Butyrate Prevents the Pathogenic Anemia‐Inflammation Circuit by Facilitating Macrophage Iron Export

Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron‐mediated, pathogenic anemia‐inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short‐chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis‐induced anemia but also reduces TNF‐α production in macrophages. Consistently, macrophage‐conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti‐TNF‐α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation. Anemia is the most common extraintestinal complication in patients with inflammatory bowel disease (IBD). As a short‐chain fatty acid (SCFA), butyrate ameliorates inflammation‐associated anemia by facilitating ferroportin (FPN)‐mediated iron export in macrophages. By this mechanism, butyrate also reduces the production of inflammatory cytokine TNF‐α in macrophages. This study uncovers a new role of butyrate as an inhibitor of the pathological “anemia‐inflammation” cycle.