Skip to main content

Advertisement

SpringerLink
Log in

Systemic Inflammatory Responses in Ulcerative Colitis Patients and Clostridium difficile Infection

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background/Aims

Finding differences in systemic inflammatory response in ulcerative colitis (UC), UC with Clostridium difficile infection (CDI), and CDI could lead to a better ability to differentiate between UC with symptomatic CDI and UC with C. difficile colonization, and could identify specific inflammatory pathways for UC or CDI, which could be therapeutic targets.

Methods

We prospectively collected sera from symptomatic UC patients whose stools were tested for toxigenic C. difficile, and from CDI patients who did not have UC (CDI-noUC). The UC patients with positive tests (UC-CDI) were further categorized into responders to CDI treatment (UC-CDI-R) and non-responders (UC-CDI-NR). We compared serum inflammatory mediators among groups using unadjusted and adjusted multivariable statistics.

Results

We included 117 UC [27 UC-CDI, 90 UC without CDI (UC-noCDI)] and 16 CDI-noUC patients. Principal component analysis (PCA) did not reveal significant differences either between UC-CDI and UC-noCDI groups, or between UC-CDI-R and UC-CDI-NR groups. In contrast, the PCA showed significant separation between the UC and CDI-noUC groups (P = 0.002). In these two groups, hepatocyte growth factor (HGF) and chemokine (C-C motif) ligand 2 (CCL2) levels were significantly lower and IL-23 levels were higher in UC patients in multivariable analyses. The model to distinguish UC from CDI including IL-23, HGF, CCL2, age, gender, and HGB had an AuROC of 0.93.

Conclusion

Inflammatory profiles could not distinguish UC-CDI from UC-noCDI, and UC-CDI-R from UC-CDI-NR. However, the UC and CDI-noUC groups were significantly different. Future work should examine whether therapeutic agents inhibiting IL-23 or stimulating HGF can treat UC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015;313:398–408.

    Article  PubMed  CAS  Google Scholar 

  2. Abraham C, Dulai PS, Vermeire S, Sandborn WJ. Lessons learned from trials targeting cytokine pathways in patients with inflammatory bowel diseases. Gastroenterology. 2017;152:374–388.

    Article  PubMed  CAS  Google Scholar 

  3. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14:329–342.

    Article  PubMed  CAS  Google Scholar 

  4. Rao K, Erb-Downward JR, Walk ST, et al. The systemic inflammatory response to Clostridium difficile infection. PLoS ONE. 2014;9:e92578.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Olson A, Diebel LN, Liberati DM. Exogenous phosphatidylcholine supplementation improves intestinal barrier defense against Clostridium difficile toxin. J Trauma Acute Care Surg. 2014;77:570–575. (discussion 576).

    Article  PubMed  CAS  Google Scholar 

  6. Brito GA, Sullivan GW, Ciesla WP Jr, Carper HT, Mandell GL, Guerrant RL. Clostridium difficile toxin A alters in vitro-adherent neutrophil morphology and function. J Infect Dis. 2002;185:1297–1306.

    Article  PubMed  CAS  Google Scholar 

  7. Klapproth JM, Sasaki M. Bacterial induction of proinflammatory cytokines in inflammatory bowel disease. Inflamm Bowel Dis. 2010;16:2173–2179.

    Article  PubMed  Google Scholar 

  8. Connelly TM, Koltun WA, Sangster W, et al. An interleukin-4 polymorphism is associated with susceptibility to Clostridium difficile infection in patients with inflammatory bowel disease: results of a retrospective cohort study. Surgery. 2014;156:769–774.

    Article  PubMed  Google Scholar 

  9. Steiner TS, Flores CA, Pizarro TT, Guerrant RL. Fecal lactoferrin, interleukin-1beta, and interleukin-8 are elevated in patients with severe Clostridium difficile colitis. Clin Diagn Lab Immunol. 1997;4:719–722.

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Jiang ZD, Garey KW, Price M, et al. Association of interleukin-8 polymorphism and immunoglobulin G anti-toxin A in patients with Clostridium difficile-associated diarrhea. Clin Gastroenterol Hepatol. 2007;5:964–968.

    Article  PubMed  CAS  Google Scholar 

  11. Sadighi Akha AA, McDermott AJ, Theriot CM, et al. Interleukin-22 and CD160 play additive roles in the host mucosal response to Clostridium difficile infection in mice. Immunology. 2015;144:587–597.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Cowardin CA, Kuehne SA, Buonomo EL, Marie CS, Minton NP, Petri WA Jr. Inflammasome activation contributes to interleukin-23 production in response to Clostridium difficile. MBio. 2015;6:e02386-14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Buonomo EL, Madan R, Pramoonjago P, Li L, Okusa MD, Petri WA Jr. Role of interleukin 23 signaling in Clostridium difficile colitis. J Infect Dis. 2013;208:917–920.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. El Feghaly RE, Stauber JL, Deych E, Gonzalez C, Tarr PI, Haslam DB. Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin Infect Dis. 2013;56:1713–1721.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. vegan: Community ecology package (2018). Available at https://CRAN.R-project.org/package=vegan.

  16. Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010;33:1–22.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Olsen T, Goll R, Cui G, et al. Tissue levels of tumor necrosis factor-alpha correlates with grade of inflammation in untreated ulcerative colitis. Scand J Gastroenterol. 2007;42:1312–1320.

    Article  PubMed  CAS  Google Scholar 

  18. Reimund JM, Wittersheim C, Dumont S, et al. Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn’s disease. J Clin Immunol. 1996;16:144–150.

