Control valve discovered in gut’s plumbing system

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Control valve discovered in gut's plumbing system

New study reveals the molecular switch that controls balance of intestinal fluid

• Constipation and diarrhea are caused by how much fluid moves into the gut
• Scientists studied a popular laxative to understand what controls fluid flow
• Team found the laxative acts on an ion channel called TRPM4
• Discovery reveals a new drug binding site that could enable more precise treatments for digestive disorders

EVANSTON, Ill. --- Although constipation and diarrhea 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 in the U.S. each year, yet scientists have not fully understood what regulates intestinal fluid balance.

Now, in a new Northwestern University study, scientists have uncovered a key molecular switch that helps control the gut's "water faucet."

By studying bisacodyl - one of the world's most widely used laxatives - the research team discovered an ion channel, called TRPM4, acts as a master switch for controlling fluid flow in the intestine.

The finding not only solves a long-standing medical mystery, but 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 diarrhea.

The study was published yesterday (Jan. 8) in the journal Nature Communications.

"Although bisacodyl has been used clinically for more than 60 years, its precise molecular target was unknown," said Northwestern's Juan Du, the study's co-corresponding author. "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.

"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," added Northwestern's Wei Lü, who co-led the study with Du.

Du and Lü are professors of molecular biosciences at Northwestern's Weinberg College of Arts and Sciences, professors of pharmacology at Northwestern University Feinberg School of Medicine and members of Northwestern's Chemistry of Life Processes Institute. They co-led the study with the laboratory of Zhengyu Cao of China Pharmaceutical University. Jinhong Hu, a postdoctoral fellow in the Lü and Du labs, led the structural studies for this work.

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. Du, Lü, Cao and their teams 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.

While scientists long have known TRPM4 responds to calcium signals inside cells, Du, Lü and Cao 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 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 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 structural work in this study, "Noncanonical calcium-independent TRPM4 signaling governs intestinal fluid homeostasis," was supported by Northwestern startup funding, a McKnight Scholar Award, Klingenstein-Simon Scholar Award, Sloan Research Fellowship and a Pew Scholar in the Biomedical Sciences award. The researchers also received support from the Structural Biology Facility (SBF) for cryo-EM data collection and computational support from Northwestern IT Research Computing and Data Services.