Bear study shows environmental impact of antibiotic use

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Using DNA harvested from a museum collection of bear fossils, scientists have established a chronology of how widespread antibiotic use in humans and animals has contaminated the environment over time in Sweden.

In a study published this week in Current Biology, researchers from Sweden's Uppsala University conducted whole-genome sequencing on calcified oral bacteria from a museum collection of brown bear fossils dating back nearly 180 years. Their findings revealed that the prevalence and diversity of antimicrobial resistance (AMR) genes in the oral microbiomes of bears increased as antibiotic use in medicine and agriculture grew in the second half of the 20th century, then declined after Sweden began limiting antibiotic use.

The researchers say their study highlights how human actions can directly impact diverse microbial communities, and how efforts to restrict antibiotics use in human and animals could curb the spread of AMR through the environment.

Bear microbiomes mirror rise of antibiotic use

For the study, the researchers collected dental calculus from 57 Swedish brown bear samples at the Swedish Museum of Natural History in Stockholm. The samples dated from 1842 to 2016. Their aim was to analyze the DNA from the bears' oral microbiome, which is preserved within the calcified dental plaque, to establish how AMR levels have changed in the environment before and after mass production of antibiotics.

The researchers chose to analyze bears because bears are omnivores and scavengers who are exposed to a wide range of potential sources of AMR genes and antibiotic residues that leak into the environment from hospitals and farms through wastewater. And while host microbiomes aren't preserved after deaths, previous research by the team has shown that sequencing DNA from dental calculus can provide information on the oral microbial community of animals, including potential pathogens and resistance genes.

Focusing on bacteria that are known to colonize the mouths of humans and pets, the team conducted shotgun metagenomic sequencing, a process that involves taking the DNA out of all the bacteria in the samples, breaking it up into small pieces, and analyzing all of it for the presence of resistance genes. The total AMR load in each sample was determined by aligning the results with the Comprehensive Antibiotic Resistance Database, a collection of molecular sequences and genes associated with drug resistance.

They divided the samples into five time periods: pre-1951, before commercial production of antibiotics began; 1951 to 1970, when antibiotic production and use in Sweden was increasing; 1971 to 1985, when concerns about AMR were first raised in Sweden but no restrictions were implemented; 1986 to 2000, when control measures, including a ban on the use of antibiotics as growth promoters in livestock, were implemented in Sweden; and post-2000, a period that has seen decreased sales of antibiotics for outpatient and veterinary use.

The results of the analysis revealed some AMR genes in the pre-antibiotics era, which was expected since environmental bacteria naturally produce resistance genes. The total AMR load in the samples increased significantly from 1951 through the early 1990s, mirroring the rising use of antibiotics in human and veterinary medicine during that period. The AMR load in the samples then declined after 2000, about 15 years after antibiotic restrictions were first implemented in Sweden.

The AMR load was notably lower among bears born after 1995, when the Swedish strategic program against antibiotic resistance (Strama) was implemented. The researchers note that the observed decline in total AMR load in the brown bear samples from 2000 onward matches results from Swedish farm animal screening, which has shown low and decreasing resistance in Escherichia coli and Staphylococcus aureus isolates.

The researchers also found that the diversity of AMR genes and resistance mechanisms in the dental calculus increased from 1986 onward, which reflects new and different types of antibiotics being used by people.

Unexpectedly, bear samples found closer to human habitations didn't have higher AMR loads despite previous studies showing a link between AMR genes in the environment and proximity to humans, the researchers note. Among the 50 bear specimens that had location information, the researchers could find no association between total AMR load and historic human population density.

"We found similar levels of antibiotic resistance in bears from remote areas and those found near human habitation. This suggests that the contamination of the environment with resistant bacteria and antibiotics is really widespread," Katerina Guschanski, PhD, lead senior author of the study with joint appointments at Uppsala University and the University of Edinburgh, said in an Uppsala University press release.

Stewardship can mitigate impacts

The hopeful news from this study is that it suggests that AMR contamination in the environment can be mitigated if countries take steps to reduce antibiotic use.

Sweden has been a leader in those efforts. It was the first country to legally ban the use of antibiotics for growth promotion in food-producing animals, and Strama has been widely recognized for raising awareness of antibiotic resistance, advocating for rational use, and reducing outpatient antibiotic use since 1995. The country routinely ranks among the European countries with the lowest rates of antibiotic consumption, both in animals and humans.

"Our case study suggests that human actions, both negative and positive, can directly impact diverse microbial communities, including those associated with wild animals, and provides evidence that large-scale policies limiting the use of antimicrobials in humans and livestock may be effective in curbing the dissemination of AMR through environmentally mediated pathways," Guschanski and her colleagues wrote.

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