A Natural TMEM16A Inhibitor with Conformational Lock Mechanism: Thymol Reverses Secretory Diarrhea via Chloride Flux Regulation and Antiinflammatory

Secretory diarrhea is characterized by excessive production of electrolytes and water by intestinal epithelial cells, resulting in persistent watery stools. This study suggested that abnormal activation of TMEM16A might contribute to its pathogenesis. A drug screening identified thymol, a natural product, as a significant inhibitor of TMEM16A channel activity. Thymol induced a conformational change in the TM3-TM6 helices by interacting with the amino acid residues K603, E633, and V543, which reduced the ionic pore size of TMEM16A to less than 3 Å and inhibited chloride transport across the membrane. In a mouse model of secretory diarrhea induced by senna, thymol significantly alleviated diarrhea symptoms by reducing intestinal smooth muscle contractions. Both cellular and mouse experiments indicated that thymol mitigated diarrhea by regulating chloride ion secretion and suppressing inflammation, and it exhibited no toxicity to normal intestinal cells or mice. Therefore, this study concluded that thymol targeted TMEM16A to treat secretory diarrhea through a dual mechanism and represented a safe and effective therapeutic candidate for diarrhea. This work provided a foundation for the development of antidiarrheal natural drugs.