Machine learning leveraging genomes from metagenomes identifies influential antibiotic resistance genes in the infant gut microbiome

Abstract

Antibiotic resistance in pathogens is extensively studied, yet little is known about how antibiotic resistance genes of typical gut bacteria influence microbiome dynamics. Here, we leverage genomes from metagenomes to investigate how genes of the premature infant gut resistome correspond to the ability of bacteria to survive under certain environmental and clinical conditions. We find that formula feeding impacts the resistome. Random forest models corroborated by statistical tests revealed that the gut resistome of formula-fed infants is enriched in class D beta-lactamase genes. Interestingly, Clostridium difficile strains harboring this gene are at higher abundance in formula-fed infants compared to C. difficile lacking this gene. Organisms with genes for major facilitator superfamily drug efflux pumps have faster replication rates under all conditions, even in the absence of antibiotic therapy. Using a machine learning approach, we identified genes that are predictive of an organisms direction of change in relative abundance after administration of vancomycin and cephalosporin antibiotics. The most accurate results were obtained by reducing annotated genomic data into five principal components classified by boosted decision trees. Among the genes involved in predicting if an organism increased in relative abundance after treatment are those that encode for subclass B2 beta-lactamases and transcriptional regulators of vancomycin resistance. This demonstrates that machine learning applied to genome-resolved metagenomics data can identify key genes for survival after antibiotics and predict how organisms in the gut microbiome will respond to antibiotic administration.\n\nImportanceThe process of reconstructing genomes from environmental sequence data (genome-resolved metagenomics) allows for unique insight into microbial systems. We apply this technique to investigate how the antibiotic resistance genes of bacteria affect their ability to flourish in the gut under various conditions. Our analysis reveals that strain-level selection in formula-fed infants drives enrichment of beta-lactamase genes in the gut resistome. Using genomes from metagenomes, we built a machine learning model to predict how organisms in the gut microbial community respond to perturbation by antibiotics. This may eventually have clinical and industrial applications.