Euphorbia pekinensis glycosphingolipids disrupt gut motility and fluid balance via TRPA1 activation in enterochromaffin cells

Background and purpose Euphorbia pekinensis (EP) is known to cause significant intestinal toxicity, primarily manifesting as severe diarrhoea, yet the precise molecular mechanisms and the active components responsible have remained elusive. This study aimed to identify the diarrheal constituents of EP and elucidate the molecular pathway through which they induce gut toxicity. Experimental Approach The laxative effects of EP components were assessed in vivo using mouse models and diarrhoea‐related indicators, with histological analysis of intestinal tissue. Ex vivo rabbit intestinal tract assays were employed to study smooth muscle contraction. The underlying mechanism was investigated using intestinal organoid fluorescence co‐localization and analysis of tryptophan metabolites in mice to determine the role of enterochromaffin (EC) cells and serotonin (5‐HT). Key Results We identified specific glycosphingolipids (GSLs), including a novel hexosylceramide (HexCer), as the primary toxic agents in EP. These GSLs act as direct agonists of the TRPA1 ion channel on intestinal EC cells. This activation triggers a TRPA1‐mediated influx of Ca 2+ into EC cells, leading to excessive 5‐HT release. The resulting localized overstimulation of 5‐HT receptors causes aberrant intestinal smooth muscle contraction and epithelial hypersecretion, culminating in severe diarrhoea. Conclusion and Implications This research reveals that the gut toxicity of EP is driven by a previously unrecognized GSL–TRPA1–5‐HT signalling pathway in the intestinal epithelium. These findings provide a clear mechanistic basis for EP‐induced diarrhoea and highlight a potential new target for managing gut toxicity.