Estrogen link could explain why women are more likely to suffer from Crohn's

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by University of Bath

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Fluorescent image of the gut region in zebrafish larvae showing macrophages, a type of immune cell. The green signal marks the center of the macrophages, while the red signal shows the cell body. Preliminary imaging suggests that estrogen treatment may alter the distribution of macrophages in the zebrafish gut, providing a way to investigate how hormone signaling affects immune cells in the intestine. Credit: McKenna Eklund, University of Bath

Scientists from the University of Bath (UK) have shed new light on how Crohn's disease develops and why it affects people differently after finding new evidence of a link between a key immune system gene in the gut and signaling of the hormone estrogen.

Crohn's disease affects around a quarter of a million people in the UK, causing chronic inflammation in the gut, with patients suffering from abdominal pain, diarrhea and fatigue. The UK has one of the highest rates of inflammatory bowel disease in the world, with cases steadily rising.

In a new study, published in the journal PLOS Biology, the researchers discovered that estrogen signaling plays a critical role in regulating gut health when the function of a gene called NOD2 is disrupted.

Their findings could open up new opportunities to explore hormone-targeted therapies for inflammatory bowel diseases.

Mutations in the NOD2 gene—which activates the immune system and triggers an immune response—have long been associated with Crohn's disease, but until now it was unclear how this gene maintains gut health.

The researchers developed a zebrafish model of Crohn's disease with a NOD2 mutation, observing which genes are active in every different type of cell found in the gut and comparing them with normal (wild type) fish.

Estrogen can drive gut dysfunction

They found that loss of NOD2 function causes widespread disruption in the gut, affecting both the intestinal lining and immune processes. Unexpectedly, they also found a marked increase in estrogen-related gene activity in the absence of NOD2.

When they exposed healthy fish to estrogen, they found it reproduced the same gut defects seen in the NOD2 mutants. Interestingly, they were able to reverse the gut damage in NOD2 mutants using an estrogen receptor inhibitor.

The researchers suggest their results indicate the estrogen signaling pathway is worth investigating further.

Professor Edan Foley, from the Centre for Evolution in the University's Department of Life Sciences, said, "We've found a direct link between estrogen and the gut inflammation seen in Crohn's disease.Our results show that regulating estrogen signaling is crucial for maintaining normal gut health, and could explain why Crohn's disease affects people differently.

"This discovery opens up new ways of thinking about Crohn's disease and could eventually lead to more personalized approaches to treatment."

Data gap between males and females

Mckenna Eklund, Ph.D. student who is the first author of the paper, said, "Inflammatory bowel disease affects so many people and is on the rise, but we don't really know why.

"Crohn's is more common in females than males, but historically, much of immunology research has relied heavily on male animal models, so there's a huge data gap that we need to fill to find out what's going on.

"Using zebrafish allows us to study gut biology in a whole living organism while generating large, well-controlled data sets, which is especially useful for investigating how genes, hormones and immune responses interact."

Publication details

Mckenna Eklund et al, Estrogen impacts NOD2-dependent regulation of intestinal homeostasis, PLOS Biology (2026). DOI: 10.1371/journal.pbio.3003766

Journal information: PLoS Biology

Key medical concepts

Crohn's DiseaseNOD2 protein, humanInflammatory Bowel Diseases

Clinical categories

GastroenterologyCommon illnesses & PreventionAllergy and immunologyWomen's health Provided by University of Bath Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

Andrew Zinin

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