Fighting the Resistome

  • Antibiotic-resistant microbes threaten the health of humans and livestock.
  • Animals and humans host a natural reservoir of microbial antibiotic resistance genes (the resistome).
  • The resistome of dairy calves is large, diverse, and highly dynamic.
  • Early life diet in calves could repress the resistome and thereby decrease the risk of spreading of microbes with resistance to antibiotics.

 

We are incredibly lucky. We live at a time when antibiotics work their magic saving people from infections. Only a few generations ago, infections reigned supreme and struck down some people in most families. It had always been that way, but memory quickly fades. Modern society assumes that the effectiveness of antibiotics is here to stay—it’s a monument to human ingenuity. However, the continuing emergence of antibiotic-resistant microbes and the lack of new antibiotics in the developmental cupboard are looming threats to human health [1, 2], and a stark reminder that today’s respite from infection could easily be temporary.

Scientists conclude that the key to maintaining an arsenal of effective antibiotics is to understand how microbial resistance to antibiotics develops and spreads so that effective containment measures can be put in place [1, 3, 4]. Antibiotic-resistant microbes naturally arise. They circulate in complex microbial ecosystems and are prevalent in areas where antibiotics are used, especially within humans, food animals, and their immediate environments [1, 3-5]. Therefore, the management of microbial antibiotic resistance requires focus on containment measures in all areas where the resistance arises.

Cattle harbor antibiotic-resistant microbes [3-8]. However, scientists have shown that these microbes are not found in food products derived from cattle due to the stringent and multilayered hygiene practices used in abattoirs and the dairy industry [3]. They also agree that there is great difficulty identifying and tracking all antibiotic-resistant microbes in cattle and their local environment, and assessing the risk that these microbes could transfer antibiotic resistance into microbes that cause infections in humans. An exciting new scientific approach, exemplified in dairy calves, generated detailed and very useful information that may help contain the spread of antibiotic-resistant microbes in livestock [4].

Tracking Antibiotic-Resistant Microbes

A recent publication in the prestigious scientific journal Nature Communications reports results from an investigation that tracked all microbial antibiotic resistance genes (the resistome) in fecal material from newborn dairy calves until they were ten weeks old [4]. The resistome reveals the potential for the development of antibiotic resistance in a community of microbes [3]. The microbes in fecal material likely mirror the composition of the complex microbial ecosystem in the calf’s digestive tract. The investigators’ results were comprehensive, surprising, and suggested simple practical ways to minimize the spread of antibiotic-resistant microbes in livestock. The eight investigators were based at the University of California Davis and the USDA. Jinxin Liu was the first author on the publication, and David Mills was leader of the multidisciplinary research team.

Microbes Killing Microbes

The microbial arms race has been going on since the dawn of life. Some microbes naturally produce antibiotics that do not affect themselves but kill other types of microbes. The microbes producing antibiotics increase their survival chances and reproductive success at the expense of other microbes. In defense, some microbes develop countermeasures to specific antibiotics. The latter microbes acquire new genes, which produce proteins that neutralize the effects of specific antibiotics and allow these microbes to prosper even in the presence of an antibiotic. This ancient ability of microbes to become resistant to antibiotics is a major problem today. The antibiotics used in humans and animals to treat infections are related to naturally occurring antibiotics and therefore are susceptible to antibiotic resistance mechanisms in microbes. During the last 80 years, many microbes that cause infection in humans rapidly became resistant to antibiotics; some are resistant to multiple antibiotics [1, 2, 9]. The warning siren is blaring.

Microbes Swap DNA

Microbes can quickly spread antibiotic resistance genes into larger populations of microbes. They pass on these genes to their descendants during normal reproduction (vertical transfer). However, scientists have repeatedly discovered that some microbes also use a much faster and promiscuous method of dispersal of antibiotic-resistant genes. These microbes contain an additional piece of DNA containing one or more antibiotic-resistant genes, which is easily transferred into very different microbes (horizontal transfer) [6, 10]. Swapping pieces of DNA is part of life for most microbes. The heightened risk with horizontal transfer is that the non-infectious antibiotic-resistant microbes can act as reservoirs for antibiotic resistance genes and opportunistically transfer these genes into microbes that cause disease. Worse, some microbes acquire resistance to multiple antibiotics through this mechanism [6].

Surprises in the Fecal Resistome

Liu and colleagues collected fecal samples from newborn dairy calves until weaning at 10 weeks of age [4]. They initially identified the range of microbial families and their abundances in each sample. The diet of the calves changed from colostrum just after birth, to milk with progressively increased amounts of a plant-based “calf starter” until weaning. The colostrum was bottle-fed to the calves only on their first day. The dietary transition was associated with large and surprisingly rapid changes in fecal microbial populations. Presumably, this was a reflection of the changes in the microbial ecosystem in the calf intestinal tract. There was also a much greater diversity of microbial species with increasing calf age as the microbial species transitioned from ones specialized in the digestion of colostrum and milk to those that digested cellulose in the plant feed. Liu and colleagues presented strong evidence that specific microbes present in the colostrum helped to “seed” the microbial population detected in fecal material at an early age. The implication is that a calf may get much more than just food from its dam.

