Scientists Finally Explain Why Women Get More Gut Pain Than Men

Women are dramatically more likely than men to suffer from irritable bowel syndrome (IBS), and scientists at UC San Francisco have finally discovered why. The answer lies in estrogen, which activates previously unknown pain pathways in the colon that make the female gut hypersensitive to certain foods and their breakdown products.

How Does Estrogen Create Gut Pain in Women?

The research team discovered that estrogen doesn't work where they expected. Instead of binding to enterochromaffin cells that send pain signals, estrogen receptors cluster in the lower colon in cells called L-cells. When estrogen binds to these L-cells, it triggers a complex chain reaction that amplifies pain sensitivity.

Here's how the process unfolds:

• Hormone Release: Estrogen causes L-cells to release peptide YY (PYY), a hormone previously thought to only suppress appetite
• Neurotransmitter Activation: PYY then acts on neighboring enterochromaffin cells, triggering them to release serotonin
• Pain Signal: The serotonin activates pain-sensing nerve fibers, creating the gut discomfort women experience

"Instead of just saying young women suffer from IBS, we wanted rigorous science explaining why," said Holly Ingraham, the Herzstein Professor of Molecular and Cellular Pharmacology at UCSF and co-senior author of the study. "We've answered that question, and in the process identified new potential drug targets."

Why Do Low-FODMAP Diets Help Some Women?

The study also explains why certain dietary approaches work for IBS patients. Estrogen creates a "double hit" effect by not only increasing baseline gut sensitivity through PYY but also making L-cells hypersensitive to short-chain fatty acids. These fatty acids are produced when gut bacteria digest fermentable foods like onions, garlic, honey, wheat, and beans.

Estrogen increases levels of Olfr78, a receptor that detects these fatty acids. With more Olfr78 receptors, L-cells become easily triggered and release more pain-signaling PYY. This explains why low-FODMAP diets, which eliminate fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, help some patients by preventing Olfr78 activation.

What Does This Mean for Treatment?

The findings point to potential new drug targets for treating IBS. When researchers gave male mice estrogen to mimic female levels, their gut pain sensitivity increased to match that of females. Conversely, removing ovaries or blocking estrogen, serotonin, or PYY dramatically reduced gut pain in female mice.

"Even for patients who see success with a low-FODMAP diet, it's nearly impossible to stick to long term," Ingraham explained. "But the pathways we've identified here might be leveraged as new drug targets."

The research also reveals why previous attempts to develop PYY as a weight-loss medication failed due to severe gut distress in participants. "PYY had never been directly described as a pain signal in the past," said co-first author Eric Figueroa. "Establishing this new role for PYY in gut pain reframes our thinking about this hormone and its local effects in the colon."

While men have the same cellular pathway, their lower estrogen levels keep it relatively quiet. However, men taking androgen-blocking medications that can elevate estrogen might experience similar digestive side effects. The researchers are now studying how potential drugs might work and investigating how other hormones like progesterone, as well as pregnancy and menstrual cycles, affect intestinal function.