Mesenteric adipocytes promote intestinal fibrosis and inflammation in Crohn's disease through epiregulin (EREG).

BACKGROUND

The global incidence rate of Crohn's disease (CD) is rising, with mesenteric adipose tissue (MAT) playing a pivotal role in CD progression, particularly in fibrosis development. This study aimed to identify key genes in MAT that contribute to CD progression, thereby providing insights for potential therapeutic strategies.

METHODS

The CD-related datasets from the GEO database were aggregated to analyze differentially expressed secreted protein genes. Colon tissue and MAT were harvested from CD subjects and healthy subjects, and H&E and Masson staining were used to detect pathological changes. The expression level of the target gene was determined using various methods (including qRT-PCR, IHC, IF, and Western blot). Primary mesenteric adipocytes of CD patients and healthy controls were isolated and cultured, and epiregulin (EREG) expression was intervened to explore its effects on inflammatory cytokine secretion and lipid metabolism. Additionally, an in-vitro co-culture system of primary adipocytes and intestinal epithelial cells (IECs) and an in-vivo 2,4,6-Trinitrobenzene sulfonic acid (TNBS)-induced CD rat model were constructed to explore the effect of EREG on CD symptoms and the underlying mechanisms.

RESULTS

EREG was highly expressed in both CD colon tissues and MAT. Overexpression of EREG in adipocytes facilitated the production of inflammatory factors and lipid metabolism, as well as promoted inflammation and fibrosis in co-cultured IECs. In vivo, EREG knockdown effectively alleviated CD symptoms and fibrosis in TNBS-induced CD rats. The underlying mechanism may be mediated by EREG, promoting epithelial-mesenchymal transition (EMT) and the PPARγ signaling pathways in IECs. Inflammatory cytokines TNF-α and IL-17A induced EREG expression in adipocytes from CD patients

CONCLUSION

The abnormal upregulation of EREG in adipocytes within MAT contributes to the pathogenesis of CD by promoting inflammation and fibrosis. Targeting EREG may offer a novel therapeutic approach for the clinical treatment of CD.