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Researchers used CRISPR-modified zebrafish to investigate how mutations in the NOD2 gene, the strongest genetic risk factor for Crohn's disease, affect intestinal health. They discovered that NOD2 deficiency disrupts both immune function and gut epithelial development, and unexpectedly increases expression of estrogen-response genes. Treatment with the estrogen receptor modulator tamoxifen reversed intestinal defects in NOD2-deficient fish, while estrogen exposure alone reproduced these defects, revealing a previously unknown regulatory connection between NOD2 and hormonal signaling.
Why it matters
This research identifies a novel link between immune genetics and sex hormones that may explain why Crohn's disease affects men and women differently, including variations in disease severity and timing of onset. The findings suggest that estrogen receptor modulators could potentially be explored as therapeutic interventions for patients with NOD2-associated inflammatory bowel disease.
by Mckenna Eklund, Edan Foley
Mutations in the innate immune receptor NOD2 are the greatest single genetic risk factor for Crohn’s disease, yet the mechanisms by which NOD2 regulates intestinal homeostasis remain unclear. We used a CRISPR-generated zebrafish model to determine the impacts of NOD2 deficiency on intestinal health. In cellular, molecular, and transcriptomic studies, we uncovered substantial effects of NOD2 deficiency on epithelial and immune compartments, including deregulated expression of developmental pathways that establish and maintain the gut epithelium, and an unexpected increase in the expression of multiple estrogen-response genes. In functional assays, we uncovered a mechanistic link between estrogenic signals and NOD2-deficiency phenotypes, whereby exposure to estrogen alone replicated the effects of NOD2-deficiency, and treatment with the estrogen receptor modulator tamoxifen reverted the epithelial defects observed in nod2 mutants. Our findings identify a NOD2-estrogen regulatory axis that supports intestinal homeostasis and suggest that hormonal signaling may contribute to sex-specific aspects of Crohn’s disease.
Source: Estrogen impacts NOD2-dependent regulation of intestinal homeostasis