Understanding IBS in Women: How Estrogen Amplifies Gut Pain
It is well known that disorders such as irritable bowel syndrome affect women far more often than men, and new research now reveals why.
The results were presented in the study “A Cellular Basis for Heightened Gut Sensitivity in Females”, authored by Archana Venkataraman, Eric E. Figueroa, Joel Castro, Fernanda Castro Navarro, Deepanshu Soota, Stuart M. Brierley, David Julius, and Holly A. Ingraham.
To understand the significance of this discovery, it helps to look back because the key player in this story is estrogen. In the early 20th century, Edgar Allen helped identify and describe the role of female sex hormones, including estrogen. At first, scientists believed its function was largely confined to the reproductive system. However, over the years, it became clear that this hormone influences a much broader range of functions in the body.
In this study, conducted on mice, researchers found that higher levels of estrogen lead to increased sensitivity to gut pain. This provided the first clear evidence that the hormone plays a direct role in regulating this type of pain. We spoke with Archana Venkataraman, PhD, a postdoc in Ingraham’s lab and co-first author of the research.
How diet and estrogen trigger stronger gut pain
The scientists discovered that estrogen does not act directly on pain-sensing cells. Instead, it targets a different type of cell in the colon known as L-cells. These cells had not previously been associated with pain, but were mainly linked to appetite regulation, making the finding particularly surprising. When estrogen acts on L-cells, it triggers a chain reaction. The L-cells begin to release a hormone called peptide YY (PYY). This hormone then acts on neighboring enterochromaffin cells, which release serotonin. Although serotonin is often referred to as the “happiness hormone,” in the gut it plays a different role: it activates nerve fibers that send pain signals to the brain. In other words, estrogen amplifies the sensitivity of the entire system.
Experiments further confirmed this mechanism. When the female mice had their source of estrogen removed, i.e., their ovaries, their pain sensitivity decreased. When male mice were given estrogen, their sensitivity increased. Similarly, blocking key parts of this pathway reduced the pain response. An even fuller picture emerges when the role of diet and gut bacteria is considered. Researchers also found that estrogen increases the number of receptors called Olfr78 on L-cells. These receptors respond to molecules produced when gut bacteria break down certain types of food, particularly fermentable carbohydrates. When such foods are consumed, bacteria produce compounds that further activate this system, leading to a stronger sensation of pain.
This discovery may explain why certain diets, such as those low in fermentable carbohydrates, can help people with IBS. By reducing the “fuel” available to gut bacteria, the activation of this pathway is also reduced. It is important to note that this mechanism exists in men as well, but is typically less active due to lower estrogen levels. Overall, this research not only answers the long-standing question of why these disorders are more common in women but also opens the door to the development of new, more targeted treatments.
We still lack a full understanding of the two-way communication between the gut and the brain
How can this be applied in practice, and how might it specifically help women?
Archana Venkataraman: Our findings show that estrogen heavily influences gut sensitivity, offering a physiological explanation for the cyclic changes in IBS symptoms that women experience. In practice, tracking IBS symptoms throughout the menstrual cycle could be helpful, especially to determine the best timing for dietary interventions. And more importantly, this work provides a mechanistic rationale for the effectiveness of low-FODMAP diets, especially in women.
What is the impact of pregnancy in this context, and are there any differences between women who have been pregnant and those who haven’t?
Archana Venkataraman: Good question. We believe that estrogen-induced tuning of gut sensitivity could be adaptive. Elevated estrogen levels during pregnancy could help improve the detection of ingested nutrients while increasing aversion to potentially harmful foods, thereby protecting the developing fetus. Experimental studies in mouse models are beginning to uncover the molecular pathways behind the remodeling of the maternal gut. However, in humans, we still lack longitudinal data to determine whether pregnancy induces lasting changes in gut sensitivity or whether there are meaningful differences between individuals who have been pregnant and those who have not.
This suggests that it is important to adapt therapy based on gender, because everything starts with hormones. On the question of what she sees as the missing link right now to achieve a complete understanding, Venkataraman concluded: “Yes, we find that normally harmless gut signals are amplified in the presence of estrogen. But we still lack a full understanding of the two-way communication between the gut and the brain, and we do not understand the mechanisms by which transient, hormone-driven sensitivity turns into chronic visceral pain. Addressing these questions will be essential for developing therapies that are better tailored to sex and hormonal states.”
Image: Archana Venkataraman, PhD. UCSF Profiles
