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

  • Int J Biol Macromol. 2025 May;308(Pt 3):142512. doi: 10.1016/j.ijbiomac.2025.142512.
Pancen Ran  1 ,  Fengxian Jiang  2 ,  Liying Pan  3 ,  Yang Shu  3 ,  Fangyan Hu  4 ,  Yahui Wang  3 ,  Rui Zhao  5 ,  Weihao Wang  5 ,  Huaiqian Mu  5 ,  Juqiong Wang  4 ,  Jian Wei  6 ,  Guobin Fu  7
Affiliations
  • 1. Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, China.
  • 2. Department of Radiation Oncology, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan 250031, China.
  • 3. The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, China.
  • 4. School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China.
  • 5. Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 6. School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China. Electronic address: [email protected].
  • 7. Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, China; Department of Medical Oncology, The Third Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250031, China. Electronic address: [email protected].
PMID: 40157659 DOI: 10.1016/j.ijbiomac.2025.142512
Abstract

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.

Keywords
CFTR; Gut microbiota; Metabolites; Polysaccharide from Atractylodes macrocephala Koidz.; Pyrotinib-induced diarrhea.
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