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 signalling 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, diarrhoea 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 signalling 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, 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 signalling 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 signalling 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 personalised approaches to treatment.”

Data gap between males and females

Mckenna Eklund, PhD student who is 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 datasets, which is especially useful for investigating how genes, hormones and immune responses interact.”