Elemental iron modifies the redox environment of the gastrointestinal tract: A novel therapeutic target and test for metabolic syndrome

Metabolic syndrome (MetS, i.e., type 2 diabetes and obesity) is often associated with dysbiosis, inflammation, and leaky gut syndrome, which increase the content of oxygen and reactive oxygen species (ROS) in the gastrointestinal (GI) tract. Using near-infrared fluorescent, in situ imaging of ROS, we evaluated the effects of oral administration of elemental iron powder (Fe0) on luminal ROS in the GI tract and related these changes to glucose metabolism and the gut microbiome. C57Bl/6J mice fed low-fat or high-fat diets and gavaged with Fe0 (2.5 g per kg), in both single- and repeat-doses, demonstrated decreased levels of luminal ROS. Fourteen days of repeated Fe0 administration reduced hyperglycemia and improved glucose tolerance in the obese and hyperglycemic animals compared to the untreated obese controls and reduced the relative amount of iron oxides in the feces, which indicated an increased redox environment of the GI tract. We determined that Fe0 administration can also be used as a diagnostic assay to assess the GI microenvironment. Improved metabolic outcomes and decreased gastrointestinal ROS in Fe0-treated, high-fat diet-fed animals correlated with the increase in a co-abundance group of beneficial bacteria, including Lactobacillus, and the suppression of detrimental populations, including Oscillibacter, Peptococcus, and Intestinimonas. Daily Fe0 treatment also increased the relative abundance of amplicon sequence variants that lacked functional enzymatic antioxidant systems, which is consistent with the ability of Fe0 to scavenge ROS and oxygen in the GI, thus favoring the growth of oxygen-sensitive bacteria. These findings delineate a functional role for antioxidants in modification of the GI microenvironment and subsequent reversal of metabolic dysfunction. [Display omitted] •GI ROS and oxygen may be therapeutic targets for non-bioavailable antioxidants to mitigate MetS.•Poorly absorbed antioxidants modify the gut microbiome and metabolic status of obese mice via luminal oxygen scavenging.•Oral administration of Fe0 reduces ROS in the GI tract of obese/hyperglycemic mice and improves their glucose metabolism.•Daily Fe0 treatment increases the relative abundance of gut microbes without functional antioxidant systems.•The rapid, non-invasive test developed to assess the GI redox environment may be applied to diagnose dysbiosis.