Effect of glucocorticoid production by the enteric nervous system on neuronal connectivity is blocked during inflammation in a GR-dependent pathway.

Glucocorticoid (GC) extra-adrenal synthesis plays a central role in maintaining local homeostasis. However, whether GCs can be synthesized by the enteric nervous system (ENS), a key regulator of gut function, and how it might affect its function remain unexplored. In this study, we used primary rat ENS cultures to determine whether local GC production occurs within the ENS and to evaluate its functional impact under both basal and inflammatory conditions. First, we demonstrated that the primary ENS cultures, especially enteric glial cells, produce GCs from 11-dehydrocorticosterone (11DHC) through the regeneration pathway. Second, 11DHC treatment significantly increased the expression and density of key molecules associated with neuronal connectivity in a glucocorticoid receptor (GR)-dependent manner. Finally, inflammation blocked the 11DHC-induced enhancement of connectivity molecule expression and was associated with a reduced pGR-232/pGR-246 ratio. Our study demonstrates that GCs locally produced by the ENS enhance enteric connectivity via a GR-dependent mechanism, which is abolished under inflammatory conditions.