"We've seen, across the board, that antibiotic consumption is going up," said Dr. Ramanan Laxminarayan, director of the Center for Disease Dynamics, Economic & Policy, during a session about fighting the AMR crisis at ASM's 2022 Microbe conference. Indeed, global antibiotic use increased 65% between 2000 and 2015-and, if no actions are taken, could double by 2030.
The rise in antibiotic use stems from many factors, including greater antibiotic accessibility and affordability, particularly in low- and middle-income regions; antibiotic misuse (e.g., to treat viral infections, like COVID-19 or influenza) and agricultural applications, among others. This increase has fueled the emergence and spread of AMR, and the world is now facing a bleak future where go-to therapies for treating microbial infections may no longer be enough. Countries are already "cycling out of [using] a set of antibiotics that were once effective and cycling into a set that should [only] be kept for problematic episodes," Laxminarayan stated.
Part of fighting the spread of AMR is identifying reservoirs of resistant organisms. As it turns out, scientists don't have to look far.
The human gut is full of diverse bacteria, many of which harbor resistance against a broad range of antibiotics. This includes pathogenic species featured in the CDC's Antibiotic Resistance Threats Report, such as vancomycin-resistant Enterococci and carbapenem-resistant Enterobacteriaceae. Humans acquire AMR organisms and antibiotic-resistance genes (ARGs) from, and can spread them to, other reservoirs, such as animals. Thus, the gut resistome-the collection of ARGs harbored by the microbiota-is an important piece of the AMR puzzle.
Antibiotic Resistance and the Gut Microbiota
While some gut-dwelling microbes are naturally resistant to antibiotics, others acquire resistance from fellow microbes. Bacteria swap genetic material, like ARGs, through several forms of horizontal gene transfer (HGT), including conjugation (the transfer of DNA between cells, often via mobile genetic elements like plasmids and transposons), transduction (bacteriophage-mediated transfer of genes between bacterial hosts) and transformation (a process through which bacteria absorb DNA from the environment and incorporate it into their genome).
HGT, and thus the exchange of ARGs, readily occurs when many microbes are cozied up together. With so many bacteria in close proximity, the gut provides ideal conditions for exchange. In fact, it is estimated that the baseline level of HGT within the gut is 25 times higher than that of soil, another microbe-rich environment. The selective pressure these microbes may face from prophylactic or therapeutic antibiotics only fuels the transfer of ARGs.
Many intestinal bacteria harboring ARGs, a large fraction of which are anaerobic commensal species, do not pose a health threat. The problem is when ARGs are acquired by microbes with pathogenic potential. For instance, nestled amongst the robust populations of anaerobic gut bacteria are a smaller number of facultative anaerobes, including Enterobacteriaceae and Enterococcaceae spp. Bacteria within these groups include common culprits of AMR infections, such as multi-drug resistant strains of E. coli, Klebsiella pneumonieae and Enterococcus faecalis. These microbes can pick up ARGs from other members of the gut microbiota. For example, a transposon harboring the vanB gene, which confers resistance against vancomycin, is common among gut anaerobes. These bacteria can transfer the vanB gene to Enterococcus species. Given vancomycin-resistant Enterococci are classified as a "serious threat" by the CDC, this is particularly concerning.
What Influences Gut Resistome Composition?
The gut resistome develops when microbes flood the gut immediately after birth. Interestingly, infants have a higher abundance of ARGs within their guts than adults. This coincides with the composition of their microbiota (e.g., the infant gut contains a higher proportion of Proteobacteria, like E . coli, which are key ARG sources). Other factors, like mode of birth and whether/how long a baby is nursed can also influence gut resistome development.
As the gut microbiota develops and evolves throughout life, so does the resistome. Though antibiotic use (and misuse) invariably contribute to AMR and the composition of the resistome, there are other factors that play a role as well.
Diet
Diet is closely intertwined with the composition of the microbiota and, presumably, the resistome. For instance, when researchers analyzed the gut microbiome and diets of 290 healthy individuals, they found that people who ate a diverse, fiber-rich diet had a lower abundance of ARGs in their gut. The scientists speculate that higher fiber "drives the composition of the gut toward a more obligate anaerobe state, reducing footholds for facultative anaerobes, which are known harbors of inflammation and antibiotic resistance." These data suggest that, by sculpting the composition of the microbiota, diet also regulates the resistome. However, other studies have reported no association between dietary habits and resistome composition. Given these discrepancies, more research is needed to understand the interaction between diet and the gut resistome.
Animals and the Environment
"The bulk of antibiotic [use] globally [occurs in] pigs, then humans, chickens, cattle and, finally, aquaculture," Laxminarayan said. The use of antibiotics in animals promotes the development of AMR organisms. As a result, humans can acquire AMR microbes and genetic elements from (and spread them to) environmental reservoirs, with animals being particularly important links in the chain of transmission.
Humans can pick up AMR organisms when handling or eating meat from animals harboring AMR microbes, consuming produce fertilized with manure containing resistant microbes or genes or contacting contaminated wastewater and animal feces. These microbes and/or ARGs can then integrate within the gut microbial community.
When scientists examined the gut resistome of veterinary students who completed internships at swine farms, they identified 270 ARGs (most of which encoded resistance to beta-lactamases, aminoglycosides and chloramphenicol) that had transferred from the swine farm environment to the students' gut microbiotas. The study highlighted the interconnectivity between environmental and human microbiomes and resistomes. This intersection is further evidenced by the fact that human populations with limited exposure to antibiotics, such as the Hadza hunger-gatherer communities in Tanzania, harbor ARGs in their guts, suggesting acquisition from environmental sources like soil.
Geography
Where someone lives influences the composition of their gut resistome. In fact, simply travelling from one part of the world to another can alter an individual's resistome. One study profiled the gut resistomes of individuals before and after travel to diverse locations, including countries in Southern Asia and Northern Africa. When the travelers returned home from abroad, they had a larger and more diverse pool of ARGs in their guts than before they left. Moreover, the resistomes of individuals returning from the same country were more similar than those returning from different countries, suggesting that each region is characterized by a distinct resistome signature.
These locational variations are likely tied to dietary differences, antibiotic and agricultural practices and environmental factors across the world. AMR is generally higher in low- or middle-income countries. These populations "have less access to newer, potentially more effective antibiotics than higher income countries, which can exacerbate the problem of resistance," said Laxminarayan. It is possible these differences are reflected in gut resistome composition.
Fighting the Battle Against AMR
According to Laxminarayan, the "need to work across the board [is both] the challenge and opportunity for battling AMR." He emphasized that capitalizing on the interconnectedness between factors, such as the intersection between AMR in animals and humans, will be a key part of the solution.
With that, the human gut microbiome does not exist in isolation. It is part of a network of microbial communities within the environment. Better understanding of the gut resistome, and how it influences and contributes to AMR on a broad scale, could be useful for monitoring and addressing the AMR crisis.
Research in this article was presented at ASM Microbe, the annual meeting of the American Society for Microbiology, held June 9-13, 2022, in Washington, D.C.
