Women of reproductive age are more likely than other people to report gut problems like irritable bowel syndrome (IBS), and can feel dismissed by doctors, as clinicians often put the pain down to diet, stress or hormones.
It was never just “in their heads.” A complex interplay between an important hormone, chemical signals, rare populations of gut cells and the output of gut bacteria could explain why, researchers report December 18 in Science. While the findings are in mice, they suggest new opportunities for treatment.
Gut pain is a visceral experience — literally, pain in the viscera, from nerves that spread throughout the torso and abdomen. “It can be bloating, it can be a sharp pain or it can be just sort of a constant, dull pain,” says David Julius, a neurophysiologist at University of California, San Francisco. About 10 percent of the global population — mostly women —suffers symptoms of IBS, which can occur with diarrhea, constipation or a mix between the two.
“What makes this so bad is that these women are feeling this pain, they go into the physician … and they were just ignored,” says Holly Ingraham, a physiologist also at the University of California, San Francisco.
Ingraham and Julius knew that the hormone estrogen played a role in this type of pain, which can fluctuate with the menstrual cycle and pregnancy. In a 2023 paper, they showed that female mice are more sensitive to this visceral pain than males. Without estrogen, that extra sensitivity disappeared.
The researchers immediately went looking for cells that might sense estrogen in the gut. To affect a given organ, its cells must have proteins called receptors that recognize estrogen and set off signals in response.
Ingraham, Julius and their colleagues were sure the receptors were on rare cells sprinkled across the large intestine. These enterochromaffin cells produce 90 percent of the body’s serotonin, an important chemical messenger. That serotonin gets picked up by the nerve cells in the gut, sending signals of pain to the brain. The simple conclusion, Julius says, is that those enterochromaffin cells could sense estrogen and release serotonin in response. But when the scientists looked, they “just kept coming up with a blank.”
To their surprise, the scientists found that estrogen connected to pain in the gut through a multi-cell process — a cellular version of the game telephone.
Tests with specially designed mice revealed estrogen receptors on another rare gut cell type — the L cell. When estrogen hits L cells in the colon, those cells in turn produce another receptor called OLFR78 and display it on their surfaces. Tests with individual L cells showed that the receptor responds to short-chain fatty acids produced by gut microbes in response to some sugars.
After sensing the fatty acids, the L cells then pump out a hormone called peptide YY (PYY). Using mouse cells grown into simplified gutlike structures called organoids, the team demonstrated that PYY heads to the enterochromaffin cells, which finally produce a surge of serotonin — triggering nerve signals to send painful messages to the brain.
The complex interplay offers new options to treat chronic gut pain, says Marie-Isabelle Garcia, a molecular and cellular biologist at the Université Libre de Bruxelles in Belgium who was not involved in the study. Current treatments target serotonin, but others could target PYY, the estrogen receptors in the gut, or the OLFR78 receptor.
The results could explain why some patients get relief from diets low in sugars called FODMAPS — depriving gut microbes of material for the short-chain fatty acids that stimulate the L cells in this pain pathway. Without the FODMAPS, people may have fewer or less severe gut serotonin spikes.
The pathway could also help explain why estrogen changes can be so closely linked to IBS symptoms. And of course, Ingraham says, development of gut problems could be a combination of susceptibility, diet and some other factor like an illness at the right time. “Not every woman of reproductive age developed IBS,” she says. “I think there absolutely has to be some other factor.”