Iron deficient diets modify the gut microbiome and reduce the severity of enteric infection in a mouse model of S. Typhimurium-induced enterocolitis

Abstract

Enteric infections are widespread in infants and children living in low-resource settings. Iron availability in the gastrointestinal tract may modify the gut microbiome and impact the incidence and severity of enteropathy. This study was designed to determine the effect of an iron-deplete compared to an iron-rich environment in the lower intestine on the gut microbiome, and whether iron availability in the lower intestine affects the host immune response and severity of enteric infection in young mice. Weanling C57BL/6 female mice were fed an iron deficient (Fe^-, <6 ppm iron) or an iron fortified (Fe⁺, 300 ppm iron) diet for 6 weeks. Mice were pretreated with streptomycin prior to oral inoculation of Salmonella enterica subspecies enterica serovar Typhimurium to induce enteric infection (Sal⁺) or saline control (Sal^-). Cecal iron concentrations were 55-fold greater with Fe⁺Sal^- compared to Fe^-Sal^-. Microbiome sequencing revealed shifts in gut microbiota with dietary iron and enteric infection. There was ∼30% more S. Typhimurium in the cecum of Fe⁺Sal⁺ compared to Fe^-Sal⁺. Plasma hepcidin increased with dietary iron and enteric infection, but was greatest in Fe⁺Sal⁺. Plasma lipocalin-2 and spleen size relative to bodyweight were greater in Fe⁺Sal⁺ compared to Fe⁺Sal^-, Fe^-Sal^- and Fe^-Sal⁺, and Fe⁺Sal⁺ lost more bodyweight compared to Fe^-Sal⁺. Unabsorbed iron in the lower intestine modifies the gut microbiome and promotes a more severe enteropathy. These findings could suggest the need for alternative iron supplementation strategies in areas where enteric infection are common.

Keywords: Anemia; Environmental enteric dysfunction; Hepcidin; Iron deficiency; Nutritional immunity.