Investigating the Role of the Tetracycline Resistance Gene tetX in the Human Gut Microbiome

Abstract

The widespread clinical and agricultural use of tetracycline antibiotics has led to the global rise of tetracycline resistance genes in bacteria. Recently, enzymatic inactivation of tetracycline has emerged as a novel and particularly powerful resistance mechanism. TetX, one such tetracycline-inactivating enzyme, acts as an oxygen-dependent destructase which degrades tetracycline. The tetX gene has been found to be present and expressed in the human gut microbiome, which may contribute to the spread of antibiotic resistance in clinical settings. However, the role of tetX in the gut environment is still unclear, given that the gut contains little to no oxygen. In order to address this paradox and evaluate whether intestinal TetX poses a threat to clinical antibiotic use, we examine the role of TetX in the human gut. Using a diverse metagenomic sequencing dataset, we first confirm the widespread prevalence and abundance of tetX in the human gut microbiome. We next show that tetX is found in a wide variety of bacterial taxa in the gut and is often found near mobile genetic elements, indicating that it may be easily genetically transferred between bacteria residing in the gut and pathogens passing through the gut. Finally, we report that the most common intestinal TetX variant is able to confer resistance to tetracycline in both aerobic and microaerophilic conditions. The ability to confer resistance in a microaerophilic environment could explain why the tetX gene is widely maintained in the human gut, as the gut may have microaerophilic areas containing bacteria that can use TetX to survive exposure to tetracycline. Because the TetX variants in the human gut microbiome are widely distributed, easily transferred, and active enzymes, we conclude that they will likely contribute to the global spread of tetracycline resistance among pathogens, which would be clinically devastating. By proactively characterizing the dissemination and function of antibiotic resistance genes found in the gut, we hope to minimize their future clinical impact.