Cannabinoid receptor type 1 in the aging gut regulates the mucosal permeability via miR-191-5p

Aging is associated with a broad loss of function throughout the body, and gastrointestinal (GI) dysfunction can occur with aging. The endocannabinoid (eCB) system plays a pivotal role in various GI diseases, and alterations in the eCB system have been observed during brain and skin aging. Therefore, we investigated the putative role of the eCB system in aging-related changes in the intestine.

The expression of cannabinoid receptor type 1 (CB₁) was investigated in rat intestinal tissues using quantitative real-time PCR. Cellular senescence was induced by hydrogen peroxide (H₂O₂) and hydroxyurea (HU) in rat and human intestinal epithelial cells. Cellular permeability was evaluated by transepithelial electrical resistance (TEER) measurement.

The expression of CB₁ was decreased in the small intestine of aged rats compared to that of young rats. Senescent cells showed reduced TEER values and decreased expression of ZO-1, indicating increased intestinal permeability, which is tightly regulated by the CB₁ signaling. In silico miRNA analysis suggested that ZO-1 was a direct target gene of miR-191-5p. Increased expression of miR-191-5p by HU was restored by CB₁ agonist ACEA co-treatment. Moreover, NF-κB p65 activation was associated with CB₁-related miR-191-5p signaling. In conclusion, aging-induced CB₁ reduction leads to increased intestinal permeability and decreased ZO-1 expression via upregulation of miR-191-5p and NF-κB p65 activation. Taken together, these results suggest that CB₁ signaling may be a useful strategy to reduce intestinal permeability in aging-related and other inflammatory conditions in the gut.