacterial gastroenteritis? A community-based, case–control study. Am J Gastroenterol. 2003;98:327–331.PubMedCrossRefGoogle Scholar
  6. 6.
    Neal KR, Barker L, Spiller RC. Prognosis in post-infective irritable bowel syndrome: a six year follow up study. Gut. 2002;51:410–413.PubMedCrossRefGoogle Scholar
  7. 7.
    Thornley JP, Jenkins D, Neal K, Wright T, Brough J, Spiller RC. Relationship of campylobacter toxigenicity in vitro to the development of postinfectious irritable bowel syndrome. J Infect Dis. 2001;184:606–609.PubMedCrossRefGoogle Scholar
  8. 8.
    Okhuysen PC, Jiang ZD, Carlin L, Forbes C, DuPont HL. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol. 2004;99:1774–1778.PubMedCrossRefGoogle Scholar
  9. 9.
    Mearin F, Perez-Oliveras M, Perello A, et al. Dyspepsia and irritable bowel syndrome after a salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology. 2005;129:98–104.PubMedCrossRefGoogle Scholar
  10. 10.
    Johnson WM, Lior H. A new heat-labile cytolethal distending toxin (cldt) produced by Campylobacter spp. Microb Pathog. 1988;4:115–126.PubMedCrossRefGoogle Scholar
  11. 11.
    Pickett CL, Cottle DL, Pesci EC, Bikah G. Cloning, sequencing, and expression of the escherichia coli cytolethal distending toxin genes. Infect Immun. 1994;62:1046–1051.PubMedGoogle Scholar
  12. 12.
    Pickett CL, Pesci EC, Cottle DL, Russell G, Erdem AN, Zeytin H. Prevalence of cytolethal distending toxin production in Campylobacter jejuni and relatedness of Campylobacter sp. Cdtb gene. Infect Immun. 1996;64:2070–2078.PubMedGoogle Scholar
  13. 13.
    Scott DA, Kaper JB. Cloning and sequencing of the genes encoding Escherichia coli cytolethal distending toxin. Infect Immun. 1994;62:244–251.PubMedGoogle Scholar
  14. 14.
    Haghjoo E, Galan JE. Salmonella typhi encodes a functional cytolethal distending toxin that is delivered into host cells by a bacterial-internalization pathway. Proc Natl Acad Sci USA. 2004;101:4614–4619.PubMedCrossRefGoogle Scholar
  15. 15.
    Smith JL, Bayles DO. The contribution of cytolethal distending toxin to bacterial pathogenesis. Crit Rev Microbiol. 2006;32:227–248.PubMedCrossRefGoogle Scholar
  16. 16.
    Heywood W, Henderson B, Nair SP. Cytolethal distending toxin: creating a gap in the cell cycle. J Med Microbiol. 2005;54:207–216.PubMedCrossRefGoogle Scholar
  17. 17.
    Lara-Tejero M, Galan JE. Cdta, cdtb, and cdtc form a tripartite complex that is required for cytolethal distending toxin activity. Infect Immun. 2001;69:4358–4365.PubMedCrossRefGoogle Scholar
  18. 18.
    Cortes-Bratti X, Frisan T, Thelestam M. The cytolethal distending toxins induce DNA damage and cell cycle arrest. Toxicon. 2001;39:1729–1736.PubMedCrossRefGoogle Scholar
  19. 19.
    Lara-Tejero M, Galan JE. Cytolethal distending toxin: limited damage as a strategy to modulate cellular functions. Trends Microbiol. 2002;10:147–152.PubMedCrossRefGoogle Scholar
  20. 20.
    Fox JG, Rogers AB, Whary MT, et al. Gastroenteritis in nf-kappab-deficient mice is produced with wild-type Campylobacter jejuni but not with C. jejuni lacking cytolethal distending toxin despite persistent colonization with both strains. Infect Immun. 2004;72:1116–1125.PubMedCrossRefGoogle Scholar
  21. 21.
    Chang C, Miller JF. Campylobacter jejuni colonization of mice with limited enteric flora. Infect Immun. 2006;74:5261–5271.PubMedCrossRefGoogle Scholar
  22. 22.
    Pimentel M, Chatterjee S, Chang C, et al. A new rat model links two contemporary theories in irritable bowel syndrome. Dig Dis Sci. 2008;53:982–989.PubMedCrossRefGoogle Scholar
  23. 23.
