Polysaccharide from Atractylodes macrocephala Koidz. alleviates pyrotinib-induced diarrhea through regulating cAMP/LKB1/AMPK/CFTR pathway and restoring gut microbiota and metabolites.

Polysaccharide from Atractylodes macrocephala Koidz. (PAMK), a bioactive component of Atractylodes macrocephala Koidz. (AMK), demonstrates a wide range of pharmacological activities, including the enhancement of gastrointestinal function and regulation of internal homeostasis. This study explores the potential of PAMK in alleviating pyrotinib-induced diarrhea and modulating gut microbiota and its metabolites. Pyrotinib is a tyrosine kinase inhibitor used in cancer treatment, is known for its side effect of diarrhea, which significantly diminishes patients' quality of life. Our prior research suggests that pyrotinib-induced diarrhea may be linked to CFTR-mediated dysregulation of chloride secretion. The present findings indicate that PAMK alleviates pyrotinib-induced diarrhea by reducing cAMP levels, activating the LKB1/AMPK pathway, and inhibiting CFTR activity, as confirmed by enzyme-linked immunosorbent assay (ELISA), qRT-PCR, and western blot analyses. PAMK effectively decreased CFTR-mediated chloride ion secretion in pyrotinib-treated cells, as shown by the MQAE assay. At specific doses, PAMK alleviated pyrotinib-induced diarrhea in rats and significantly restored intestinal barrier integrity. Furthermore, PAMK treatment rebalanced the gut microbiota, reversing the pyrotinib-induced increase in Clostridium and Erysipelotrichi species. Metabolomic profiling further highlighted the involvement of the AMPK signaling pathway. These findings provide a basis for future research aimed at developing cancer treatments with reduced side effects.