In the Literature

Uncontacted Amerindians: Highly Diverse Microbiomes but With a Reservoir of Antibiotic Resistance Genes

Clemente JC, Pehrsson EC, Blaser MJ, et al. The microbiome of uncontacted Amerindians. Sci Adv 2015;1. pii:e1500183.

The diversity of the human microbiome, which plays a significant role in health is altered by many aspects of modern life. The resulting perturbation of the co-evolution and symbiotic relationship between humans and their microbiomes raises important concerns of potential consequent effects on human well-being at the population level [1]. Previous studies have examined the microbiomes of isolated populations. Some of these populations, however, were not completely isolated in that they had experienced at least limited prior contact with the modern world. Examination of the microbiome as well as the resistome (the array of antimicrobial resistance genes) of a truly uncontacted population would add further strength to these findings.

Clemente and colleagues sampled forearm skin, oral mucosa, and feces of 34 Yanomami subjects between 4 and 50 years of age for microbiome and resistome analysis. Similar samples were obtained from control groups. The Yanomami are a group of seminomadic hunter-gatherers in the Amazon who were first contacted by the outside world in the mid-1960s. In Venezuela, they live in a protected region and the individuals included in this study had no prior contact with non-Yanomami.

The Yanomami subjects proved to have the highest microbiome bacterial diversity relative to all control groups studied. More strikingly that diversity was the greatest of any human group reported.

Phenotypic testing of 131 Escherichia coli strains from 11 fecal specimens obtained from Yanomami subjects found that all were susceptible to all 23 antibiotics tested. Creation of functional libraries derived from genomic DNA of 38 of these isolates, nonetheless, led to the identification of resistance genes against 8 antibiotics. Four of these had been included in the phenotypic screen that failed to reveal resistance, indicating a lack of sensitivity of phenotypic resistance testing. Shotgun metagenomic libraries allowed the identification of a total of 28 functional antibiotic resistance genes; these included, in addition to an extended-spectrum β-lactamase, genes associated with resistance to semisynthetic and fully synthetic antibiotics.

This study confirms the evolutionary change that has occurred in the human microbiome in association with changes in the experiences associated with modern human life. The implications of this loss of diversity for ongoing human evolution remain unclear, but it is certain to have significant effects. The identification of genes associated with antimicrobial resistance in this previously uncontacted population is consistent with earlier reported findings in perhaps less “virginal” populations and also demonstrates that antimicrobial resistance genes, including ones to fully synthetic antibiotics are present in the microbiomes of in truly uncontacted populations. Such genes against naturally occurring antibiotics may have become part of the human resistome as the result of exchange with antibiotic-producing organisms in the soil. The origin of genes encoding resistance against synthetic antibiotics is more difficult to explain. Also of interest, however, is that these resistance genes were maintained in the Yanomami in the absence of exposure to the selective pressure exerted by antibiotic exposure; as the investigators point out, their persistence, suggests an explanation for the rapid emergence of resistance once individuals are exposed to antibiotics.

Reference

Plasmid-Mediated Resistance to Colistin: Present in at Least 3 Continents

Liu YY, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2015. doi:10.1016/S1473-3099(15)00424-7.

The relentless emergence of multidrug resistance among aerobic gram-negative bacilli has made the polymyxin antibiotics, colistin (polymyxin E) and polymyxin B, the antibiotics of last resort some cases. The increasing number of reports of organisms resistant even to these polypeptide antibiotics is, however, of great concern, especially as this it is often accompanied by the presence of resistance to all available β-lactam antibiotics with the exception of ceftazidime-avibactam. A recent global survey of Enterobacteriaceae found that 12.0% of carbapenemase-positive isolates were resistant to colistin [1]. Resistance to these polymyxin antibiotics has been known to be the result of alterations in lipid A as a consequence of chromosomal mutations that are non-transferable, thus limiting their spread.

Liu and colleagues in China, during routine surveillance of antimicrobial resistance of Escherichia coli in food animals, identified an isolate from a pig with transferable colistin resistance that was mediated by a gene, mcr-1, that was carried on a plasmid. The plasmid could be mobilized to a recipient E. coli at high frequency and could be maintained in Klebsiella pneumoniae and Pseudomonas aeruginosa. The action of MCR-1 results in addition of phosphoethanolamine to lipid A, altering its charge and thus its affinity for polymyxins. The investigators identified E. coli carrying mcr-1 in 8 of 523 (15%) samples of raw meat and 166 of 804 (21%) animals during 2011–2014. In addition, they examined 1322 isolates from hospitalized patients with infection and identified mcr-1 in 16 (1%), including samples of urine, sputum, from drainage fluid, ascitic fluid, bile, and a wound.

Unfortunately, the fact that the presence of this resistance gene is not restricted to China has rapidly become apparent. Liu and colleagues noted that 5 E. coli DNA contigs containing mcr-1–like genes from Malaysia had recently been submitted to the European Molecular Biology Laboratory. Shortly after the findings of Liu and colleagues were published, Hasman and colleagues reported the identification of mcr-1 in an E. coli isolate (which also carried an additional 15 antibiotic resistance genes) recovered from the blood of a patient in Denmark as well as from 5 imported chicken meat samples [2]. Of 2002 returned Dutch travelers prospectively studied, 6 had acquired E. coli carrying the mcr-1 gene in their feces; none had taken antibiotics and none received medical care during travel [3]. The countries visited were Peru, Bolivia, China, Thailand, Vietnam, Laos, and Cambodia. Screening of samples from a number of countries also identified the gene in 19 isolates, 12 of which were identical to that described in China. These included E. coli strains recovered from asymptomatic people, pigs, and chickens in Laos, Thailand, and Algeria [4]. It has also been identified in turkeys in Italy. Finally (for now, as it is certain that more is to come), mcr-1 has been detected in Canada in 1 human infection sample and 2 ground beef samples [5].

The mcr-1 gene is not limited to E. coli. Screening of 8664 Salmonella isolates from the French agricultural food sector identified 5 (0.06%) that were colistin-resistant, and 4 of the 5 carried the mcr-1 gene on plasmids whose backbone was, however, distinct from that reported by Liu and colleagues. The gene has also been detected in Salmonella typhimurium from a food sample in Portugal [6].

The time of the initial emergence of the mcr-1 gene is yet to be determined. One of the Canadian samples containing the gene dates to 2010. In addition, examination of datasets derived from 1267 human fecal samples believed to have been sampled before 2011 found the MCR-1 gene in 3 Chinese intestinal microbiomes [7]. The reason for its emergence is likely related to the widespread use of colistin in agriculture.

References