Scientists have uncovered a key biological reason why women are significantly more likely to experience the debilitating pain of irritable bowel syndrome (IBS), pointing the finger directly at female sex hormones.
The Hormonal Link to Gut Pain
A landmark study from the University of California, San Francisco (UCSF), published in the prestigious journal Science, has identified how the hormone oestrogen activates specific pain pathways in the colon. This discovery provides the first rigorous scientific explanation for the long-observed gender disparity in IBS, a chronic condition causing abdominal pain, bloating, and digestive distress.
When male mice were given oestrogen to mimic levels found in females, their gut pain sensitivity increased to match that of female mice, demonstrating the hormone's direct role. The research team, co-led by Professor Holly Ingraham, stated their goal was to move beyond simply noting that young women suffer more from IBS to understanding the precise 'why'.
A Surprising Cellular Discovery
While previous research had hinted at oestrogen's involvement, the mechanism was unknown. The UCSF team mapped oestrogen receptors in the gut, expecting to find them in known pain-signalling cells. Instead, they made a surprising discovery.
The receptors were clustered in the lower colon within a different cell type called L-cells, as explained by co-first author Dr Archana Venkataraman. This finding set the stage for unravelling a complex chain reaction. When oestrogen binds to these L-cells, it triggers the release of a hormone called PYY.
For decades, PYY was believed to primarily suppress appetite. However, the new study reveals a completely different function: PYY acts as a potent pain signal in the gut. This aligns with failed clinical trials from years ago where PYY-based weight-loss drugs caused severe digestive distress—a side-effect that now makes sense.
Double Hit: Sensitivity and Diet Triggers
The hormone's impact doesn't stop there. Oestrogen also increases levels of a molecule called Olfr78 on L-cells. This molecule detects short-chain fatty acids, which are metabolites produced when gut bacteria digest certain foods.
"It means that oestrogen is really leading to this double hit," said Dr Venkataraman. "First, it’s increasing the baseline sensitivity of the gut by increasing PYY, and then it’s also making L-cells more sensitive to these metabolites floating around in the colon."
This dual mechanism elegantly explains two longstanding IBS mysteries: why women's symptoms often fluctuate with their menstrual cycles as hormone levels change, and why low-FODMAP diets help some patients. These diets eliminate fermentable foods like onions, garlic, and wheat, thereby reducing the metabolites that can hypersensitive L-cells.
New Avenues for Treatment
The discovery opens promising new avenues for therapy. Professor Ingraham noted that while a low-FODMAP diet can be effective, it is notoriously difficult to maintain long-term. The newly identified pathways involving PYY and Olfr78 offer fresh potential drug targets for treating IBS in both men and women.
Nobel laureate and co-senior author Professor David Julius added that the study reveals "how hormones can dial that [pain] sensitivity up by tapping into this system through an interesting and potent cellular connection."
The research also suggests that men with lower oestrogen levels have a quieter version of this pathway, though it could become engaged in those taking certain androgen-blocking medications. The UCSF team is now investigating how to leverage these findings for drug development and exploring whether other hormones, like progesterone, play a similar role.
