Multiple micronutrient deficiencies in early life cause multi-kingdom alterations in the gut microbiome and intrinsic antibiotic resistance genes in mice

Abstract

Globally, ~340 million children suffer from multiple micronutrient deficiencies, accompanied by high pathogenic burden and death due to multidrug-resistant bacteria. The microbiome is a reservoir of antimicrobial resistance (AMR), but the implications of undernutrition on the resistome is unclear. Here we used a postnatal mouse model that is deficient in multiple micronutrients (that is, zinc, folate, iron, vitamin A and vitamin B12 deficient) and shotgun metagenomic sequencing of faecal samples to characterize gut microbiome structure and functional potential, and the resistome. Enterobacteriaceae were enriched in micronutrient-deficient mice compared with mice fed an isocaloric experimental control diet. The mycobiome and virome were also altered with multiple micronutrient deficiencies including increased fungal pathogens such as Candida dubliniensis and bacteriophages. Despite being antibiotic naïve, micronutrient deficiency was associated with increased enrichment of genes and gene networks encoded by pathogenic bacteria that are directly or indirectly associated with intrinsic antibiotic resistance. Bacterial oxidative stress was associated with intrinsic antibiotic resistance in these mice. This analysis reveals multi-kingdom alterations in the gut microbiome as a result of co-occurring multiple micronutrient deficiencies and the implications for antibiotic resistance. A postnatal multiple micronutrient deficiency mouse model reveals shifts in bacterial, fungal and viral components of the gut microbiome with implications for microbiome-encoded intrinsic antibiotic resistance mechanisms.