Psychological Stress Disrupts Goblet Cell Function and Intestinal Barrier via 5-HT/HTR7-Mediated NLRP6 and Autophagy Suppression

Psychological stress is closely associated with intestinal barrier dysfunction, yet the underlying mechanisms remain incompletely understood. Here, using a 14-day restraint stress mouse model and an HT-29 cell model, we demonstrate that stress-induced elevation of serotonin (5-HT) disrupts intestinal mucosal barrier function through the 5-HT/HTR7/PPAR-γ/NLRP6/autophagy axis. Restraint stress significantly increased 5-HT levels in serum and intestinal tissues, accompanied by reduced goblet cell numbers, impaired mucin 2 secretion, and increased intestinal permeability. Mechanistically, 5-HT acts via HTR7 to downregulate PPAR-γ, which transcriptionally controls NLRP6, thereby suppressing NLRP6 inflammasome activity and autophagy. Pharmacological inhibition of 5-HT synthesis with PCPA or activation of PPAR-γ with rosiglitazone reversed these pathological phenotypes in vivo, and the 5-HT/HTR7/PPAR-γ axis was further validated in vitro. These findings establish a novel downstream mechanism linking psychological stress to NLRP6 inflammasome dysfunction, impaired autophagy, defective goblet cell function, and intestinal mucosal barrier damage.