Females Are More Resistant to Ischemia-Reperfusion-induced Intestinal Injury Than Males A Human Study

Inca H. R. Hundscheid, Dirk H. S. M. Schellekens, Joep Grootjans, Joep P. M. Derikx, Wim A. Buurman, Cornelis H. C. Dejong, Kaatje Lenaerts*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background and Objective: Sex differences in responses to intestinal ischemia-reperfusion (IR) have been recognized in animal studies. We aimed to investigate sexual dimorphism in human small intestinal mucosal responses to IR. Methods: In 16 patients (8 men and 8 women) undergoing pancreaticoduodenectomy, an isolated part of jejunum was subjected to IR. In each patient, intestinal tissue and blood was collected directly after 45 minutes of ischemia without reperfusion (45I-0R), after 30 minutes of reperfusion (45I-30R), and after 120 minutes of reperfusion (45I-120R), as well as a control sample not exposed to IR, to assess epithelial damage, unfolded protein response (UPR) activation, and inflammation. Results: More extensive intestinal epithelial damage was observed in males compared to females. Intestinal fatty acid binding protein (I-FABP) arteriovenous (V-A) concentrations differences were significantly higher in males compared to females at 45I-0R (159.0 [41.0-570.5] ng/mL vs 46.9 [0.3-149.9] ng/mL). Male intestine showed significantly higher levels of UPR activation than female intestine, as well as higher number of apoptotic Paneth cells per crypt at 45I-30R (16.4% [7.1-32.1] vs 10.6% [0.0-25.4]). The inflammatory response in male intestine was significantly higher compared to females, with a higher influx of neutrophils per villus at 45I-30R (4.9 [3.1-12.0] vs 3.3 [0.2-4.5]) and a higher gene expression of TNF-alpha and IL-10 at 45I-120R. Conclusion: The human female small intestine seems less susceptible to IR-induced tissue injury than the male small intestine. Recognition of such differences could lead to the development of novel therapeutic strategies to reduce IR-associated morbidity and mortality.

Original languageEnglish
Pages (from-to)1070-1079
Number of pages10
JournalAnnals of Surgery
Issue number6
Publication statusPublished - Dec 2020


  • apoptosis
  • endoplasmic reticulum stress
  • female resistance
  • inflammation
  • ischemia


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