Neonatal Injury Increases Gut Permeability by Epigenetically Suppressing E-Cadherin in Adulthood

Area of Science:

• Gastroenterology
• Immunology
• Molecular Biology

Background:

• Altered intestinal epithelial integrity is a key factor in inflammatory bowel disease (IBD) susceptibility.
• Early life stressors are linked to increased IBD risk in adulthood.

Purpose of the Study:

• To investigate the mechanisms by which early-life trauma exacerbates IBD in adulthood.
• To explore the molecular pathways underlying aggravated mucosal injury in a "double-hit" neonatal inflammation (NI) and adult inflammation (AI) rat model.

Main Methods:

• Utilized a "double-hit" NI + AI rat model to study sustained colonic permeability and E-cadherin expression.
• Employed quantitative RT-PCR and microRNA microarrays to identify gene and microRNA expression changes.
• Investigated epigenetic modifications, including histone acetylation and RNA polymerase II binding at the Mir155 promoter.
• Performed in vitro knockdown and overexpression studies, and in vivo treatment with a miR-155 inhibitor.

Main Results:

• NI + AI rats exhibited sustained increases in colonic permeability and decreased E-cadherin expression.
• Cdh1 mRNA levels were reduced, and miR-155 was significantly overexpressed in NI + AI rats.
• Histone hyperacetylation and increased RNA polymerase II binding were observed at the Mir155 promoter.
• miR-155 mimics increased permeability and decreased E-cadherin; miR-155 inhibition reversed NI + AI-induced permeability.

Conclusions:

• Early-life inflammatory stressors induce sustained epithelial injury by suppressing E-cadherin.
• Epigenetic mechanisms, specifically miR-155 upregulation via histone hyperacetylation, mediate this suppression.
• Targeting miR-155 offers a potential therapeutic strategy for IBD linked to early-life stress.