Scientists at Northwestern University have made a molecular discovery that explains how fluid balance is regulated in the intestines, potentially paving the way for more effective treatments for constipation and diarrhea.
اضافة اعلان
Although constipation and diarrhea appear to be opposite conditions, they share a common underlying cause: the amount of fluid reaching the intestines. Until now, scientists did not fully understand the mechanisms that maintain fluid balance in the digestive system.
In the new study, the research team focused on bisacodyl, one of the most widely used laxatives in the world, and discovered that its effect relies on an ion channel called TRPM4, which acts as a key regulator of fluid flow in the intestines.
Juan Du, a co-author of the study, said: “Although bisacodyl has been used clinically for over 60 years, its precise molecular target was unknown. We have clarified its mechanism at the atomic level and gained a comprehensive understanding of its effects on the intestines.”
Wei Lu from Northwestern University added: “Our results demonstrate the role of TRPM4 as a central regulator of intestinal fluid balance, identify a new drug target, and provide a roadmap for developing next-generation therapies for gastrointestinal disorders.”
How the TRPM4 Channel Works
TRPM4 is important in the epithelial cells lining the intestinal wall, controlling the movement of salts and water. When activated by bisacodyl, sodium ions flow into the cells, which in turn activates the chloride channel—an ion channel that allows chloride ions to move from the cells into the intestinal lumen. This ion flow naturally draws water along with it, producing a laxative effect and helping move fluids through the intestines.
While scientists previously knew that TRPM4 responds to intracellular calcium signals, the team discovered that bisacodyl activates the channel independently of calcium. Using cryogenic electron microscopy, they identified a new molecular pocket where the drug binds and activates the channel.
To confirm the channel’s role, the researchers tested bisacodyl on genetically modified mice lacking TRPM4. In normal mice, the drug increased water content in the stool, making it softer, while in the modified mice, it had no effect.
Significance of the Discovery
This finding represents a major advance in understanding how intestinal fluid balance is regulated and offers opportunities to develop precise drugs to treat chronic constipation or diarrhea. The research builds on years of intensive studies of TRPM4, which have revealed how the channel is structured, how it opens and closes, how temperature affects its function, and how it interacts with drugs.
The study’s results were published in Nature Communications.
