Women Are More Likely to Have Irritable Bowel Syndrome. This Newfound Gut Pain Pathway Might Explain Why

The hormone estrogen—which female animals typically have more of than males—triggers a molecular cascade in the gut that leads to pain signals, a study in mice suggests

Sara Hashemi

– Daily Correspondent

December 24, 2025 6:00 a.m.

Between 25 million and 45 million people in the United States live with irritable bowel syndrome (IBS), a chronic disorder that causes cramps, diarrhea, bloating and other painful symptoms. Around two-thirds of IBS sufferers are women.

Now, scientists may have figured out a contributing factor to the disproportionate impact. Experiments in mice hint that the hormone estrogen—which female animals typically produce more of than their male counterparts—triggers a molecular pathway in the gut that sparks pain, and can make the colon more sensitive to some foods. The findings, published on December 18 in the journal Science, could lead to new treatments for IBS and other gastrointestinal problems.

“Instead of just saying young women suffer from IBS, we wanted rigorous science explaining why,” says Holly Ingraham, a study co-author and molecular physiologist at the University of California, San Francisco, in a statement. “We’ve answered that question, and in the process identified new potential drug targets.”

Researchers already knew that women’s gastrointestinal pain can worsen during pregnancy and at certain times in their menstrual cycles due to fluctuating estrogen levels. But they didn’t know which cells in the gut respond to the hormone.

So Ingraham and her colleagues searched for estrogen’s target in mice. They found proteins that the hormone fits into, or estrogen receptors, in a rare type of intestinal cell called L cells. Further analysis revealed that estrogen causes L cells to release a hormone called peptide YY (PYY). PYY then instructs a different type of gut cell to release serotonin, both a hormone and nerve cell messenger, which sends pain signals to the brain.

“It’s this chain of events, this cross talk between these two rare cell types in the gut, that mediates the sensation of pain,” Ingraham tells Science’s Catherine Offord. “Estrogen is amplifying this whole pathway.”

The work may also help explain why a low-FODMAPS diet—which limits foods with fermentable carbohydrates, such as yogurt, garlic and beans—can ease IBS symptoms. When gut bacteria digest those carbs, they leave behind molecules called short-chain fatty acids. Estrogen makes L cells produce more receptors that respond to short-chain fatty acids, the team found, and when activated, the receptors cause L cells to pump out PYY, resulting in pain.

“It means that estrogen is really leading to this double hit,” says Archana Venkataraman, a study co-author and neuroscientist at the University of California, San Francisco, in the statement. “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 newfound cascade could help researchers come up with novel ways to alleviate chronic gut pain, Marie-Isabelle Garcia, a molecular and cellular biologist at the Université Libre de Bruxelles in Belgium who was not involved in the study, tells Bethany Brookshire at Science News. The team behind the new study looking into how drugs that target this pathway might work, according to the statement.

The study is also crucial for understanding factors that affect pain, write Amélie Joly and Irene Miguel-Aliaga, physiologists at the Francis Crick Institute in England who were also not involved in the research, in an accompanying commentary in Science.

“Recognizing the ways in which sex and gender influence the biological, psychological and social dimensions of pain will be essential for developing more effective, precision-based strategies for pain management,” they write.