New research sheds light on why women are more susceptible to pain from irritable bowel syndrome (IBS), pointing to hormonal influences as a key factor. This chronic condition, characterized by abdominal pain, bloating, and digestive issues, has long been observed to affect women more frequently than men.

A team of American researchers has discovered that the hormone oestrogen plays a significant role in this disparity. It triggers previously unknown pathways in the colon that can lead to pain and increase sensitivity to certain foods in women. When male mice were given doses of oestrogen to mimic female hormone levels, their sensitivity to gut pain increased to levels seen in females.

This groundbreaking study, conducted by scientists at the University of California, San Francisco (UCSF) and published in the journal Science, holds promise for advancing IBS treatment strategies. Professor Holly Ingraham, co-senior author of the study, remarked, “We wanted to move beyond the assumption that young women simply suffer more from IBS and instead provide a scientific rationale. Our research not only answers that question but also highlights new drug targets.”

Additionally, the study offers explanations for why low-FODMAP diets, which eliminate certain fermentable foods like onions, garlic, honey, wheat, and beans, are helpful for some IBS patients. It also provides insight into the fluctuation of gut symptoms in women throughout their menstrual cycles, as reported by the Mirror.

Professor David Julius, a co-senior author of the study and a Nobel Prize laureate in 2021 for his work on pain sensation, elaborated: “While we understood that the gut has a complex pain-sensing system, this research shows how hormones can intensify that sensitivity by engaging this system through a unique and powerful cellular connection.”

Previous studies had implicated oestrogen in the higher prevalence of IBS among women, though the exact mechanism remained elusive. The UCSF research team first needed to pinpoint where oestrogen was acting within the gut to clarify its role in IBS.

Study co-first author Dr Archana Venkataraman explained: “At the time I started this project, we didn’t know where and how oestrogen signalling 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 researchers anticipated finding oestrogen receptors in enterochromaffin (EC) cells, which were already recognised for transmitting pain signals from the gut to the spinal cord. However, they were astonished to discover that oestrogen receptors were concentrated in the lower colon and in a distinct cell type called L-cells.

The researchers uncovered a complex chain reaction triggered when oestrogen attaches to the L-cells, involving a hormone known as PYY. For years, scientists had believed PYY chiefly reduced appetite.

Pharmaceutical companies had even tried to develop it as a weight-loss treatment. However, the clinical trials were unsuccessful due to a concerning side effect that remained unexplained: participants suffered severe gut distress.

The latest findings support this observation and point towards an entirely new function for PYY.

Co-first author Dr Eric Figueroa stated: “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.”

Elevated PYY wasn’t the sole way L-cells reacted to oestrogen, the research revealed. Levels of another molecule, known as Olfr78, also increased in response to the hormone.

Olfr78 identifies short-chain fatty acids – metabolites generated when gut bacteria break down certain foods. With additional Olfr78 receptors, L-cells become “hypersensitive” to those fatty acids and are more readily triggered into action, releasing greater amounts of PYY.

Dr Venkataraman explained: “It means that oestrogen 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 researchers suggest the discovery may explain why low-FODMAP diets benefit some IBS sufferers. By consuming fewer FODMAPs, patients may prevent the activation of Olfr78 and, consequently, stop L-cells from producing additional pain-signalling PYY.

While men possess the same cellular pathway, their lower oestrogen levels typically keep it subdued, according to the researchers. However, this pathway could become active in men who are on androgen-blocking medications.

These drugs inhibit the effects of testosterone and can sometimes increase oestrogen levels, potentially leading to digestive side-effects.

The research team believes their findings could pave the way for new treatments for IBS in both men and women. Professor Ingraham stated: “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 team is now exploring how these potential drugs might function, and whether other hormones, including progesterone, could also influence gut sensitivity.