Intestinal
ischemia/reperfusion (I/R) induces disruption of the intestinal barrier function. Aryl
hydrocarbon receptor (AhR) has a vital role in maintaining the intestinal barrier function. However, the precise mechanism by which AhR maintains intestinal barrier function remains unclear. Notch1 signaling is downstream of AhR, and has also been reported to have a role in the development of tight junctions (TJs) and maintenance of intestinal homeostasis. Therefore, we hypothesized that AhR activation may attenuate the intestinal barrier dysfunction through increased activation of Notch1 signaling. Adult C57BL/6J mice were divided into three groups:
Sham, I/R and I/R + 6-formylindolo(3,2-b)carbazole (
Ficz) groups. Mice were sacrificed after I/R for 6 h and the intestine was harvested for histological examination,
mRNA and
protein content analysis, and mucosal permeability investigation. Additionally, a hypoxic Caco‑2 cell culture model was used to evaluate the role of AhR‑Notch1 signaling in the development of TJs and epithelial permeability in vitro. The AhR‑Notch1 signaling components and TJ
proteins were assessed by reverse transcription‑quantitative polymerase chain reaction, western blotting, immunohistochemistry or immunofluorescence staining. Epithelial permeability was detected by transepithelium electrical resistance. The data demonstrated that
Ficz significantly attenuated the intestinal tissue damage and the disrupted distribution of TJs, increased the expression of TJ
proteins, reversed the decrease in TER and upregulated epithelial Notch1 signaling following intestinal I/R in vivo and
hypoxia in vitro. Furthermore, inhibition of Notch1 signaling by N‑[N‑(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl
ester (inhibitor of Notch signaling) counteracted the effects of
Ficz on the development of TJs in hypoxic Caco‑2 cells. In conclusion, AhR activation ameliorated epithelial barrier dysfunction following intestinal I/R and
hypoxia through upregulation of Notch1 signaling, which suggests that AhR may be a potential pharmaceutical agent to combat this condition.