Estrogen found to trigger gut pain, explaining higher IBS rates in women: Study - Medical Dialogues

Estrogen found to trigger gut pain, explaining higher IBS rates in women: Study  Medical Dialogues

For years, scientists have known that women are far more likely than men to suffer from irritable bowel syndrome (IBS)-a chronic disorder marked by abdominal pain, bloating, and digestive distress. But why has remained a mystery. Now, researchers from UC San Francisco may have found the answer. In a study published in Science, the team discovered that estrogen directly activates pain pathways in the colon, making the female gut more sensitive to certain foods and inflammation.

Working with mouse models, the team led by Dr. Holly Ingraham and Nobel laureate Dr. David Julius began by tracing where estrogen acts in the gut. They expected to find receptors in enterochromaffin (EC) cells—the usual suspects in transmitting pain signals from the gut to the nervous system. Instead, they found that estrogen receptors cluster in a different cell type called L cells, particularly in the lower colon. This discovery led to a deeper exploration of how L cells might contribute to gut sensitivity.

Through a series of molecular and behavioral experiments, the researchers uncovered a chain reaction triggered by estrogen. When the hormone binds to L cells, they release peptide YY (PYY)—a hormone once thought to primarily suppress appetite. PYY, in turn, stimulates neighboring EC cells to release serotonin, which then activates pain sensing nerve fibers in the colon. When researchers removed the ovaries or blocked estrogen, serotonin, or PYY in female mice, their gut pain responses dropped to male like levels. Injecting estrogen into male mice, however, amplified gut sensitivity—matching that seen in females.

The study also identified another molecule, Olfr78, that becomes more active in response to estrogen. This receptor detects short chain fatty acids produced when gut bacteria digest certain carbohydrates. More Olfr78 means L cells become hypersensitive to these metabolites, producing even more PYY—and therefore more pain signaling.

This “double hit” of estrogen and microbial metabolites explains why low FODMAP diets, which reduce fermentable carbohydrates, often relieve IBS symptoms—especially in women. It also sheds light on why menstrual cycles, pregnancy, or hormone therapies can influence gut sensitivity.

“These findings move us beyond speculation to mechanism,” said Ingraham. “We can now see exactly how hormones tune gut pain pathways, opening new doors for gender specific IBS treatments.” The team is now exploring how targeting PYY or Olfr78 could lead to safer, easier to follow alternatives to restrictive diets for gut pain disorders.

REFERENCE: Venkataraman, A., et al. (2025). A cellular basis for heightened gut sensitivity in females. Science. doi: 10.1126/science.adz1398. https://www.science.org/doi/10.1126/science.adz1398

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