One of the strategies used by vertebrate hosts to defend against bacterial pathogens is that of sequestering transition metals required for intracellular and extracellular pathogen survival. This process is called “nutritional immunity” and, in response, bacteria have evolved strategies to access metals and counteract this host mechanism of defense.
A new review, led by Dr. Christopher Lopez and Prof. Eric P. Skaar from the Vanderbilt University Medical Center in Nashville (USA), focuses on mechanisms leading to increased susceptibility to bacterial infection in the context of interactions between dietary transition metals, the microbiota and the host.
Both mammalian hosts and the commensal microbiota living within and on them require transition metals for essential biological processes. Zinc, iron and manganese are the most common transition metals with co-factor or structural roles in mammalian and bacterial proteins. However, they may become toxic at high concentrations, highlighting the importance of tightly controlled concentrations in maintaining homeostasis.
The review explores how dietary transition metal deficiency or excess affects the distribution and function of the gut microbiota, focusing on the impact of metal-host-microbe interactions on the outcome of disease.
Dietary transition metal availability in the intestine shapes microbiota-host interactions and bacterial pathogenesis. Zinc deficiency drives microbiota homeostasis away from beneficial bacteria such as Akkermansia muciniphila and creates a low inflammatory environment that favors susceptibility to enteric infections caused by an increase in members of the Enterobacteriaceae family and Enterococcus genus associated with intestinal dysbiosis. The clinical translation of this observation is that zinc supplementation is being used to maintain gut homeostasis by directly inhibiting pathogen virulence or by selecting beneficial microbes for growth. However, mice data has shown that an excess of zinc could alter the microbiota and decrease resistance to Clostridium difficile infection.
In parallel with low zinc, high iron in a diet may reduce overall commensal bacterial diversity. This allows for an increase in the abundance of members of the Enterobacteriaceae family, many of which are pathogenic and encode high-affinity metal transporters and siderophores to obtain nutrient metals. When it comes to the role of manganese on the gut ecosystem, how dietary deficiency or excess in humans affects the gut microbiota composition is unknown.
The review also covers how changes to metal absorption and transport may affect extraintestinal sites through alterations in the immune system, metal localization, and bacterial access to metals. Zinc deficiency may lead to an increased susceptibility to infection through a depression of the adaptive immune response to infection. However, as slow intracellular bacterial replication has also been reported in response to zinc limitation—pathogens have evolved mechanisms to acquire zinc for growth—the authors are cautious regarding zinc supplementation for improving disease outcome.
Iron overload and deficiency also has an impact on bacterial growth. Iron overload may increase risk of death from Mycobacterium tuberculosis by providing an iron-replete intracellular environment in the alveoli and inhibiting host primary innate defenses against M. tuberculosis. On the other hand, iron supplementation aimed at correcting iron deficiency, has been related to an increased risk of infection with the malarial parasite Plasmodium and the risk of co-morbidities such as bacteraemia with an overgrowth of Gram-positive as well as Gram-negative pathogens that preferentially use heme as an iron source. Another example that illustrates how bacteria take advantage of iron deficiency is Helicobacter pylori, which manipulates host iron metabolism under iron-deplete conditions to survive in the stomach. Together, these findings suggest that due to tightly regulated responses of transition metals on both the host and its microbiota, it is not always easy to predict the success of supplementing with the lacking metal for better health outcomes. Here, excess iron supplementation should be carefully personalized to avoid collateral alterations in infection risk.
Beyond zinc, iron and manganese, other less abundant metals such as dietary copper, nickel, cobalt and molybdenum also take part in the proper functioning of several cellular processes. All are important in many bacterial enzymes and contribute to pathogen virulence and growth, as well as affecting other transition metal homeostasis.
In conclusion, the review provides an update of how transition metal deficiency and overload affect the survival of both mammals and microbes through highly regulated mechanisms. Overall, these data support the utility of exploiting these systems as targets for developing new antimicrobials against the current emerging infectious threat seen in some countries.
Lopez CA, Skaar EP. The impact of dietary transition metals on host-bacterial interactions. Cell Host Microbe. 2018; 23(6):737-48. doi: 10.1016/j.chom.2018.05.008.