Skip to main content

Advertisement

SpringerLink
Log in

Gut barrier protein levels in serial blood samples from critically ill trauma patients during and after intensive care unit stay

  • Original Article
  • Published:
European Journal of Trauma and Emergency Surgery Aims and scope Submit manuscript

Abstract

Purpose

In an effort to better manage critically ill patients hospitalised in the intensive care unit (ICU) after experiencing multiple traumas, the present study aimed to assess whether plasma levels of intestinal epithelial cell barrier proteins, including occludin, claudin-1, junctional adhesion molecule (JAM-1), tricellulin and zonulin, could be used as novel biomarkers. Additional potential markers such as intestinal fatty acid-binding protein (I-FABP), d-lactate, lipopolysaccharide (LPS) and citrulline were also evaluated. We also aimed to determine the possible relationships between the clinical, laboratory, and nutritional status of patients and the measured marker levels.

Methods

Plasma samples from 29 patients (first, second, fifth and tenth days in the ICU and on days 7, 30 and 60 after hospital discharge) and 23 controls were subjected to commercial enzyme-linked immunosorbent assay (ELISA) testing.

Results

On first day (admission) and on the second day, plasma I-FABP, d-lactate, citrulline, occludin, claudin-1, tricellulin and zonulin levels were high in trauma patients and positively correlated with lactate, C-reactive protein (CRP), number of days of ICU hospitalisation, Acute Physiology and Chronic Health Evaluation II (APACHE II) score and daily Sequential Organ Failure Assessment (SOFA) scores (P < 0.05–P < 0.01).

Conclusion

The results of the present study showed that occludin, claudin-1, tricellulin and zonulin proteins, as well as I-FABP, d-lactate and citrulline, may be used as promising biomarkers for the evaluation of disease severity in critically ill trauma patients, despite the complexity of the analysis of various barrier markers. However, our results should be supported by future studies.

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

Similar content being viewed by others

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

APACHE II:

Acute Physiology and Chronic Health Evaluation II

ASPEN:

American Society of Enteral and Parenteral Nutrition

BMI:

Body mass index

CRP:

C-reactive protein

EDTA:

Ethylenediaminetetraacetic acid

ELISA:

Enzyme-linked immunosorbent assay

EN:

Enteral nutrition

ESPEN:

European Society for Clinical Nutrition and Metabolism

IBD:

Inflammatory bowel disease

ICU:

Intensive care unit

I-FABP:

Intestinal fatty acid-binding protein

Ig:

Immunoglobulin

IQR:

Interquartile range

JAM:

Junctional adhesion molecule

LPS:

Lipopolysaccharide

mNUTRIC:

Modified nutrition risk in the critically ill

PN:

Parenteral nutrition

ROC:

Receiver operating characteristic

SOFA:

Sequential Organ Failure Assessment

TRISS:

Trauma and Injury Severity Score

References

  1. Puleo F, Arvanitakis M, Van Gossum A, Preiser J-C. Gut failure in the ICU. Semin Respir Crit Care Med. 2011;32(5):626–38.

    Article  PubMed  Google Scholar 

  2. Ackland G, Grocott MP, Mythen MG. Understanding gastrointestinal perfusion in critical care: so near, and yet so far. Crit Care. 2000;4(5):1–13.

    Article  Google Scholar 

  3. Denk S, Wiegner R, Hönes FM, Messerer DA, Radermacher P, Weiss M, Kalbitz M, Ehrnthaller C, Braumüller S, McCook O. Early detection of junctional adhesion molecule-1 (JAM-1) in the circulation after experimental and clinical polytrauma. Mediators Inflamm. 2015;2015:1–7.

    Article  Google Scholar 

  4. Reintam Blaser A, Jakob SM, Starkopf J. Gastrointestinal failure in the ICU. Curr Opin Crit Care. 2016;22(2):128–41.

    PubMed  Google Scholar 

  5. Li H, Chen Y, Huo F, Wang Y, Zhang D. Association between acute gastrointestinal injury and biomarkers of intestinal barrier function in critically ill patients. BMC Gastroenterol. 2017;17:1–8.

    Article  Google Scholar 

  6. Asrani VM, Brown A, Huang W, Bissett I, Windsor JA. Gastrointestinal dysfunction in critical illness: a review of scoring tools. J Parenter Enter Nutr. 2020;44(2):182–96.

    Article  Google Scholar 

  7. Reintam Blaser A, Preiser J-C, Fruhwald S, Wilmer A, Wernerman J, Benstoem C, Casaer MP, Starkopf J, van Zanten A, Rooyackers O. Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine. Crit Care. 2020;24:1–17.

