In the context of ulcerative colitis (UC), iron deficiency anemia (IDA) is often presented as a prevalent systemic manifestation. However, there is an absence of an effective strategy for the specific case of UC with IDA. Herein, mendelian randomization (MR) analysis is applied to confirm the causal association between UC and iron-related conditions. Accordingly, we have developed a probiotic-based therapeutic approach that synergistically alleviates inflammation and IDA. Probiotic Escherichia coli Nissle 1917 (EcN) is functionalized by the Fe(3)O(4) nanoenzyme and hyaluronan (HA) through electrostatic layer-by-layer (LBL) adsorption. As expected, the obtained EcN@Fe(3)O(4)/HA exhibits excellent properties in vitro, such as gastric acid resistance and ROS-scavenging capability. Upon oral administration, EcN@Fe(3)O(4)/HA shows remarkable adhesion in vivo, particularly in inflamed mice. Moreover, EcN@Fe(3)O(4)/HA shows a "two birds with one stone" effect in dextran sulfate sodium (DSS)-induced mice. First, it exerts anti-inflammatory effects through promoting the expression of tight junction proteins and regulating the gut microbiota. Second, it addresses the issue of IDA. EcN@Fe(3)O(4)/HA effectively ameliorates IDA in DSS-induced mice through iron supplementation, EPO upregulation, and iron homeostasis modulation, resulting in enhanced RBC morphology and elevated cell counts. Therefore, the proposed strategy provides inspiration for future management of diseases and related complications.