    Dasti JI, Tareen AM, Lugert R, Zautner AE, Gross U. Campylobacter jejuni: a brief overview on pathogenicity-associated factors and disease-mediating mechanisms. Int J Med Microbiol. 2010;300:205–211.PubMedCrossRefGoogle Scholar
  24. 24.
    Tauxe R. Incidence, trends and sources of campylobacteriosis in developed countries: an overview. The increasing incidence of human campylobacteriosis. 2001; 42–43.Google Scholar
  25. 25.
    Lastovica A, Skirrow M. Clinical significance of campylobacter and related species other than Campylobacter jejuni and C. coli. In: Nachamkin I, Blaser M, eds. Campylobacter. Washington, DC: ASM Press; 2000:89–120.Google Scholar
  26. 26.
    Blaser MJ, Reller LB. Campylobacter enteritis. N Engl J Med. 1981;305:1444–1452.PubMedCrossRefGoogle Scholar
  27. 27.
    Drake AA, Gilchrist MJ, Washington JA 2nd, Huizenga KA, Van Scoy RE. Diarrhea due to Campylobacter fetus subspecies jejuni. A clinical review of 63 cases. Mayo Clin Proc. 1981;56:414–423.PubMedGoogle Scholar
  28. 28.
    Karmali MA, Fleming PC. Campylobacter enteritis. Can Med Assoc J. 1979;120:1525–1532.PubMedGoogle Scholar
  29. 29.
    Pitkanen T, Ponka A, Pettersson T, Kosunen TU. Campylobacter enteritis in 188 hospitalized patients. Arch Intern Med. 1983;143:215–219.PubMedCrossRefGoogle Scholar
  30. 30.
    Robinson DA. Campylobacter infection. R Soc Health J. 1981;101:138–140.PubMedCrossRefGoogle Scholar
  31. 31.
    Johnson RJ, Nolan C, Wang SP, Shelton WR, Blaser MJ. Persistent Campylobacter jejuni infection in an immunocompromised patient. Ann Intern Med. 1984;100:832–834.PubMedGoogle Scholar
  32. 32.
    Melamed I, Bujanover Y, Igra YS, Schwartz D, Zakuth V, Spirer Z. Campylobacter enteritis in normal and immunodeficient children. Am J Dis Child. 1983;137:752–753.PubMedGoogle Scholar
  33. 33.
    Perlman DM, Ampel NM, Schifman RB, et al. Persistent Campylobacter jejuni infections in patients infected with the human immunodeficiency virus (HIV). Ann Intern Med. 1988;108:540–546.PubMedGoogle Scholar
  34. 34.
    Watson RO, Novik V, Hofreuter D, Lara-Tejero M, Galan JE. A myd88-deficient mouse model reveals a role for nramp1 in Campylobacter jejuni infection. Infect Immun. 2007;75:1994–2003.PubMedCrossRefGoogle Scholar
  35. 35.
    Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126:693–702.PubMedCrossRefGoogle Scholar
  36. 36.
    Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, t lymphocytes, and increased gut permeability following acute campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804–811.PubMedCrossRefGoogle Scholar
  37. 37.
    Mansfield LS, Bell JA, Wilson DL, et al. C57bl/6 and congenic interleukin-10-deficient mice can serve as models of Campylobacter jejuni colonization and enteritis. Infect Immun. 2007;75:1099–1115.PubMedCrossRefGoogle Scholar
  38. 38.
    Pigrau C, Bartolome R, Almirante B, Planes AM, Gavalda J, Pahissa A. Bacteremia due to campylobacter species: clinical findings and antimicrobial susceptibility patterns. Clin Infect Dis. 1997;25:1414–1420.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Walter Morales
    • 1
  • Mark Pimentel
    • 1
  • Laura Hwang
    • 1
  • David Kunkel
    • 1
  • Venkata Pokkunuri
    • 1
  • Benjamin Basseri
    • 1
  • Kimberly Low
    • 1
  • Hanlin Wang
    • 1
  • Jeffrey L. Conklin
    • 1
  • Christopher Chang
    • 1
  1. 1.GI Motility Program, Division of GastroenterologyCedars-Sinai Medical CenterLos AngelesUSA

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