Mckenna Eklund peered through the microscope at zebrafish larvae, their tiny guts glowing with green and red signals marking immune cells called macrophages, and saw something unexpected—estrogen was shifting how these cells were arranged, a clue that could unravel why hundreds of thousands of women face a higher risk of Crohn’s disease. At the University of Bath, a team led by Eklund and Professor Edan Foley has uncovered a direct biological link between estrogen signaling and the function of the NOD2 gene, a critical player in gut immunity. Their findings, published in PLOS Biology, could transform how we understand and treat inflammatory bowel disease—one of the UK’s most pressing digestive health crises, affecting over 250,000 people.
Crohn’s disease has long puzzled scientists, particularly because it strikes women more often than men. While mutations in the NOD2 gene were known to increase risk, the mechanism behind its role in gut health remained unclear. Using genetically modified zebrafish with a disrupted NOD2 gene, the researchers mapped gene activity across every cell type in the gut. What they found was striking: the absence of functional NOD2 triggered widespread gut disruption and, surprisingly, a surge in estrogen-related gene activity. Even more telling, when healthy zebrafish were exposed to estrogen, they developed the same intestinal damage seen in the mutants—damage that could be reversed with an estrogen receptor inhibitor.
This discovery doesn’t just explain a biological disparity—it opens a door to new treatments. For decades, immunology research has leaned heavily on male animal models, creating a significant data gap in understanding female-predominant diseases. Eklund, the study’s first author, emphasizes that using zebrafish allows researchers to observe complex interactions between genes, hormones, and immune responses in a living organism, generating robust, controlled data. Their work suggests that hormone-targeted therapies, long used in other fields like oncology, could now be explored for Crohn’s—offering hope for more personalized, effective care.
The implications ripple beyond the lab. With inflammatory bowel disease rates rising across the UK and globally, understanding the role of sex hormones could lead to earlier diagnoses and tailored interventions, especially for women. As the science evolves, so too does the vision for a future where treatment isn’t one-size-fits-all, but finely tuned to the biology of the individual. This breakthrough reminds us that sometimes, the answers to chronic illness lie not in a single gene or hormone, but in how they talk to each other—and in the courage to look where science has overlooked.