By Stephen Beech
Women are more likely to suffer pain from irritable bowel syndrome due to their hormones, according to a new study.
Previous research has shown that many more women than men have the chronic condition, known as IBS, that causes abdominal pain, bloating, and digestive discomfort.
Now, American scientists have discovered that the female sexual and reproductive hormone estrogen activates previously unknown pathways in the colon that can trigger pain and make the female gut more sensitive to certain foods.
When male mice were given estrogen to mimic the levels found in females, their gut pain sensitivity increased to match that of females.
The University of California, San Francisco (UCSF), research team say their findings, published in the journal Science, could lead to better IBS treatments.
Study co-senior author Professor Holly Ingraham said: “Instead of just saying young women suffer from IBS, we wanted rigorous science explaining why.
“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 including onions, garlic, honey, wheat, and beans – help some IBS patients, and why women’s gut symptoms often fluctuate with their menstrual cycles.
Study co-senior author Prof. David Julius, who won a Nobel Prize in 2021 for his work on pain sensation, said: “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.”
Previous research had hinted that oestrogen was to blame for higher rates of IBS in women, but not why.
To understand how oestrogen might be involved, UCSF researchers first needed to see exactly where the hormone was working in the gut.
Study co-first author Dr. Archana Venkataraman said: “At the time I started this project, we didn’t know where and how oestrogen signaling is set up in the female intestine.
“So, our initial step was to visualise the oestrogen receptor along the length of the female gut.”
The team expected to see oestrogen receptors in enterochromaffin (EC) cells, which were already known to send pain signals from the gut to the spinal cord.
But they were surprised to find oestrogen 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 oestrogen binds to the L-cells, involving a hormone called PYY.
For decades, scientists believed PYY primarily suppressed appetite.
Pharmaceutical firms even tried developing it as a weight-loss medication.
But the clinical trials failed due to a troubling side effect that was never fully explained: participants experienced severe gut distress.
The new findings tie in with that observation and suggest a completely new role for PYY.
Co-first author Dr. Eric Figueroa said: “PYY had never been directly described as a pain signal in the past.
“Establishing this new role for PYY in gut pain reframes our thinking about this hormone and its local effects in the colon.”
Increased PYY wasn’t the only way that L-cells responded to oestrogen, according to the findings.
Levels of another molecule, called Olfr78, also went up in response to the hormone.
Olfr78 detects short-chain fatty acids – metabolites produced when gut bacteria digest certain foods.
With more Olfr78 receptors, L-cells become “hypersensitive” to those fatty acids and are more easily triggered to become active, releasing more PYY.
Dr. Venkataraman said: “It means that estrogen is really leading to this double hit.
“First it’s increasing the baseline sensitivity of the gut by increasing PYY, and then it’s also making L-cells more sensitive to these metabolites that are floating around in the colon.”
The UCSF team say the finding may explain why low-FODMAP diets help some IBS patients.
By eating fewer FODMAPs, patients may be preventing the activation of Olfr78, and, in turn, keeping L-cells from churning out more of the pain signalling PYY.
While men have the same cellular pathway, the researchers say ther lower estrogen levels keep it relatively quiet.
But the pathway could engage in men taking androgen-blocking medications, which block the effects of testosterone and can elevate estrogen in some cases, potentially leading to digestive side-effects.
The new work suggests potential ways to treat IBS in both men and women, according to the research team.
Prof Ingraham added: “Even for patients who see success with a low-FODMAP diet, it’s nearly impossible to stick to long term.
“But the pathways we’ve identified here might be leveraged as new drug targets.”
The research team is now studying how such drugs might work, as well as looking at if other hormones, including progesterone, might play a role in gut sensitivity.