    Article  Google Scholar 

  8. Zhang X, Wang L, Chen D-C. Effect of rhubarb on gastrointestinal dysfunction in critically III patients: a retrospective study based on propensity score matching. Chin Med J. 2018;131(10):1142–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Blaser A, Padar M, Tang J, Dutton J, Forbes A. Citrulline and intestinal fatty acid-binding protein as biomarkers for gastrointestinal dysfunction in the critically ill. Anaesthesiol Intensive Ther. 2019;51(3):230–9.

    Article  PubMed  Google Scholar 

  10. Ewaschuk JB, Naylor JM, Zello GA. d-lactate in human and ruminant metabolism. J Nutr. 2005;135(7):1619–25.

    Article  CAS  PubMed  Google Scholar 

  11. Fragkos KC, Forbes A. Citrulline as a marker of intestinal function and absorption in clinical settings: a systematic review and meta-analysis. United Eur Gastroenterol J. 2018;6(2):181–91.

    Article  CAS  Google Scholar 

  12. Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal barrier dysfunction, LPS translocation, and disease development. J Endocrine Soc. 2020;4(2):bvz039.

    Article  Google Scholar 

  13. Monroe GR, van Eerde AM, Tessadori F, Duran KJ, Savelberg SM, van Alfen JC, Terhal PA, van der Crabben SN, Lichtenbelt KD, Fuchs SA. Identification of human D lactate dehydrogenase deficiency. Nat Commun. 2019;10(1):1477.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Moonen P-J, Blaser A, Starkopf J, Oudemans-van Straaten H, Van der Mullen J, Vermeulen G, Malbrain M. The black box revelation: monitoring gastrointestinal function. Anestezjol Intens Ter. 2019;50(1):73–82.

    Google Scholar 

  15. Peoc’h K, Nuzzo A, Guedj K, Paugam C, Corcos O. Diagnosis biomarkers in acute intestinal ischemic injury: so close, yet so far. Clin Chem Lab Med (CCLM). 2018;56(3):373–85.

    Article  PubMed  Google Scholar 

  16. Piton G, Manzon C, Cypriani B, Carbonnel F, Capellier G. Acute intestinal failure in critically ill patients: is plasma citrulline the right marker? Intensive Care Med. 2011;37:911–7.

    Article  PubMed  Google Scholar 

  17. Pohanka M. d-lactic acid as a metabolite: toxicology, diagnosis, and detection. BioMed Res Int. 2020;2020:1–9.

    Article  Google Scholar 

  18. Shi H, Wu B, Wan J, Liu W, Su B. The role of serum intestinal fatty acid binding protein levels and d-lactate levels in the diagnosis of acute intestinal ischemia. Clin Res Hepatol Gastroenterol. 2015;39(3):373–8.

    Article  CAS  PubMed  Google Scholar 

  19. Voth M, Duchene M, Auner B, Lustenberger T, Relja B, Marzi I. I-FABP is a novel marker for the detection of intestinal injury in severely injured trauma patients. World J Surg. 2017;41:3120–7.

    Article  CAS  PubMed  Google Scholar 

  20. Garcia-Hernandez V, Quiros M, Nusrat A. Intestinal epithelial claudins: expression and regulation in homeostasis and inflammation. Ann N Y Acad Sci. 2017;1397(1):66–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol. 2009;124(1):3–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Krug SM, Fromm M. Special issue on “The tight junction and its proteins: more than just a barrier.” Int J Mol Sci. 2020;21:4612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee B, Moon KM, Kim CY. Tight junction in the intestinal epithelium: its association with diseases and regulation by phytochemicals. J Immunol Res. 2018;2018:1–11.

    Article  Google Scholar 

  24. Wang W, Uzzau S, Goldblum SE, Fasano A. Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci. 2000;113(24):4435–40.

    Article  CAS  PubMed  Google Scholar 

  25. Zeisel MB, Dhawan P, Baumert TF. Tight junction proteins in gastrointestinal and liver disease. Gut. 2019;68(3):547–61.

    Article  CAS  PubMed  Google Scholar 

  26. Halbgebauer R, Braun CK, Denk S, Mayer B, Cinelli P, Radermacher P, Wanner GA, Simmen H-P, Gebhard F, Rittirsch D. Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma. J Crit Care. 2018;44:229–37.

    Article  PubMed  Google Scholar 

  27. McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, McCarthy MS, Davanos E, Rice TW, Cresci GA. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J Parenter Enteral Nutr. 2016;40(2):159–211.

