Women suffer from irritable bowel syndrome (IBS) and other functional disorders of the digestive system significantly more often than men. These are chronic conditions that are not life-threatening but can completely change everyday life: from abdominal pain, bloating, and unpredictable bowel movements to constant worry about whether symptoms will appear at work, during travel, or in the middle of a social event. For years, it was speculated that hormones were "to blame," but without a clear explanation of exactly how sex hormones intensify intestinal pain. A new study by scientists from the University of California, San Francisco (UCSF) describes for the first time in detail the chain of events in the gut by which estrogen intensifies the sensation of pain and offers an explanation for why women more frequently experience digestion-related abdominal pain.

IBS is classified as a disorder of gut sensitivity, so-called visceral pain, and according to current data, it affects millions of people worldwide. Estimates suggest that between 5 and 10 percent of the population suffers from irritable bowel syndrome, depending on the study and applied diagnostic criteria, and many analyses show that women of reproductive age predominate among those affected. In this group, symptoms often vary during the menstrual cycle, pregnancy, breastfeeding, and perimenopause, which has long pointed to a clear link with hormones, but the exact biological mechanism remained unclear until recently.

Estrogen and gut cells – unexpected protagonists

Estrogen is the primary female sex hormone, also present in men but in lower concentrations. Its role goes far beyond the reproductive system: it participates in the regulation of metabolism, bone health, brain function, and blood vessels, and an increasing amount of data suggests that it strongly influences the digestive tract. Hormones act through receptors – protein "sensors" on the surface or inside cells – that recognize the presence of hormones and trigger an entire cascade of intracellular events. To understand exactly how estrogen acts in the intestines, researchers first had to see where its receptors are even located in the intestinal mucosa.

The logical first suspects were enterochromaffin (EC) cells. These are specialized cells in the gut lining that produce serotonin – known in the brain as the "happiness hormone," and in the digestive system as a key signal transmitter that regulates gut motility and participates in the generation of pain sensation. EC cells were already well known for "talking" via serotonin to nerve fibers that transmit information from the gut to the spinal cord and brain. However, when scientists began to "map" estrogen receptors along the gut using precise methods, a surprise awaited them.

The highest concentration of estrogen receptors was not in EC cells, but in another group of enteroendocrine cells – so-called L-cells in the lower part of the large intestine. L-cells are a kind of built-in "endocrine glands" in the intestinal mucosa, which produce and release hormones as soon as food passes through the gut or certain signals from the internal environment appear. Among these hormones, peptide YY (PYY) occupies a special place, whose role was until recently mainly associated with appetite reduction and prolonging the feeling of fullness after a meal.

PYY – from satiety hormone to pain signal

PYY has long been in the focus of the pharmaceutical industry as a potential target for anti-obesity drugs. The idea was simple: if the PYY signal is intensified, people would feel full sooner and theoretically lose weight more easily. Several candidates for such drugs reached clinical trials, but the programs were halted. Although the hormone indeed reduced appetite, many participants in those studies reported significant digestive issues, cramps, a feeling of pressure, and abdominal discomfort, which limited the safety and acceptability of the therapy. At that time, no one knew why this was happening.

In the new study, PYY specifically receives a completely new, unexpected role – the role of a pain signal intensifier. Scientists tracked what happens when estrogen reaches the L-cells in the large intestine of female mice. It turned out that estrogen, by binding to its receptors in L-cells, stimulates these cells to secrete significantly more PYY than usual. This PYY then does not only travel to the brain, where it participates in appetite regulation, but also acts locally, in the immediate vicinity.

Specifically, PYY reaches neighboring enterochromaffin cells and binds to their specific receptors. This gives EC cells a "signal for action," and they release larger amounts of serotonin into the surrounding tissue. Serotonin then activates sensory nerve fibers in the gut wall – the same ones that record stretching, cramps, or the presence of irritants in the intestinal lumen. The increased release of serotonin also means an increased flow of impulses through these nerves to the spinal cord and brain, which is subjectively experienced as more intense pain, pressure, or discomfort in the abdomen.

