Women have higher rates of irritable bowel syndrome (IBS) than men, and IBS comes with high rates of gut pain and other symptoms. New research may explain why.

Scientists at the University of California, San Francisco (UCSF) have linked estrogen with pain receptors in the colon. The findings, published in Science, may not only explain why women experience more gut pain but also offer potential pathways to treat it.

“One of the really frustrating things with irritable bowel syndrome is that there’s no pathology to speak of,” said Holly Ingraham, PhD, Herzstein Professor of Molecular and Cellular Pharmacology at UCSF and co-senior author of the study. “There are no morphological changes that can be seen. And yet these women, especially of reproductive age, are experiencing this chronic visceral pain or gut pain that can’t somehow be explained.”

The Road to Discovery

Ingraham has studied the role of hormones in the body for a long time. “I decided about 15 or 20 years ago that I would try to figure out what estrogen is doing in different tissues, other than just looking at its role in breast cancer or the reproductive system,” she said.

She and her team had previously worked with the lab run by David Julius, PhD, at UCSF to examine sex differences in mice. That study was published in Nature.

“We found that there were sex differences within the mice that we were looking at, where female mice appeared to have enhanced visceral sensitivity that the male mice didn’t have,” said Eric Figueroa, PhD, a postdoctoral scholar at Julius’ lab. “So it gave us clues that there might be some sex hormones playing a role.”

The team set out in this new study to answer what they thought was a very basic question. The answer wasn’t what they expected.

“We went in to figure out where the receptors for estrogen might be located [in the gut],” said Ingraham. “That’s where we got our first indication that we were on to something because we looked at the major transducer, a detector of estrogen, and we found that it was highly expressed in the colon vs the other gut segments. So right away we said, ‘oh, that’s interesting’ because that’s where you sense pain.”

“Within the gut, there are many different cell types,” Ingraham continued. “Some of them are abundant, and some of them are rare. And it turned out that estrogen receptor alpha (ERα) was expressed in one of these rare cell types in the colon called the L cell. We expected it to be in enterochromaffin (EC) cells, which we think are the main gatekeepers of pain in the colon. So that was our big surprise.”

What This Could Mean for Gut Health — and Women’s Health

“Very exciting,” is how David Artis, PhD, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine in New York City, described the findings (he was not involved in the research). “The study identifies a new pathway linking hormones, enteroendocrine cells, and inflammatory pathways that contribute to chronic pain in diseases like IBS. These findings offer the potential for new combination therapies that target this pathway, along with other anti-inflammatory agents to treat these chronic disorders.”

One immediate benefit: It’s been long accepted that low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyol (FODMAP) diets can help ease IBS symptoms. This study may help explain why.

FODMAPs are carbohydrates that gut bacteria ferment. “As you eat foods that are considered high-FODMAP, they produce more acetate propionate, which then can engage with this pathway that we identified in the gut, causing more pain signaling,” said Figueroa. “So if you decrease the FODMAPs in your diet, you could potentially lower this vector that feeds into the signaling.”

Ingraham hopes that “as more investigators start unraveling some basic pathways that make female physiology different than male physiology, every little study that can come out really helps pave the way for improving women’s health.”

Figueroa agrees: “I think it’s important to continue to look at sex differences in biology, and I hope this [study] is a good example of why it’s worthwhile.”

What’s Next?

“I think we perhaps just scratched the surface in terms of what estrogen is doing,” said Ingraham.

She is also interested in looking at different female life stages, such as the menstrual cycle (estrus cycle in mice), pregnancy, lactation, and perimenopause. “We do know that during pregnancy and lactation, there are huge changes in the gut,” she said. There’s been some research in this area, but “we don’t know all of the cellular and molecular changes that are occurring. Because the gut, if you think about it, is a really important organ that needs to respond during [times like] pregnancy when you’re trying to absorb all the nutrients you can for progeny or during lactation.”

The whole team is looking forward to what’s next. “I’m hoping that people will be excited by this,” said Ingraham. “There’s so much more to do in this space.”

This study was funded by grants from the National Institutes of Health and the National Health and Medical Research Council. The authors declared having no competing interests.