High Dietary Carbonyl Iron Reshapes the Gut Microbiome and Impairs Hepatic Insulin Sensitivity in a Time‐Dependent Manner

The gut microbiome is widely viewed as an important regulator of host metabolism and immunity. Loss of microbial diversity can lead to gut dysbiosis, which has been linked to cardiometabolic and inflammatory disorders. Iron is an important micronutrient for both host and microbes, but its excess is toxic. To investigate the impact of dietary iron on the intestinal microbiome and host metabolism, wild type mice on standard chow were switched at baseline to a high-iron diet, containing 2% carbonyl iron for 3 weeks. Other groups of mice were switched to the high-iron diet only during the final 3 or 7 days of the 3-week period; control animals remained on standard chow. Fecal samples were collected at baseline (t = 0) and at the endpoint (t = 1) for microbiome analysis, while liver and skeletal muscle samples were analyzed for Akt phosphorylation as a marker of insulin sensitivity. Feeding with high carbonyl iron significantly altered the intestinal microbiome and increased overall alpha and beta diversity in a time-dependent manner. Differential abundance and network analyses revealed extensive taxonomic and structural reorganization, with notable increases in Akkermansiaceae, Rikenellaceae, Bilophila, Ruminiclostridium, and Lactobacillus, and decreases in Bifidobacteriaceae and Clostridiaceae_1. Iron overload was accompanied by reduced Akt phosphorylation, evident in the liver but not skeletal muscles at the 3-week endpoint. Together, these results demonstrate that feeding of mice with a high carbonyl iron diet reshapes gut microbial composition, increases diversity, and reorganizes microbial community networks. However, iron overload mitigates insulin responsiveness in the liver.