High‐Dose Parenteral Iron Corrects Iron Deficiency Anemia While Disrupting Gut Microbiota and Metabolic Homeostasis in Neonatal Piglets

ABSTRACT Iron deficiency anemia (IDA) is a common nutritional disorder in mammals, particularly affecting neonates and neonatal piglets. Parenteral iron supplementation is widely used but carries toxicity risks at high doses. Due to rapid growth and low iron stores at birth, piglets serve as an ideal model for investigating early life iron supplementation and its impact on gut health. In this study, neonatal piglets were assigned to three groups: control (CON, no iron supplementation), moderate‐dose (MI, two low doses), and high‐dose (HI, a single high dose), all administered via intramuscular iron dextran. We found that both iron supplementation protocols significantly increased hemoglobin levels ( p < 0.01) and effectively alleviated IDA. However, the HI group exhibited significant adverse effects, including elevated aspartate aminotransferase (AST) ( p < 0.01), suppressed anti‐inflammatory cytokines (IL‐10, p < 0.01), and increased tissue iron accumulation, whereas the MI group showed no such adverse effects. Gut microbiota analysis revealed that the HI group disrupted the gut microbiota, with a greater impact on fungal diversity than bacterial diversity, as indicated by α‐diversity metrics ( p < 0.05), and also altered the intestinal metabolite profiles. Protein–protein interaction network analysis identified key genera and metabolites, including Fusarium , Geotrichum , Parabacteroides , Candida , and cholest‐4‐en‐3‐one, associated with duodenal iron accumulation. This study demonstrates that although high‐dose parenteral iron effectively corrects IDA, it causes liver dysfunction, immune suppression, systemic iron overload, and altered gut microbiota. Our findings highlight the importance of appropriate iron dosing and reveal broader roles of trace elements in shaping gut microbiota.