That such a chain is indeed dependent on estrogen was confirmed by a series of experiments. When researchers surgically removed the ovaries of female mice, estrogen levels fell, L-cells secreted less PYY, EC cells less serotonin, and the animals showed weaker reactions to stimuli in the gut. A similar effect was achieved by using drugs that block the action of estrogen, PYY, or serotonin: every break in the chain between L-cells, EC cells, and nerve fibers significantly alleviated the sensation of pain. When, however, male mice were given doses of estrogen approaching the levels in females, their intestinal sensitivity increased and practically equaled the sensitivity of females.

The role of gut microbiota and the Olfr78 receptor

Another key piece of the puzzle is a receptor called Olfr78. Although it belongs to the large family of olfactory receptors, which is most often associated with the sense of smell in the nose, this receptor is also found in the gut. Its task is to recognize short-chain fatty acids – substances like acetate and propionate that are produced when gut bacteria ferment certain types of carbohydrates. It turned out that estrogen affects not only the amount of PYY, but also how many Olfr78 receptors L-cells express.

The more Olfr78 on the surface of L-cells, the more sensitive those cells are to short-chain fatty acids circulating in the contents of the large intestine. In practice, this means that the same amount of bacterial metabolites – produced from the same meal – will more strongly "wake up" L-cells in the presence of higher estrogen levels. Once L-cells are activated, the chain is already known: PYY release, stimulating EC cells to increase serotonin release, activation of nerve fibers, and a more intense experience of pain.

In this way, estrogen creates a kind of "double blow" to gut sensitivity. On one hand, a higher hormone level initially increases PYY secretion, so the basic level of gut sensitivity is elevated. On the other hand, the increase in the number of Olfr78 receptors makes L-cells much more sensitive to signals coming from the gut microbiota. Short-chain fatty acids, which are otherwise an important energy source for large intestine cells and have numerous beneficial effects, in this context become a trigger for an excessively strong signal to the nervous system.

This mechanism elegantly connects three key elements: sex hormones, gut cells that produce hormones and neurotransmitters, and the bacteria that inhabit the gut. In women, it seems, this system works at "increased volume," so the same degree of food fermentation in the gut can result in visibly stronger pain than in men. This provides a potential explanation for why women, especially during their reproductive years, are more sensitive to certain types of food and more frequently report abdominal pain after meals.

Diet, FODMAPs, and gut sensitivity

Short-chain fatty acids are formed when gut bacteria break down fermentable carbohydrates, known by the collective acronym FODMAP (fermentable oligo-, di-, and monosaccharides and polyols). It is precisely on this group of carbohydrates that the low-FODMAP diet is based, one of the most researched dietary approaches in the treatment of IBS. In the first phase of this diet, the emphasis is on a strong reduction of FODMAPs – foods rich in fructose and fructans (such as apples, pears, watermelon, wheat, onions, and garlic), lactose (certain types of milk and dairy products), galactans (legumes), and polyols (sorbitol, mannitol, and similar sweeteners) are temporarily eliminated from the diet.

Numerous randomized trials have shown that such a restrictive phase of low-FODMAP nutrition can reduce abdominal pain, bloating, gas, and bowel movement disorders in a significant portion of patients. Comparisons with classical drug therapy show that carefully managed nutrition can be equally effective, and sometimes better than standard drugs in alleviating symptoms. However, expert guidelines warn that such a restrictive phase should be carried out for a limited time and under professional supervision, as long-term elimination of entire food groups can impoverish the diet and negatively affect the diversity of the gut microbiota.

The key part of the low-FODMAP approach is actually the second phase – the gradual reintroduction of individual FODMAP groups into the diet and testing personal tolerance. Instead of a permanent ban on "problematic" foods, the goal is to find the amount and combinations that do not cause significant symptoms for the individual. New insight into the role of estrogen, PYY, and the Olfr78 receptor now also provides a biological explanation for why the same menu does not work equally for everyone and why symptoms in the same person can differ from month to month.

