Although constipation and diarrhoea may seem like opposite problems, they both hinge on the same underlying issue: how much fluid moves into the gut. These common issues affect millions of people each year. However, medics have not fully understood what regulates intestinal fluid balance.
This may have been addressed through a Northwestern University study. Here, scientists have uncovered a key molecular switch that helps control the gut’s “water faucet.”
Bisacodyl
By studying bisacodyl — one of the world’s most widely used laxatives — researchers discovered an ion channel, called TRPM4, which acts as a master switch for controlling fluid flow in the intestine.
Bisacodyl is a derivative of triphenylmethane. It was first used as a laxative in 1953 because of its structural similarity to phenolphthalein.
The finding solves a long-standing medical mystery. In addition, it also provides a blueprint for designing more targeted treatments. On the one hand, researchers could design drugs to activate this channel to increase fluid flow for treating chronic constipation. On the other hand, newly designed drugs could inhibit the pathway to curb diarrhoea.
“Although bisacodyl has been used clinically for more than 60 years, its precise molecular target was unknown,” says Northwestern’s Juan Du, the study’s co-corresponding author, in a research note. “By combining structural biology, electrophysiology, cell-based assays and animal models, we constructed a rare, comprehensive view of drug action — from atomic-level interactions to whole-organism physiology.”
Outlining the research implications, Du says: “Together, our findings establish TRPM4 as a central regulator of intestinal fluid balance, identify a new druggable site and provide a roadmap for developing next-generation therapies for gastrointestinal disorders”.
Uncovering a hidden pocket
Healthy digestion depends on a delicate balance of fluid in the gut. At the heart of that balance are epithelial cells, which line the intestinal wall and control how salt and water move in and out of the gut. The researchers discovered that bisacodyl’s active form (deacetyl bisacodyl) works by flipping on a molecular switch inside these cells.
When activated, TRPM4 allows sodium ions to rush into intestinal epithelial cells. That electrical shift sets off a chain reaction: calcium flows in, activating a chloride channel that releases chloride ions into the gut and water naturally follows. A laxative effect results.
Bisacodyl activates differently
While scientists long have known TRPM4 responds to calcium signals inside cells, the science team discovered that bisacodyl activates the channel in a completely different way that does not require calcium.
Using high-resolution cryo-electron microscopy, the team visualized TRPM4 at the atomic level and identified a previously unknown drug-binding pocket. Bisacodyl’s active metabolite binds in this pocket, flipping the channels into an active state.
“We uncovered a new epithelial signaling pathway that coordinates multiple ion channels to regulate intestinal fluid movement,” Du said. “This newly defined signaling axis provides a broader framework for understanding how epithelial tissues maintain balance in health — and how this balance is disrupted in disease.”
To confirm that TRPM4 is truly essential to controlling fluids in the gut, researchers in Cao’s lab tested bisacodyl in a mouse model, genetically engineered to lack the TRPM4 channel. In typical mice, bisacodyl worked as expected, increasing water content and softening stools. But in mice without TRPM4, the drug had no effect at all.
Longstanding focus on TRPM4
This discovery builds on years of work by the Lü and Du labs to understand TRPM4 function at the molecular level. In 2017, the teams published the first atomic-resolution structures of TRPM4 in the science journal Nature, revealing how the channel assembles and how small molecules can modulate its activity.
More recently, in 2024, the labs showed that studying TRPM4 at physiological temperature reveals a previously unseen “warm” conformation that is essential for channel opening and normal function. These studies, also published in Nature, demonstrated that temperature profoundly reshapes TRPM4 structure, drug binding and gating —providing critical context for understanding how TRPM4 operates in living systems.
The research is published in Nature and titled “Noncanonical calcium-independent TRPM4 signaling governs intestinal fluid homeostasis” .
