Abstract
Endoplasmic reticulum (ER) stress is caused by accumulation of unfolded and misfolded proteins in the ER, thereby compromising its vital cellular functions in protein production and secretion. Genome wide association studies in humans as well as experimental animal models linked ER stress in intestinal epithelial cells (IECs) with intestinal disorders including inflammatory bowel diseases. However, the mechanisms linking the outcomes of ER stress in IECs to intestinal disease have not been clarified. In this study, we investigated the impact of ER stress on intestinal epithelial barrier function using human colon carcinoma-derived Caco-2 monolayers. Tunicamycin-induced ER stress decreased the trans-epithelial electrical resistance of Caco-2 monolayers, concomitant with loss of cellular plasma membrane integrity. Epithelial barrier disruption in Caco-2 cells after ER stress was not caused by caspase- or RIPK1-dependent cell death but was accompanied by lysosomal rupture and up-regulation of the ER stress markers Grp78, sXBP1 and Chop. Interestingly, several bifidobacteria species inhibited tunicamycin-induced ER stress and thereby diminished barrier disruption in Caco-2 monolayers. Together, these results showed that ER stress compromises the epithelial barrier function of Caco-2 monolayers and demonstrate beneficial impacts of bifidobacteria on ER stress in IECs. Our results identify epithelial barrier loss as a potential link between ER stress and intestinal disease development, and suggest that bifidobacteria could exert beneficial effects on this phenomenon.
Highlights
Intestinal immune homeostasis is maintained by multiple signalling pathways acting in intestinal epithelial cells (IECs) to preserve epithelial permeability
Different concentrations of the endoplasmic reticulum (ER) stress inducer tunicamycin (TM) were added to fully differentiated Caco-2 monolayers. While both vehicle treatment and 1 μg/ml TM did not cause a significant disruption of Caco-2 monolayer integrity during 48 hours of incubation, a concentration of 10 μg/ml of TM resulted in a gradual decrease of epithelial integrity to 32% of the initial trans-epithelial electrical resistance (TEER) value after 48 hours (Fig 1A)
When Caco-2 monolayers were pretreated with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), the TM-induced TEER decrease was significantly inhibited to 57% of the original TEER value after 48 hours (Fig 1B)
Summary
Intestinal immune homeostasis is maintained by multiple signalling pathways acting in intestinal epithelial cells (IECs) to preserve epithelial permeability. ER stress is caused by accumulating misfolded proteins, which induces signalling pathways that collectively initiate the unfolded protein response (UPR) attempting to restore protein folding, increase ER biosynthetic machinery and maintain cellular homeostasis.[3, 4] excessive ER stress can lead to failure in protein secretion, cell injury or even cell death,[5] all of which can contribute to disrupting intestinal homeostasis.[6] genetic polymorphisms in the UPR transcription factor X-box binding protein (XBP)-1 predisposes to IBD development.[7] In accordance with this potential pathologic role for ER stress in human intestinal diseases, elevated ER stress was detected in IECs from IBD as well as NEC patients.[8,9,10,11] These observations in patients suggesting ER stress involvement in intestinal disease pathogenesis were confirmed in multiple experimental mouse models showing a causative role for ER stress in intestinal inflammation.[7, 8, 12,13,14,15,16,17] In addition, administration of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) was shown to ameliorate various models of colitis in mice.[13, 15, 18] the cellular outcomes of ER stress in human IECs and the underlying mechanisms regulating these effects are not fully understood
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