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Species-Level Analysis of the Human Gut Microbiome Shows Antibiotic Resistance Genes Associated With Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) is the second leading cause of cancer deaths and continuously increases new cancer cases globally. Accumulating evidence links risks of CRC to antibiotic use. Long-term use and abuse of antibiotics increase the resistance of the gut microbiota; however, whether CRC is associated with antibiotic resistance in gut microbiota is still unclear. In this study, we performed a de novo assembly to metagenomic sequences in 382 CRC patients and 387 healthy controls to obtain representative species-level genome bins (rSGBs) and plasmids and analyzed the abundance variation of species and antibiotic resistance genes (ARGs). Twenty-five species and 65 ARGs were significantly enriched in the CRC patients, and among these ARGs, 12 were multidrug-resistant genes (MRGs), which mainly included acrB, TolC, marA, H-NS, Escherichia coli acrR mutation, and AcrS. These MRGs could confer resistance to fluoroquinolones, tetracyclines, cephalosporins, and rifamycin antibiotics by antibiotic efflux and inactivation. A classification model was built using the abundance of species and ARGs and achieved areas under the curve of 0.831 and 0.715, respectively. Our investigation has identified the antibiotic resistance types of ARGs and suggested that E. coli is the primary antibiotic resistance reservoir of ARGs in CRC patients, providing valuable evidence for selecting appropriate antibiotics in the CRC treatment.

SUBMITTER: Liu C

PROVIDER: S-EPMC8715872 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Antibiotic resistance in pathogens is extensively studied, and yet little is known about how antibiotic resistance genes of typical gut bacteria influence microbiome dynamics. Here, we leveraged 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 found 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 than C. difficile strains lacking this gene. Organisms with genes for major facilitator superfamily drug efflux pumps have higher 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 organism's direction of change in relative abundance after administration of vancomycin and cephalosporin antibiotics. The most accurate results were obtained by reducing annotated genomic data to five principal components classified by boosted decision trees. Among the genes involved in predicting whether an organism increased in relative abundance after treatment are those that encode 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 treatment and predict how organisms in the gut microbiome will respond to antibiotic administration. IMPORTANCE The process of reconstructing genomes from environmental sequence data (genome-resolved metagenomics) allows 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 applications.

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Species-Level Analysis of the Human Gut Microbiome Shows Antibiotic Resistance Genes Associated With Colorectal Cancer.

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