Enterolignans Improve the Expression of Iron-Related Genes in a Cellular Model of Inflammatory Bowel Disease

Anemia is the most common extraintestinal comorbidity of inflammatory bowel diseases (IBDs). Inflammatory cytokines are produced and exert their effects within the bowel microenvironment of IBD patients and, among them, Interleukin 6 (IL-6) induces the expression of hepcidin, encoded by the HAMP gene, contributing to the development of anemia. Enterodiol (END) and Enterolactone (ENL) are enterolignans that are known for their nutraceutical, anti-inflammatory, anti-oxidant, and estrogenic properties. Here, we used the Caco-2 cell line as an in vitro model of bowel disease to evaluate the potential nutraceutical effects of enterolignans on iron metabolism under an inflammatory stimulus induced by IL-6. As is known, IL-6 treatment induces the upregulation of HAMP gene expression. Notably, both END and ENL showed a pronounced anti-inflammatory effect, lowering HAMP mRNA levels and partially counteracting the effect induced by IL-6. The expression of iron-related genes was also studied to evaluate the effects on iron metabolism. IL-6 downregulated the expression of almost all genes studied. Notably, END and ENL mitigated the effect of IL-6, ameliorating the expression level of HAMP, FTH1, and ACO1, in addition to other END- or ENL-specific effects. The results of this study evidenced the interesting anti-inflammatory properties of enterolignans, which improved the iron homeostasis during inflammation, suggesting a possible role in the management of IBD patients with anemia.