Early-life exposure to multiple micronutrient deficiencies induces clinically-relevant antibiotic resistance in a pre-clinical murine model

Abstract Globally, ~340 million children (<5 years) suffer from multiple micronutrient deficiencies, accompanied by high pathogenic burden and death due to multi-drug resistant bacteria. The role of early-life micronutrient deficiencies in mitigating antibiotic resistance within the host microbiota remains unexplored. We developed a postnatal preclinical murine model deficient in multiple micronutrients: zinc, folate, iron, vitamin A, and vitamin B12. Fecal metagenomic sequencing after dietary exposure revealed enrichment in the relative abundance of pathobionts and antibiotic resistance mechanisms including efflux pumps, target drug site alteration, antibiotic degrading enzymes, permeability, and acquisition of antibiotic resistance genes (ARGs). Despite being antibiotic naïve, we observed increased abundance of genes encoding resistance to several antibiotic classes: tetracycline, vancomycin, methicillin, fosfomycin, aminoglycosides and glycopeptides. Moreover, in vitro antibiotic susceptibility testing revealed clinically-relevant resistance to multiple antibiotic classes, namely vancomycin, methicillin, amoxicillin and erythromycin in mice fed the low-micronutrient diet. These novel findings present an unappreciated and profound role of cooccurring multiple micronutrient deficiencies in contributing to the global burden of antibiotic resistance, with significant clinical implications for undernourished children living in low-to-mid income countries.