New research from the University of California, San Francisco (UCSF) and the South Australian Health and Medical Research Institute (SAHMRI) shows that the female hormone estrogen directly increases gut pain in women. This discovery could explain why women are much more likely than men to suffer from conditions like irritable bowel syndrome, or IBS. The study, published recently in the journal Science, identifies specific pathways in the colon that estrogen activates, making the female gut more sensitive to pain signals and certain food-related substances.^{[1][2][3][4][5]} ### How Estrogen Triggers Pain Scientists found that estrogen binds to special cells, called L-cells, in the lower part of the colon. This binding causes L-cells to release a hormone called PYY, or peptide YY. PYY then acts on nearby EC cells, which are enterochromaffin cells. These EC cells respond by releasing serotonin, a neurotransmitter. It is this release of serotonin that then activates pain-sensing nerve fibers in the gut. This complex chain reaction is what leads to heightened pain sensitivity in women.^[1][2][4] Holly Ingraham, PhD, the Herzstein Professor of Molecular and Cellular Pharmacology at UCSF and co-senior author of the study, emphasized the importance of this finding. "Instead of just saying young women suffer from IBS, we wanted rigorous science explaining why," Ingraham said. "We've answered that question, and in the process identified new potential drug targets."^[1] The research also revealed what scientists call a "double hit" mechanism. Estrogen not only increases the gut's baseline sensitivity by boosting PYY, but it also makes L-cells more responsive to short-chain fatty acids. These fatty acids are byproducts created when gut bacteria digest certain foods. Estrogen achieves this by increasing the number of Olfr78 receptors on L-cells. With more receptors, these cells become hypersensitive to the fatty acids, leading to more PYY release and thus more pain.^[1][4] This finding offers a clearer understanding of why low-FODMAP diets, which limit certain fermentable foods like onions, garlic, and beans, can help some IBS patients. By reducing the intake of foods that produce these short-chain fatty acids, the diet may lessen the triggers for estrogen-sensitized guts.^[1][2][4] ### Hormones and Gut Discomfort Across Life Women are significantly more prone to gut pain disorders. For instance, women are about twice as likely, and in some reports, up to six times more likely, than men to experience IBS, a chronic condition marked by abdominal pain, bloating, and digestive discomfort.^[1][6][7][8] This new research directly addresses this long-observed difference between sexes. Researchers confirmed this link by giving estrogen to male mice, which then showed increased gut pain sensitivity similar to females.^[1][2] The severity of gut pain often changes with a woman's hormonal cycle. Many women report worse digestive symptoms, including pain, bloating, constipation, or diarrhea, during different phases of their menstrual cycle.^{[9][10][11][12][13][8][14]} Symptoms are frequently most pronounced during menstruation, when levels of both estrogen and progesterone are at their lowest.^[11][13] This drop in hormones can decrease the pain threshold, making cramps and bellyaches feel more intense.^[6][15][16] Progesterone, another key female hormone, also plays a role. Higher levels of progesterone, such as during the luteal phase (the second half of the menstrual cycle before a period) or during pregnancy, can slow down the movement of food through the intestines. This slower transit can lead to constipation, gas, and bloating.^{[9][10][11][17][13][8][18]} Additionally, during menstruation, the body releases hormone-like chemicals called prostaglandins. These cause the uterus to contract to shed its lining, but they can also affect the smooth muscles in the gut, leading to increased bowel contractions, which can result in diarrhea or cramps.^{[10][13][8][14]} As women transition through menopause, the decline in estrogen levels can also trigger various digestive issues. Some post-menopausal women report increased acid reflux, changes in bowel habits, or even new IBS symptoms.^[9][17][8] Conversely, the incidence of IBS in women tends to decrease after menopause, further highlighting the significant impact of these hormones on gut health.^[11][12] ### Hope for New Treatments The findings from this international study, which involved collaboration with Professor Stuart Brierley at SAHMRI, bring together years of research into the cellular mechanisms behind chronic visceral pain.^[4] David Julius, PhD, the Morris Herzstein Chair in Molecular Biology and Medicine at UCSF and co-senior author, noted that the study reveals how hormones can increase gut sensitivity by tapping into a sophisticated pain-sensing system. Julius won the 2021 Nobel Prize for Physiology or Medicine for his work on pain sensation.^[1] Professor Brierley expressed optimism about the future. "If we can interrupt this pathway at the right point, we may be able to reduce chronic gut pain without affecting the normal digestive functions of these hormones," Brierley said. "That is incredibly promising for women living with IBS and other debilitating visceral pain disorders like endometriosis."^[4] This research opens doors for developing new targeted treatments that could help millions of women who experience severe gut pain. By understanding the precise ways hormones influence gut sensitivity, scientists aim to create therapies that offer more effective relief.^[1][4][5]

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