Differences in how intestinal cells respond to hormones may help explain why women experience more frequent and severe intestinal pain than men, a study in mice suggests.
Irritable bowel syndrome (IBS) affects approximately 10% to 15% of people worldwide, and women are diagnosed with IBS up to twice as often as men. IBS symptoms such as pain, constipation, diarrhea, gas, and bloating often worsen in response to triggers such as stress or certain foods. However, the reasons behind the difference in IBS rates between women and men remain unclear.
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“Female hormones have long been suspected to be involved in intestinal pain, but the exact mechanism was unknown,” lead study author David Julius, a neurophysiologist at the University of California, San Francisco, told Live Science. “Our findings point to a clear pathway for how estrogen amplifies pain signals.”
The study, published Dec. 18 in the journal Science, first compared the intestinal pain response of male and female mice by recording neural activity in response to intestinal stimulation and observing how the mice responded to mild colonic distention. Both tests showed that female mice’s intestines were more sensitive at baseline.
However, when the mice’s ovaries were removed to stop estrogen production, this sensitivity dropped to the same level as in males. Then, restoring estrogen to normal levels reversed the increased pain response seen in female mice.
To find out where and how estrogen exerts its effects, the research team looked at different intestinal cells. Based on previous studies, they expected that estrogen receptors would be on enterochromaffin cells. These cells produce about 90% of the body’s serotonin, a chemical messenger involved in activating pain-sensing nerves that send signals to the brain. But surprisingly, the researchers discovered estrogen receptors not on enterochromaffin cells, but on specialized rare cells in the lining of the intestine.
When these cells, known as L cells, detect estrogen, they increase their production of a receptor called OLFR78. This receptor senses short-chain fatty acids, which are byproducts produced when gut bacteria digest food. The addition of additional receptors makes the L cells more sensitive to these byproducts, resulting in the release of more hormones that help the stomach tell the brain that it is full immediately after eating.
To better understand this chain reaction, the researchers created a miniature model of the intestine in the lab. They discovered that a satiety hormone called PYY signals nearby enterochromaffin cells to release additional serotonin. Serotonin activates the nerves that sense pain. This chain reaction caused by estrogen could potentially explain why women experience more severe bowel pain than men.
Experiments using genetically engineered mice lacking estrogen receptors on L cells showed that these mice had weaker neural responses and decreased serotonin release compared with mice with intact receptors, confirming the role of cells in intestinal sensitivity.
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“Because estrogen levels fluctuate with the menstrual cycle, this mechanism provides insight into the varying severity of irritable bowel syndrome seen in women,” said Marissa Scavuzzo, assistant professor of medicine at Case Western Reserve University School of Medicine, who was not involved in the study.
“We will also examine the experience of patients with high estrogen levels and those who are menstruating. This is important because differences in how women experience pain have historically been ignored or ignored,” she said.
The results of this study, although preliminary, may inform future treatments for intestinal pain. “PYY and OLFR78 may be promising targets for the treatment of IBS in women,” Julius suggested. The study may also help explain why a “low FODMAP” diet, which aims to reduce intake of sugars that feed gut bacteria, can reduce IBS symptoms in some patients, he added.
Scavuzzo agreed that the study may point to a promising treatment. “By pinpointing PYY and L cell signaling, this study has identified specific molecular targets that can guide more precise treatment of IBS,” she said.
Additionally, the study “highlights the importance of considering how hormonal changes affect IBS symptoms, not only in menstruating women, but also in postmenopausal patients and those receiving hormone therapy as part of gender-affirming care.”
Care must be taken in transferring these findings from mice to humans. The human gut is more complex than that of mice, and factors such as lifestyle, genetics, and gut microbial diversity can influence an individual’s hormone-gut interactions.
“Mouse models provide a starting point, but clinical studies are essential to draw firm conclusions about intestinal pain in humans,” Julius said.
This article is for informational purposes only and does not provide medical advice.
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