Highlights

• • Endogenous phenethylamine (PEA) levels are significantly elevated in IBS-D mice and correlate with diarrhea severity.
• • Exogenous PEA exacerbates diarrhea phenotypes, intestinal inflammation, and barrier dysfunction.
• • PEA disrupts tight junction protein expression and promotes proinflammatory cytokine release in the colon.
• • Activation of the colonic TAAR1-PKC signaling pathway mediates PEA-induced pathological effects.
• • Pharmacological blockade of TAAR1 with EPPTB partially attenuates PEA-driven inflammation and barrier impairment.

Conclusions: This ALE meta-analysis identified functionally impaired brain regions consistently altered in IBS-D, providing novel insights into its central mechanisms and potential targets for future research and therapeutic interventions.