Women are significantly more likely than men to experience irritable bowel syndrome (IBS), a chronic condition marked by abdominal pain, bloating, and digestive discomfort. Researchers at UC San Francisco have identified estrogen as a key factor behind this disparity.
The study, published in Science, found that estrogen activates previously unknown pathways in the colon that can increase pain sensitivity and make the female gut more reactive to certain foods and their breakdown products. When male mice were administered estrogen at levels similar to those in females, their gut pain sensitivity increased to match that of females.
These findings offer an explanation for why women are more prone to gut pain disorders and suggest new approaches for treatment. The research also provides insight into why low-FODMAP diets—which restrict fermentable foods like onions, garlic, honey, wheat, and beans—can benefit some IBS patients. It may also clarify why women's gut symptoms often change with their menstrual cycles.
"We knew the gut has a sophisticated pain-sensing system, but this study reveals how hormones can dial that sensitivity up by tapping into this system through an interesting and potent cellular connection," said David Julius, PhD, co-senior author of the study and chair of Physiology at UCSF. Julius is recognized for his Nobel Prize-winning work on pain sensation.
Previous studies had suggested estrogen was linked to higher rates of IBS in women but did not explain the mechanism. To investigate further, researchers examined where estrogen acts within the gut.
"At the time I started this project, we didn't know where and how estrogen signaling is set up in the female intestine," said Archana Venkataraman, PhD, postdoctoral researcher and co-first author. "So, our initial step was to visualize the estrogen receptor along the length of the female gut."
Contrary to expectations that estrogen receptors would be found in enterochromaffin (EC) cells—known for sending pain signals from the gut—the team discovered clusters of these receptors in L-cells located in the lower colon.
The researchers mapped out a sequence where estrogen prompts L-cells to release peptide YY (PYY), which then stimulates neighboring EC cells to produce serotonin. This neurotransmitter activates nerve fibers responsible for sensing pain. In experiments with female mice, removing ovaries or blocking estrogen, serotonin, or PYY reduced heightened gut pain responses.
Historically, PYY was thought mainly to suppress appetite; previous drug trials targeting PYY for weight loss failed due to severe gastrointestinal side effects. The new findings suggest PYY also plays a role as a local pain signal in the colon.
"PYY had never been directly described as a pain signal in the past," said Eric Figueroa, PhD, co-first author of the study. "Establishing this new role for PYY in gut pain reframes our thinking about this hormone and its local effects in the colon."
Additionally, researchers observed that L-cells increased production of Olfr78—a molecule that detects short-chain fatty acids produced when bacteria digest certain foods—in response to estrogen. With more Olfr78 receptors present, L-cells became hypersensitive and released more PYY when exposed to these fatty acids.
"It means that estrogen is really leading to this double hit," Venkataraman explained. "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 that are floating around in the colon."
This process may explain why low-FODMAP diets help some IBS patients: reducing intake of fermentable carbohydrates lowers production of fatty acids sensed by Olfr78 receptors on L-cells—potentially decreasing PYY-driven pain signaling.
While men possess this same pathway at a cellular level, their lower estrogen levels mean it is less active. However, men taking androgen-blocking medications—which reduce testosterone effects but can raise estrogen—may experience digestive side effects if this pathway becomes engaged.
The research points toward possible treatments targeting these pathways for both women and men with IBS.
"Even for patients who see success with a low-FODMAP diet, it's nearly impossible to stick to long term," said Holly Ingraham (not quoted directly), suggesting that newly identified pathways could serve as drug targets.
Ongoing research will examine how such drugs might function and whether other hormones—including progesterone—or life events like pregnancy influence intestinal sensitivity.
