Application of Intestinal Barrier Molecules in the Diagnosis of Acute Cellular Rejection After Intestinal Transplantation

Overview

Journal Transpl Int

Specialty General Surgery

Date 2023 Sep 25

PMID 37745643

Authors

Yun Chen

Sheng-Hong Tseng

Chih-Yen Chen

Ya-Hui Tsai

Affiliations

Soon will be listed here.

Abstract

Diagnosing acute rejection after intestinal transplantation currently heavily relies on histopathological analysis of graft biopsies. However, the invasive risks associated with ileoscopic examination and the inaccessibility for biopsy after ileostomy closure hinder real-time detection of rejection responses. Molecules comprising the intestinal barrier have been identified as physiological and molecular biomarkers for various bowel conditions and systemic diseases. To investigate the potential of barrier function-related molecules in diagnosing rejection after intestinal transplantation, plasma samples were collected longitudinally from transplant recipients. The samples were categorized into "indeterminate for rejection (IND)" and "acute rejection (AR)" groups based on clinical diagnoses at each time point. The longitudinal association between plasma levels of these barrier function-related molecules and acute rejection was analyzed using the generalized estimating equations (GEE) method. Logistic GEE models revealed that plasma levels of claudin-3, occludin, sIgA, and zonulin were independent variables correlated with the clinical diagnosis of acute rejection. The subsequent prediction model demonstrated moderate ability in discriminating between IND and AR samples, with a sensitivity of 76.0%, specificity of 89.2%, and accuracy of 84.6%. In conclusion, monitoring plasma levels of claudin-3, occludin, sIgA, and zonulin shows great potential in aiding the diagnosis of acute rejection after intestinal transplantation.

References

Genser L, Aguanno D, Soula H, Dong L, Trystram L, Assmann K . Increased jejunal permeability in human obesity is revealed by a lipid challenge and is linked to inflammation and type 2 diabetes. J Pathol. 2018; 246(2):217-230. DOI: 10.1002/path.5134. View

Lu Z, Ding L, Lu Q, Chen Y . Claudins in intestines: Distribution and functional significance in health and diseases. Tissue Barriers. 2014; 1(3):e24978. PMC: 3879173. DOI: 10.4161/tisb.24978. View

Carroll R . Endoscopic Follow-up of Intestinal Transplant Recipients. Gastroenterol Clin North Am. 2018; 47(2):381-391. DOI: 10.1016/j.gtc.2018.01.012. View

Konig J, Wells J, Cani P, Garcia-Rodenas C, MacDonald T, Mercenier A . Human Intestinal Barrier Function in Health and Disease. Clin Transl Gastroenterol. 2016; 7(10):e196. PMC: 5288588. DOI: 10.1038/ctg.2016.54. View

Luettig J, Rosenthal R, Barmeyer C, Schulzke J . Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. Tissue Barriers. 2015; 3(1-2):e977176. PMC: 4372021. DOI: 10.4161/21688370.2014.977176. View

Qi Y, Goel R, Kim S, Richards E, Carter C, Pepine C . Intestinal Permeability Biomarker Zonulin is Elevated in Healthy Aging. J Am Med Dir Assoc. 2017; 18(9):810.e1-810.e4. PMC: 5581307. DOI: 10.1016/j.jamda.2017.05.018. View

Thoo L, Noti M, Krebs P . Keep calm: the intestinal barrier at the interface of peace and war. Cell Death Dis. 2019; 10(11):849. PMC: 6838056. DOI: 10.1038/s41419-019-2086-z. View

Pietrzak B, Tomela K, Olejnik-Schmidt A, Mackiewicz A, Schmidt M . Secretory IgA in Intestinal Mucosal Secretions as an Adaptive Barrier against Microbial Cells. Int J Mol Sci. 2020; 21(23). PMC: 7731431. DOI: 10.3390/ijms21239254. View

Kim J, Heo J, Baek K, Kim S, Kim J, Baek K . Zonulin level, a marker of intestinal permeability, is increased in association with liver enzymes in young adolescents. Clin Chim Acta. 2018; 481:218-224. DOI: 10.1016/j.cca.2018.03.005. View

10.

Lansing M, Turner J, Wizzard P, Lavallee C, Lim D, Muto M . Plasma citrulline is not a biomarker for intestinal adaptation in short bowel syndrome, studied in piglets: a model for human neonates. Pediatr Surg Int. 2019; 35(6):657-663. DOI: 10.1007/s00383-019-04475-4. View

11.

Tang Y, Clayburgh D, Mittal N, Goretsky T, Dirisina R, Zhang Z . Epithelial NF-kappaB enhances transmucosal fluid movement by altering tight junction protein composition after T cell activation. Am J Pathol. 2009; 176(1):158-67. PMC: 2797878. DOI: 10.2353/ajpath.2010.090548. View

12.

Arsenescu R, Bruno M, Rogier E, Stefka A, McMahan A, WRIGHT T . Signature biomarkers in Crohn's disease: toward a molecular classification. Mucosal Immunol. 2008; 1(5):399-411. DOI: 10.1038/mi.2008.32. View

13.

Atreya R, Neurath M . IBD pathogenesis in 2014: Molecular pathways controlling barrier function in IBD. Nat Rev Gastroenterol Hepatol. 2014; 12(2):67-8. DOI: 10.1038/nrgastro.2014.201. View

14.

Lauro A, Marino I, Matsumoto C . Advances in allograft monitoring after intestinal transplantation. Curr Opin Organ Transplant. 2016; 21(2):165-70. DOI: 10.1097/MOT.0000000000000279. View

15.

Vanuytsel T, Vermeire S, Cleynen I . The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease. Tissue Barriers. 2014; 1(5):e27321. PMC: 3943850. DOI: 10.4161/tisb.27321. View

16.

Wu Y, Kudsk K, DeWitt R, Tolley E, Li J . Route and type of nutrition influence IgA-mediating intestinal cytokines. Ann Surg. 1999; 229(5):662-7; discussion 667-8. PMC: 1420810. DOI: 10.1097/00000658-199905000-00008. View

17.

Pappas P, Tzakis A, Gaynor J, Carreno M, Ruiz P, Huijing F . An analysis of the association between serum citrulline and acute rejection among 26 recipients of intestinal transplant. Am J Transplant. 2004; 4(7):1124-32. DOI: 10.1111/j.1600-6143.2004.00469.x. View

18.

Loo L, Vrakas G, Reddy S, Allan P . Intestinal transplantation: a review. Curr Opin Gastroenterol. 2017; 33(3):203-211. DOI: 10.1097/MOG.0000000000000358. View

19.

Kuo W, Shen L, Zuo L, Shashikanth N, Ong M, Wu L . Inflammation-induced Occludin Downregulation Limits Epithelial Apoptosis by Suppressing Caspase-3 Expression. Gastroenterology. 2019; 157(5):1323-1337. PMC: 6815722. DOI: 10.1053/j.gastro.2019.07.058. View

20.

Bischoff S, Barbara G, Buurman W, Ockhuizen T, Schulzke J, Serino M . Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol. 2014; 14:189. PMC: 4253991. DOI: 10.1186/s12876-014-0189-7. View