    Article  CAS  PubMed  Google Scholar 

  28. Singer P, Blaser AR, Berger MM, Alhazzani W, Calder PC, Casaer MP, Hiesmayr M, Mayer K, Montejo JC, Pichard C. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48–79.

    Article  PubMed  Google Scholar 

  29. van Zanten ARH, De Waele E, Wischmeyer PE. Nutrition therapy and critical illness: practical guidance for the ICU, post-ICU, and long-term convalescence phases. Crit Care. 2019;23(1):1–10.

    Google Scholar 

  30. Osuka A, Kusuki H, Matsuura H, Shimizu K, Ogura H, Ueyama M. Acute intestinal damage following severe burn correlates with the development of multiple organ dysfunction syndrome: a prospective cohort study. Burns J Int Soc Burn Injuries. 2017;43(4):824–9.

    Article  Google Scholar 

  31. Blikslager AT, Moeser AJ, Gookin JL, Jones SL, Odle J. Restoration of barrier function in injured intestinal mucosa. Physiol Rev. 2007;87(2):545–64.

    Article  CAS  PubMed  Google Scholar 

  32. Slifer ZM, Blikslager AT. The integral role of tight junction proteins in the repair of injured intestinal epithelium. Int J Mol Sci. 2020;21(3):972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kuo WT, Shen L, Zuo L, Shashikanth N, Ong M, Wu L, Zha J, Edelblum KL, Wang Y, Wang Y, Nilsen SP, Turner JR. Inflammation-induced occludin downregulation limits epithelial apoptosis by suppressing caspase-3 expression. Gastroenterology. 2019;157(5):1323–37.

    Article  CAS  PubMed  Google Scholar 

  34. Poritz LS, Harris LR, Kelly AA, Koltun WA. Increase in the tight junction protein claudin-1 in intestinal inflammation. Dig Dis Sci. 2011;56:2802–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhu L, Han J, Li L, Wang Y, Li Y, Zhang S. Claudin family participates in the pathogenesis of inflammatory bowel diseases and colitis-associated colorectal cancer. Front Immunol. 2019;10:1441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lameris AL, Huybers S, Kaukinen K, Mäkelä TH, Bindels RJ, Hoenderop JG, Nevalainen PI. Expression profiling of claudins in the human gastrointestinal tract in health and during inflammatory bowel disease. Scand J Gastroenterol. 2013;48(1):58–69.

    Article  CAS  PubMed  Google Scholar 

  37. Mineta K, Yamamoto Y, Yamazaki Y, Tanaka H, Tada Y, Saito K, Tamura A, Igarashi M, Endo T, Takeuchi K. Predicted expansion of the claudin multigene family. FEBS Lett. 2011;585(4):606–12.

    Article  CAS  PubMed  Google Scholar 

  38. Weber CR, Nalle SC, Tretiakova M, Rubin DT, Turner JR. Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation. Lab Invest. 2008;88(10):1110–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cording J, Günther R, Vigolo E, Tscheik C, Winkler L, Schlattner I, Lorenz D, Haseloff RF, Schmidt-Ott KM, Wolburg H. Redox regulation of cell contacts by tricellulin and occludin: redox-sensitive cysteine sites in tricellulin regulate both tri-and bicellular junctions in tissue barriers as shown in hypoxia and ischemia. Antioxid Redox Signal. 2015;23(13):1035–49.

    Article  CAS  PubMed  Google Scholar 

  40. Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol. 2005;171(6):939–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Krug S, Bojarski C, Fromm A, Lee I, Dames P, Richter J, Turner J, Fromm M, Schulzke J. Tricellulin is regulated via interleukin-13-receptor α2, affects macromolecule uptake, and is decreased in ulcerative colitis. Mucosal Immunol. 2018;11(2):345–56.

    Article  CAS  PubMed  Google Scholar 

  42. Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012;42:71–8.

    Article  CAS  PubMed  Google Scholar 

  43. Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, Goldblum SE. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355(9214):1518–9.

    Article  CAS  PubMed  Google Scholar 

  44. Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016;4(4): e1251384.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Tripathi A, Lammers KM, Goldblum S, Shea-Donohue T, Netzel-Arnett S, Buzza MS, Antalis TM, Vogel SN, Zhao A, Yang S. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci. 2009;106(39):16799–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Klaus DA, Motal MC, Burger-Klepp U, Marschalek C, Schmidt EM, Lebherz-Eichinger D, Krenn CG, Roth GA. Increased plasma zonulin in patients with sepsis. Biochem Med. 2013;23(1):107–11.

