Genome-wide analysis of Ischaemia-Reperfusion damage in human bowel

Comprehensive understanding of the transcriptional foundations of human intestinal ischemia-reperfusion (IR) injury is imperative to find therapeutic targets and improve patient outcome. Here we analysed transcriptomes of the IR-injured human intestine, and showed that over 1,800 genes were significantly differentially expressed, predominantly during reperfusion. Intriguingly, protein processing in endoplasmic reticulum (ER) was one of the most perturbed pathways, which was supported by ontology analysis. The IR-triggered transcriptome is organized into distinct co-expression networks, and implied a role for HIF1-alpha in the response towards unfolded proteins. Unfolded protein response activation as a consequence of ER stress was further validated in a large sample set, revealing strong correlations between expression of ER stress genes IRE1, XBP1 and BiP and autophagy gene LC3B. Moreover, signs of ER stress and autophagy, particularly ER phagy, were apparent in Paneth cells. Collectively, these findings provide new evidence for key involvement of protein folding stress in IR-induced intestinal injury in man. The ensuing ER stress, together with its manifestations in Paneth cells, likely contributes to IR-induced complications including bacterial penetration and inflammation. Total RNA obtained from jejunal segments subjected to 45-60 minutes of ischaemia or following 30 minutes or 120 minutes of reperfusion, or control segments, during a Whipple surgery procedure. This work was supported by the Dutch Society for Gastroenterology (Gastrostart grant 2009-23 9 to K. Lenaerts).