The exploitation of nutrient metals by bacteria for survival and infection in the gut

Trace transition metals are required for cellular life processes, such as respiration, metabolism, and DNA replication. At high levels, nutrient metals can be toxic due to oxidative stress and mismetallation of critical metalloenzymes. All organisms tightly regulate intracellular trace metal levels to ensure sufficiency for essential processes while avoiding excess. Microbes including bacteria, viruses, fungi, and archaea colonize hosts forming the microbiota, which in vertebrates is most abundant in the gastrointestinal tract. Invading pathogens compete for metals not only with the host but also with the resident gut microbiota, which provides colonization resistance. To prevent severe infection by enteric pathogens, vertebrate hosts leverage the narrow viable range of trace metal concentrations via both metal sequestration and intoxication in a process called nutritional immunity. In response, microbes have evolved trace metal uptake and export mechanisms to maintain homeostatic levels. In this review, we discuss how the trace transition metals iron, zinc, manganese, and copper influence the composition of the gut microbiota and its subsequent ability to compete with enteric pathogens. We explore the specialized mechanisms that pathogens employ to successfully acquire nutrient metals during infection in the gut and describe how these systems could be exploited for therapeutic development. Finally, we report the powerful mechanisms utilized by the microbiota to compete with enteric pathogens for metals and how they can inspire potential antipathogenic tools.