Important findings for women’s gastrointestinal pain and another piece of the puzzle of intestinal fluid balance control.
Why is gut pain worse for women and what controls intestinal fluid regulation?
A research team, led by the South Australian Health and Medical Research Institute (SAHMRI), has identified the cellular driver of the long-observed sex differences in chronic visceral pain.
“We found that estrogen directly amplifies communication between two specialised gut cell types, triggering heightened sensitivity to pain signals in females,” Professor Stuart Brierley, Director of the Visceral Pain Research Group, Director of the Hopwood Centre for Neurobiology and Co-Theme Leader of Lifelong Health at SAHMRI, told media.
“Estrogen activates a pathway in the colon that increases the release of the gut hormone PYY. PYY then stimulates neighbouring serotonin-producing enterochromaffin cells, boosting serotonin output and sensitising the nerves that send pain messages to the brain.”
The pathway had been under scrutiny for years, but researchers said this latest study brought the pieces together and identified a clear target for potential treatments.
“If we can interrupt this pathway at the right point, we may be able to reduce chronic gut pain without affecting the normal digestive functions of these hormones,” Professor Brierley said.
“That is incredibly promising for women living with IBS and other debilitating visceral pain disorders like endometriosis.”
The findings also helped explain why dietary interventions, such as low FODMAP diets, may help reduce symptoms. Estrogen was revealed to increase the gut’s responsiveness to short-chain fatty acids.
“We now understand that certain foods can feed into this estrogen-sensitive pathway through the metabolites they produce,” Professor Brierley said.
“This gives us a clearer biological rationale for why dietary changes may help and how they could be refined.”
The study was published in Science.
In other news, a new study from Northwestern University in the US and the laboratory of Zhengyu Cao of China Pharmaceutical University has identified a molecular switch which controls fluid flow in the intestine.
Regulation of the gut’s “water faucet” has been poorly understood, but constipation and diarrhea – which affects millions of people every year – both hinge on how much fluid moves in and out of the intestines.
The researchers discovered that the ion channel TRPM4 acts as a master switch for controlling intestinal fluid flow.
The study, published in Nature Communications, looked at bisacodyl (e.g., Dulcolax).
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“Although bisacodyl has been used clinically for more than 60 years, its precise molecular target was unknown,” said Professor Juan Du, co-corresponding author from the department of molecular biosciences at Northwestern University.
The discovery not only expanded the understanding of how laxatives work, but created the opportunity to explore the design of more targeted treatments.
The next generation of drugs could activate the channel to increase fluid flow to treat chronic constipation or inhibit the pathway to curb diarrhea, the researchers explained.
“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,” said Professor Du.
The researchers explained that at the heart of the delicate fluid balance in the gut were epithelial cells, which house the TRPM4 switch. Using high-resolution cryo-electron microscopy, they were able to look at the switch at the atomic level and find a previously unknown drug-binding pocket.
Deacetyl bisacodyl (the active metabolite of bisacodyl) binds in this pocket and activates it, causing sodium to rush in and setting off a chain reaction of calcium flow, chloride channel activation and water movement, resulting in a laxative effect.
Using a mouse model, researchers then compared bisacodyl efficacy in normal mice and genetically engineered mice who lacked the TRPM4 channel. The drug worked as intended in the regular mice and had no effect on the mice without TRPM4.
“We uncovered a new epithelial signalling pathway that coordinates multiple ion channels to regulate intestinal fluid movement,” Professor Du said.
“This newly defined signalling axis provides a broader framework for understanding how epithelial tissues maintain balance in health — and how this balance is disrupted in disease.”