If estrogen intensifies the sensitivity of L-cells to short-chain fatty acids, it is understandable that the same meal rich in FODMAPs will cause a stronger response in a woman in a phase of the cycle with higher estrogen levels than, for example, in the early follicular phase or after menopause. This matches the experiences of many patients who state that their pain, bloating, and bowel changes worsen in the days before menstruation or in periods of hormonal fluctuations. Research is also examining how other hormones, such as progesterone, and conditions such as pregnancy and breastfeeding further modulate the functioning of this sensitive intestinal circuit.

Broader hormonal context: women, men, and hormone therapies

An important aspect of the new work is also a broader understanding of sex differences. In men, the same basic system of cells and receptors exists in the gut, but due to significantly lower estrogen levels, it is usually "quieter." When researchers gave experimental male mice estrogen doses similar to those found in females, their intestinal sensitivity increased sharply. This raises the question of whether similar processes might be involved in digestive side effects in men on therapies that lower testosterone, for example in the treatment of prostate cancer, where the hormonal balance shifts in favor of estrogen.

Although today irritable bowel is spoken of as a "gut-brain disease," this study clearly shows that the endocrine system should also be included in the story – especially when talking about women. Differences in estrogen levels throughout life (puberty, fertile age, pregnancy, breastfeeding, perimenopause, and menopause) could affect the dynamics of the PYY/serotonin/Olfr78 circuit and thus at least partially explain the fluctuations in symptoms over the years. This is an important message for clinicians who follow patients with IBS and other functional bowel disorders.

Perspectives for new targeted treatments

From a practical standpoint, uncovering such a detailed signaling pathway opens the door to the development of new therapies. If PYY is the key link that transmits the signal from estrogen-dependent L-cells to EC cells, one potential solution is the targeted blocking of its receptors in the gut. Another possibility is modulating the activity of the Olfr78 receptor or other sensory mechanisms for short-chain fatty acids to reduce hypersensitivity to fermentation products of gut bacteria. In theory, drugs could be developed that would quiet this "amplified loudspeaker" of pain without completely shutting down the beneficial functions of hormones and metabolites.

But such drug development will require caution. PYY participates in the control of appetite and body mass, and short-chain fatty acids are important for nourishing large intestine cells, strengthening the intestinal barrier, and anti-inflammatory effects. Overly aggressive blocking of these pathways could have unwanted consequences on metabolism, immunity, and the structure of the intestinal mucosa. Therefore, future drugs will have to be precise – for example, acting locally in the gut, in exactly specified cell populations, or in certain phases of the cycle, to achieve a balance between pain reduction and preservation of physiological functions.

What does this mean for patients today?

Although new research brings exciting insights, it is important to emphasize that this is primarily work on an animal model and detailed cellular analyses. This does not mean that the only cause of IBS in humans has been discovered, nor that a new drug for women with irritable bowel will follow tomorrow. Irritable bowel syndrome remains a complex condition in which genetics, gut microbiota, the immune system, the gut-brain axis, psychological factors, and daily habits intertwine.

For people living with IBS, current expert guidelines still emphasize an individual approach. In practice, this means careful adjustment of nutrition (which may include a low-FODMAP diet, but also other patterns like the Mediterranean or moderately low-carbohydrate diet), targeted drug therapy according to dominant symptoms (pain, diarrhea, constipation, or a combination), and the application of psychological interventions that help regulate communication between the brain and gut. There is more and more evidence that quality sleep, regular movement, stress management techniques, and professional support can be just as important as the choice of medications themselves.

The latest data on the role of estrogen, PYY, and the Olfr78 receptor therefore primarily help to finally fit the experiences of patients into a clear biological framework. Instead of a vague explanation that "hormones affect the gut," today it is better understood on which cells these hormones bind, which molecules they trigger, and how they ultimately change the way the brain receives signals from the gut. This opens the way to more precise, sex-specific therapies that in the future could mean less pain and a better quality of life for millions of women who fight daily with irritable bowel and other chronic digestive troubles.