Gut microbial metabolism shifts towards a more toxic profile with supplementary iron in a kinetic model of the human large intestine. TIM2_iron_study

Safety of oral iron administration in African children has been questioned as it is associated with an increased burden of infectious disease. However, it remains unclear to which extent oral iron administration affects the intestinal microbiome. Therefore, we here investigated the impact of multiple iron preparations and doses on the growth and metabolism of a human gut microbiota in a well-controlled in vitro model of the large intestine. Microbiome analysis showed clear iron-induced changes and prominent shifts included a decrease of Bifidobacteriaceae and Lactobacillaceae under iron-rich conditions, paralleled by an increase of Roseburia and Prevotella. Metagenomic analyses showed a general enrichment of bacterial motility-chemotaxis systems under iron-rich conditions. Metabolome profiling showed that gut microbial activity markedly shifted from a saccharolytic to a proteolytic profile in response to iron. Levels of branched chain fatty acids and ammonia increased significantly, in particular under ferrous sulfate-rich conditions. Importantly, cell viability tests showed increased cytotoxicity of metabolite-containing effluent from iron-rich conditions. We also identified microbial metabolites with siderophoric activity that were specifically produced under low-iron conditions. Our data indicate that in the absence of host influences, iron induces a more hostile intestinal environment characterized by i) reduction of beneficial microbes and increase of certain bacterial species with pathogenic potential, ii) increased levels of bacterial metabolites that can impair the barrier function of the gut wall, and iii) increase of virulence-associated pathways of enteric pathogens. It can be envisaged that these in vitro phenomena also contribute to an increased risk for enteric infections in vivo.