    Article  PubMed  CAS  Google Scholar 

  19. West GA, Matsuura T, Levine AD, Klein JS, Fiocchi C. Interleukin 4 in inflammatory bowel disease and mucosal immune reactivity. Gastroenterology. 1996;110:1683–1695.

    Article  PubMed  CAS  Google Scholar 

  20. Czepiel J, Biesiada G, Brzozowski T, et al. The role of local and systemic cytokines in patients infected with Clostridium difficile. J Physiol Pharmacol. 2014;65:695–703.

    PubMed  CAS  Google Scholar 

  21. Tahara Y, Ido A, Yamamoto S, et al. Hepatocyte growth factor facilitates colonic mucosal repair in experimental ulcerative colitis in rats. J Pharmacol Exp Ther. 2003;307:146–151.

    Article  PubMed  CAS  Google Scholar 

  22. Srivastava M, Zurakowski D, Cheifetz P, Leichtner A, Bousvaros A. Elevated serum hepatocyte growth factor in children and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2001;33:548–553.

    Article  PubMed  CAS  Google Scholar 

  23. Sturm A, Schulte C, Schatton R, et al. Transforming growth factor-beta and hepatocyte growth factor plasma levels in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2000;12:445–450.

    Article  PubMed  CAS  Google Scholar 

  24. Sorour AE, Lonn J, Nakka SS, Nayeri T, Nayeri F. Evaluation of hepatocyte growth factor as a local acute phase response marker in the bowel: the clinical impact of a rapid diagnostic test for immediate identification of acute bowel inflammation. Cytokine. 2015;71:8–15.

    Article  PubMed  CAS  Google Scholar 

  25. McCormack G, Moriarty D, O’Donoghue DP, McCormick PA, Sheahan K, Baird AW. Tissue cytokine and chemokine expression in inflammatory bowel disease. Inflamm Res. 2001;50:491–495.

    Article  PubMed  CAS  Google Scholar 

  26. Kim JM, Kim JS, Jun HC, Oh YK, Song IS, Kim CY. Differential expression and polarized secretion of CXC and CC chemokines by human intestinal epithelial cancer cell lines in response to Clostridium difficile toxin A. Microbiol Immunol. 2002;46:333–342.

    Article  PubMed  CAS  Google Scholar 

  27. Mohammadi M, Hayatbakhsh MM, Zahedi MJ, Jalalpour MR, Pakgohar A. Serum interleukin-23 levels in patients with ulcerative colitis. Iran J Immunol.. 2011;8:183–188.

    PubMed  CAS  Google Scholar 

  28. Mirsattari D, Seyyedmajidi M, Zojaji H, et al. The relation between the level of interleukin-23 with duration and severity of ulcerative colitis. Gastroenterol Hepatol Bed Bench. 2012;5:49–53.

    PubMed  PubMed Central  Google Scholar 

  29. Zheng ZD, Wan XQ, Liu LY. Serum contents of IL-23 and IL-17 in the patients with ulcerative colitis and the clinical significance. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2011;27:203–206.

    PubMed  CAS  Google Scholar 

  30. Peng LL, Wang Y, Zhu FL, Xu WD, Ji XL, Ni J. IL-23R mutation is associated with ulcerative colitis: a systemic review and meta-analysis. Oncotarget. 2017;8:4849–4863.

    PubMed  Google Scholar 

  31. Liu M, Zhu W, Wang J, et al. Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: a meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39:516–525.

    Article  PubMed  CAS  Google Scholar 

  32. Rao K, Higgins PD. Epidemiology, diagnosis, and management of Clostridium difficile infection in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2016;22:1744–1754.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author’s contribution

PDRH and KR were involved in study concept and design; JL, LJ, AR, and EB acquired data; JL, KR, and PDRH analyzed and interpreted the data; JL and KR drafted the manuscript; RWS, SMG, AKW, AR, and PDRH critically revised the manuscript for important intellectual content; PDRH was involved in study supervision.

Funding

This work was supported by the following grants. JL: Anandamahidol Foundation, Thailand. KR: the Claude D. Pepper Older Americans Independence Center [Grant Number AG-024824] and the Michigan Institute for Clinical and Health Research [Grant Number 2UL1TR000433]. PDRH: NIH R01 DK109032, R01 GM097117, and R21 AI122098. AKW: a Career Development Award (CDA 11-217) from the United States (U.S.) Department of Veterans Affairs Health Services Research and Development Service. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA

    Julajak Limsrivilai, Krishna Rao, Ryan W. Stidham, Shail M. Govani, Akbar K. Waljee, Laura Johnson, Emily Briggs & Peter D. R. Higgins

  2. Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Julajak Limsrivilai

  3. VA Center for Clinical Management Research, Ann Arbor, MI, USA

    Shail M. Govani & Akbar K. Waljee

  4. Gastroenterology, Veterans Affairs Medical Center, Minneapolis, MN, USA

    Andrew Reinink

  5. Brown University, Providence, RI, USA

    Emily Briggs

Authors
  1. Julajak Limsrivilai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krishna Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryan W. Stidham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shail M. Govani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akbar K. Waljee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew Reinink
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laura Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Emily Briggs
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter D. R. Higgins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter D. R. Higgins.

Ethics declarations

Conflict of interest

All authors report no conflicts.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 44 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Limsrivilai, J., Rao, K., Stidham, R.W. et al. Systemic Inflammatory Responses in Ulcerative Colitis Patients and Clostridium difficile Infection. Dig Dis Sci 63, 1801–1810 (2018). https://doi.org/10.1007/s10620-018-5044-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-018-5044-1

Keywords

Search

Navigation