Women are dramatically more likely than men to suffer from irritable bowel syndrome (IBS), a chronic condition causing abdominal pain, bloating, and digestive discomfort. Now,scientists at UC San Francisco have discovered why.
Estrogen, the researchers report in Science, activates previously unknown pathways in the colon that can trigger pain and make the female gut more sensitive to certain foods and their breakdown products. When male mice were given estrogen to mimic the levels found in females, their gut pain sensitivity increased to match that of females.
The findings not only explain the female predominance in gut pain disorders but also point to potential new ways to treat the conditions.
“Instead of just saying young women suffer from IBS,we wanted rigorous science explaining why,” said Holly Ingraham,PhD,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.”
The research also suggests why low-FODMAP diets – which eliminate certain fermentable foods, such as onions, garlic, honey, wheat, and beans – help some IBS patients, and why women’s gut symptoms often fluctuate with their menstrual cycles.
“We knew the gut has a sophisticated pain-sensing system,but this study reveals how hormones can dial that sensitivity up by tapping into this system through an interesting and potent cellular connection,” said co-senior author David Julius,PhD,the Morris Herzstein Chair in Molecular Biology and Medicine and chair of Physiology. Julius won the 2021 Nobel Prize for Physiology or Medicine for his work on pain sensation.
A zoomed in image of the lining of the colon. Cells that produce the hormone PYY (peptide YY) are in green. Cells that produce the neurotransmitter serotonin are in magenta.PYY triggers the release of serotonin,which activates pain-sensing nerve fibers. Image by Archana Venkataraman/UCSF
Search for estrogen
Previous research had hinted that estrogen was to blame for higher rates of IBS in females, but not why. To understand how estrogen might be involved, Ingraham’s and Julius’s teams first needed to see exactly where the hormone was working in the gut.
“At the time I started this project, we didn’t know where and how estrogen signaling is set up in the female intestine,” said Archana Venkataraman, PhD, a postdoc in Ingraham’s lab and co-first author of the research. “So, our initial step was to visualize the estrogen receptor along the length of the female gut.”
The team expected to see estrogen receptors in enterochromaffin (EC) cells, which were already known to send pain signals from the gut to the spinal cord. Instead, they got a surprise: estrogen receptors were clustered in the lower part of the colon and in a different cell type known as L-cells.
The scientists pieced together a complex chain reaction that occurs when estrogen binds to the L-cells. First, estrogen causes L-cells to release a hormone called PYY (peptide YY). PYY then acts on neighboring EC cells, triggering them to release the neurotransmitter
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