Though a popular sci-fi TV show popularized the phrase that “resistance is futile,” I don’t think they were referring to the population of microbes that inhabited our intestinal tract. Yet now, new evidence from a collaborative study led by investigators at the Institut National de la Recherche Agronomique (INRA) in France and Kings College London solidifies the hypothesis that the human intestinal microbiome is considered a major reservoir for antibiotic resistance determinants (ARDs). Moreover, the research team has used an innovative approach to identify thousands of antibiotic resistance genes found in bacteria that inhabit the human gut.
“Most gut bacteria live in a harmless relationship with the human host. However, the gut is also home to bacteria that can cause infections in hospitalized patients,” explained study investigator Willem van Schaik, Ph.D., professor at the Institute of Microbiology and Infection at University of Birmingham, U.K. “Unfortunately, these bacteria are becoming increasingly resistant to antibiotics and we need to understand the processes that contribute to this development.
Findings from the new study were published recently in Nature Microbiology through an article titled “Prediction of the intestinal resistome by a three-dimensional structure-based method.”
The human gut is home to trillions of microorganisms, mainly bacteria. Most of these are sensitive to antibiotics, but a significant number of bacteria in the human gut have mechanisms that make them resistant to antibiotics. However, we still lack a mechanistic understanding of the genes that confer resistance to antibiotics in gut bacteria.
The research team developed a new method to identify resistance genes in gut bacteria by comparing the three-dimensional structures of known antibiotic resistance enzymes to the proteins that are produced by gut bacteria.
“An accurate census of intestinal ARDs (that is, the intestinal resistome) has not yet been fully determined,” the authors wrote. “For this purpose, we developed and validated an annotation method (called pairwise comparative modeling) on the basis of a three-dimensional structure (homology comparative modeling), leading to the prediction of 6,095 ARDs in a catalog of 3.9 million proteins from the human intestinal microbiota. We found that the majority of predicted ARDs (pdARDs) were distantly related to known ARDs (mean amino acid identity 29.8%) and found little evidence supporting their transfer between species. According to the composition of their resistome, we were able to cluster subjects from the MetaHIT cohort (n = 663) into six resistotypes that were connected to the previously described enterotypes.”
Applying this method to a catalog of several million genes of the gut, the research team was able to identify more than 6,000 antibiotic resistance genes that are very different from previously identified genes in pathogenic bacteria.
“By comparing the structures of known antibiotic resistance proteins to proteins that are produced by the bacteria of the human gut, we found thousands of new antibiotic resistance genes in the human gut, highlighting the immense diversity of antibiotic resistance genes in this environment,” Dr. van Schaik noted. “Most of these genes appeared to be present in bacteria that live in a harmless relationship with the human host, so may not be an immediate threat to human health. However, the continuing use of antibiotics may lead to these resistance genes being transferred to pathogenic bacteria, thereby further reducing the effectiveness of antibiotics in treating infections.”
The study authors were encouraged by their findings and concluded that “our results indicate that the majority of intestinal microbiota ARDs can be considered intrinsic to the dominant commensal microbiota and that these genes are rarely shared with bacterial pathogens.”