    Article  CAS  Google Scholar 

  47. Moreno-Navarrete JM, Sabater M, Ortega F, Ricart W, Fernandez-Real JM. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PLoS ONE. 2012;7(5): e37160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Żak-Gołąb A, Kocełak P, Aptekorz M, Zientara M, Juszczyk Ł, Martirosian G, Chudek J, Olszanecka-Glinianowicz M. Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects. Int J Endocrinol. 2013;2013:1–9.

    Article  Google Scholar 

  49. Robinson BD, Tharakan B, Lomas A, Wiggins-Dohlvik K, Alluri H, Shaji CA. Jupiter D, Isbell CL (2020) Exploring blood–brain barrier hyperpermeability and potential biomarkers in traumatic brain injury. In: Baylor University Medical Center proceedings: 2020. Taylor & Francis, pp 199–204

  50. Blaser AR, Padar M, Mändul M, Elke G, Engel C, Fischer K, Giabicani M, Gold T, Hess B, Hiesmayr M, Jakob SM, Loudet CI, Meesters DM, Mongkolpun W, Paugam-Burtz C, Poeze M, Preiser JC, Renberg M, Rooijackers O, Tamme K, Wernerman J, Starkopf J. Development of the gastrointestinal dysfunction score (GIDS) for critically ill patients—a prospective multicenter observational study (iSOFA study). Clin Nutr. 2021;40(8):4932–40.

    Article  Google Scholar 

Download references

Funding

This work was funded by the Scientific Research Projects Coordination Unit of Erciyes University (Project ID: 8633).

Author information

Authors and Affiliations

  1. Department of Medical Biology, Medical Faculty, Erciyes University, 38030, Kayseri, Turkey

    Hamiyet Donmez-Altuntas, Pinar Altin-Celik, Hamiyet Eci̇roglu & Ramazan Uzen

  2. Division of Intensive Care Medicine, Department of Internal Medicine, Medical Faculty, Erciyes University, 38030, Kayseri, Turkey

    Serap Sahin Ergul, Kadir Bulut, Gulsah Gunes Sahin, Nurhayat Tugra Ozer, Sahin Temel, Recep Civan Yuksel, Murat Sungur & Kursat Gundogan

  3. 100/2000 CoHE PhD Scholarship Program, Institute of Health Sciences, 38030, Kayseri, Turkey

    Serap Sahin Ergul, Pinar Altin-Celik, Ramazan Uzen, Gulsah Gunes Sahin & Nurhayat Tugra Ozer

  4. Health Services Vocational School, Alanya Alaaddin Keykubat University, 07425, Antalya, Turkey

    Hamiyet Eci̇roglu

  5. Department of Nutrition and Dietetics, School of Health Sciences, Cappadocia University, 50000, Nevşehir, Turkey

    Gulsah Gunes Sahin

  6. Department of General Surgery, Medical Faculty, Erciyes University, 38030, Kayseri, Turkey

    Turkmen Bahadir Arikan

  7. Department of Anaesthesiology and Reanimation, Medical Faculty, Erciyes University, 38030, Kayseri, Turkey

    Aliye Esmaoglu

Authors
  1. Hamiyet Donmez-Altuntas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Serap Sahin Ergul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pinar Altin-Celik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kadir Bulut
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hamiyet Eci̇roglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ramazan Uzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gulsah Gunes Sahin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nurhayat Tugra Ozer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sahin Temel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Turkmen Bahadir Arikan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Aliye Esmaoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Recep Civan Yuksel
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Murat Sungur
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kursat Gundogan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HD-A, SSE, PA-C, KB, HE, RU and KG: conception, design, and development of the study; acquisition, analysis and interpretation of the data; interpretation of results and writing and critical review of the manuscript. GGS, NTO, ST, TBA, AE, RCY and MS: acquisition, analysis, and interpretation of the data; writing and critical review of the manuscript.

Corresponding author

Correspondence to Hamiyet Donmez-Altuntas.

Ethics declarations

Conflict of interest

All the authors declare that they have no competing interests.

Ethics approval

Study design and protocol were approved by the University Medical Faculty Research Ethics Committee (No. 2018/525).

Consent for publication

Written informed consent for the use of blood samples was obtained from each patient (or a relative of the patient) and healthy volunteers before the collection of blood samples.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 714 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Donmez-Altuntas, H., Sahin Ergul, S., Altin-Celik, P. et al. Gut barrier protein levels in serial blood samples from critically ill trauma patients during and after intensive care unit stay. Eur J Trauma Emerg Surg 49, 2203–2213 (2023). https://doi.org/10.1007/s00068-023-02298-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00068-023-02298-6

Keywords

Search

Navigation