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©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Human small intestine is capable of restoring barrier function after short ischemic periods
Dirk HSM Schellekens, Inca HR Hundscheid, Claire AJI Leenarts, Joep Grootjans, Kaatje Lenaerts, Wim A Buurman, Cornelis HC Dejong, Joep PM Derikx
Dirk HSM Schellekens, Inca HR Hundscheid, Claire AJI Leenarts, Kaatje Lenaerts, Cornelis HC Dejong, Joep PM Derikx, Department of Surgery, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
Dirk HSM Schellekens, Inca HR Hundscheid, Claire AJI Leenarts, Joep Grootjans, Kaatje Lenaerts, Wim A Buurman, Cornelis HC Dejong, Joep PM Derikx, NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
Joep Grootjans, Department of Gastroenterology, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands
Wim A Buurman, MHeNs School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
Joep PM Derikx, Pediatric Surgical Center of Amsterdam, Emma Children's Hospital Academic Medical Center and VU University Medical Center, Amsterdam 1100 DE, the Netherlands
Author contributions: Schellekens DHSM, Hundscheid IHR, Grootjans J and Buurman WA developed the concept and designed experiments; Schellekens DHSM, Hundscheid IHR and Leenarts CAJI contributed to acquisition of the data and carried out most of the experiments; Schellekens DHSM, Hundscheid IHR, Grootjans J, Lenaerts K, Buurman WA, Dejong CHC and Derikx JPM analyzed and interpreted the data; Schellekens DHSM, Hundscheid IHR and Grootjans J wrote the paper; Buurman WA, Dejong CHC. and Derikx JPM revised the manuscript critically for important intellectual content.; all authors have read and approved the final manuscript
Supported by Dutch Digestive Foundation (MLDS grant WO10-57 to Dejong CHC and Lenaerts K) and MLDS Career development grant CDG13-14 to Derikx JPM); the Netherlands Organisation for Scientific Research (Rubicon grant 2013/07161/ALW to Grootjans J).
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Committee of the Maastricht University Medical Center.
Informed consent statement: All study participants, or their legal guardian, provided written consent prior to study enrollment.
Conflict-of-interest statement: No conflicts of interest exist.
Data sharing statement: Technical appendix, statistical code, and dataset is available from the corresponding author. Informed consent for data sharing was not obtained but the presented data are anonymized and risk of identification is low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
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Received: April 25, 2017
Peer-review started: April 25, 2017
First decision: May 9, 2017
Revised: August 8, 2017
Accepted: August 15, 2017
Article in press: August 15, 2017
Published online: December 28, 2017
Processing time: 246 Days and 9.1 Hours
AIM
To assess intestinal barrier function during human intestinal ischemia and reperfusion (IR).
METHODS
In a human experimental model, 6 cm of jejunum was selectively exposed to 30 min of ischemia (I) followed by 30 and 120 min of reperfusion (R). A sham procedure was also performed. Blood and tissue was sampled at all-time points. Functional barrier function was assessed using dual-sugar absorption tests with lactulose (L) and rhamnose (R). Plasma concentrations of citrulline, an amino acid described as marker for enterocyte function were measured as marker of metabolic enterocytes restoration. Damage to the epithelial lining was assessed by immunohistochemistry for tight junctions (TJs), by plasma marker for enterocytes damage (I-FABP) and analyzed by electron microscopy (EM) using lanthanum nitrate as an electrondense marker.
RESULTS
Plasma L/R ratio’s were significantly increased after 30 min of ischemia (30I) followed by 30 min of reperfusion (30R) compared to control (0.75 ± 0.10 vs 0.20 ± 0.09, P < 0.05). At 120 min of reperfusion (120R), ratio’s normalized (0.17 ± 0.06) and were not significantly different from control. Plasma levels of I-FABP correlated with plasma L/R ratios measured at the same time points (correlation: 0.467, P < 0.01). TJs staining shows distortion of staining at 30I. An intact lining of TJs was again observed at 30I120R. Electron microscopy analysis revealed disrupted TJs after 30I with paracellular leakage of lanthanum nitrate, which restored after 30I120R. Furthermore, citrulline concentrations closely paralleled the histological perturbations during intestinal IR.
CONCLUSION
This study directly correlates histological data with intestinal permeability tests, revealing that the human gut has the ability of to withstand short episodes of ischemia, with morphological and functional recovery of the intestinal barrier within 120 min of reperfusion.
Core tip: Using an unique experiment human intestinal ischemia and reperfusion (IR) model, this is the first study to directly correlate histological data with intestinal permeability tests. The results reveal the ability of the intestine to withstand short episodes of ischemia, with morphological and functional recovery of the intestinal barrier within 120 min of reperfusion. These results explain why there are often no signs of inflammation or bacterial translocation after short periods of intestinal ischemia. Exploration of the mechanisms responsible for this rapid recovery might impact understanding and treatment of intestinal diseases. Data from the dual-sugar absorption tests and citrulline reflect the histological perturbations during intestinal IR, highlighting the potential diagnostic value of these tests in patients with intestinal diseases associated with intestinal barrier loss.