The investigators then focused attention on the microbial resistome in the fecal samples [4]. They obtained huge quantities of DNA sequence information from the massive number and diversity of microbes present in the samples. By comparison of the DNA sequences with a database of DNA sequences coding for known microbial antibiotic resistance genes, Liu and colleagues identified a resistome consisting of over 300 genes that potentially conferred resistance to 17 classes of antibiotics. The resistome was large and complex. Over 50% of the antimicrobial resistance genes identified when the calves were two days of age likely came from microbes containing multiple resistance genes. Hence, some microbes could potentially have resistance to multiple classes of antibiotics. However, the investigators noted that the abundance of the latter microbes decreased as the calves aged, as did the entire resistome. The investigators predicted that the resistome came from 75 bacterial families, although just a few microbial families carrying the antibiotic resistance genes were overwhelmingly dominant in terms of microbial population numbers [4]. The resistome, like the microbial populations, changed dramatically with age, although the changes were more extensive than simply a reflection of the changes in the microbial populations.

The investigators determined the relationship between the age-related changes in the resistome and the corresponding changes in microbial genes that produced specific proteins involved in feed digestion [4]. They concluded that the decrease in the resistome with age was associated with the increasing numbers of microbes that digest plant polysaccharides, which, coincidently, contained few antibiotic resistance genes. Thus, diet can modify the resistome. Liu and colleagues also identified about 70 antibiotic resistance genes on small pieces of DNA with potential capability for horizontal transfer between different types of microbes. These genes potentially conferred resistance to 10 classes of antibiotics and came from a wide diversity of fecal microbial species. Perhaps these genes will be high priorities in the future for the monitoring of antibiotic-resistant microbes.

Implications

Liu and collaborators demonstrated that pre-weaned dairy calves “serve as a reservoir” for antibiotic resistance genes [4]. Their research highlighted a new way of detecting and tracking all antibiotic resistance genes in highly dynamic and complex microbial ecosystems. The investigators suggested that the dairy industry should better control the collection and handling of colostrum to reduce the introduction of antibiotic-resistant microbes to newborn calves. Liu and colleagues concluded that exposing calves to prebiotic foods or probiotic bacteria very early in life may displace microbes carrying antibiotic resistance genes and “reduce the likelihood of further environmental spread.” Vigilance and simple changes to industry practices could help contain the livestock microbial resistome and ensure the continuing availability of effective antibiotics for use in humans and animals.

 

1. World Health Organization. Antimicrobial resistance: global report on surveillance. 2014 [Available from: https://apps.who.int/iris/bitstream/handle/10665/112647/WHO_HSE_PED_AIP_2014.2_eng.pdf].

2. Ferri M, Ranucci E, Romagnoli P, Giaccone V. Antimicrobial resistance: A global emerging threat to public health systems. Crit Rev Food Sci Nutr. 2017;57(13):2857-2876.

3. Noyes NR, Yang X, Linke LM, Magnuson RJ, Dettenwanger A, Cook S, Geornaras I, Woerner DE, Gow SP, McAllister TA, Yang H, Ruiz J, Jones KL, Boucher CA, Morley PS, Belk KE. Resistome diversity in cattle and the environment decreases during beef production. Elife. 2016;5:e13195.

4. Liu J, Taft DH, Maldonado-Gomez MX, Johnson D, Treiber ML, Lemay DG, DePeters EJ, Mills DA. The fecal resistome of dairy cattle is associated with diet during nursing. Nat Commun. 2019;10(1):4406.

5. Noyes NR, Yang X, Linke LM, Magnuson RJ, Cook SR, Zaheer R, Yang H, Woerner DR, Geornaras I, McArt JA, Gow SP, Ruiz J, Jones KL, Boucher CA, McAllister TA, Belk KE, Morley PS. Characterization of the resistome in manure, soil and wastewater from dairy and beef production systems. Sci Rep. 2016;6:24645.

6. Michael GB, Freitag C, Wendlandt S, Eidam C, Feßler AT, Lopes GV, Kadlec K, Schwarz S. Emerging issues in antimicrobial resistance of bacteria from food-producing animals. Future Microbiol. 2015;10(3):427-443.

7. Rovira P, McAllister T, Lakin SM, Cook SR, Doster E, Noyes NR, Weinroth MD, Yang X, Parker JK, Boucher C, Booker CW, Woerner DR, Belk KE, Morley, PS. Characterization of the microbial resistome in conventional and “raised without antibiotics” beef and dairy production systems. Front Microbiol. 2019;10:1980.

8. Cuny C, Arnold P, Hermes J, Eckmanns T, Mehraj J, Schoenfelder S, Ziebuhr W, Zhao Q, Wang Y, Fessler AT, Krause G, Schwarz S, Witte W. Occurrence of cfr-mediated multiresistance in staphylococci from veal calves and pigs, from humans at the corresponding farms, and from veterinarians and their family members. Vet Microbiol. 2017;200:88-94.

9. Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. P&T Community. 2015;40(4):277-283.

10. Lerminiaux NA, Cameron ADS. Horizontal transfer of antibiotic resistance genes in clinical environments. Can J Microbiol. 2019;65(1):34-44.

11. US Food and Drug Administration. Summary report on antimicrobials sold or distributed for use in food-producing animals. 2018 [Available from: https://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM628538.pdf].

 

Dr. Ross Tellam (AM)
Research Scientist
Brisbane, Australia