Abstract
Antibiotic resistance is an emerging risk for human and animal health, and mitigating the risk requires an improved understanding of various sources of risks and identifying the level of threats for each source. Many antibiotics are currently used against pathogens for treating infections in animals and humans, and it is considered that antibiotic resistance genes (ARGs) acquired by pathogens may have an environmental origin. Because of contamination in ambient waterways, it is likely that ARGs may affect both organic and non-organic farming. While health risk as a consequence of ARGs is difficult to determine because of lack of understanding of dose-response, the presence of ARGs in human waste and animal manure, and the subsequent application of these organic wastes as fertilizers has a potential of spreading ARGs in the environment. Additional research is needed to understand the presence, growth, and transport of ARGs through animal wastes such as dairy manure. In this review, we focus on synthesizing information regarding the occurrence of ARGs in dairy manure, potential transport pathways, and factors responsible for the spread of ARGs in the environment. Besides, we also explore potential treatment methods that may contribute to the ARG removal in dairy manure and help alleviate ARG contamination.
1 Introduction
Antibiotic resistance, which represents the ability of an antibiotic resistant bacteria to protect themselves against antibiotic drugs, has become one of the major health concerns around the world due to an increasing number of infections and its related economic cost [1,2]. The risk caused by antibiotic resistance is considered to be one of the major threats to global health [3,4].
Since the first commercial antibiotic agents were introduced in 1935 (sulfonamides) and 1942 (penicillin), hundreds of subsequent antibiotic agents were discovered and made clinically available to the public [5,6]. Newer antibiotic agents continue to be discovered, though the rate of discovery has decreased [7,8]. Along with the slowed down discovery, resistance to antibiotics is also being observed with increasing frequency. Since the 1950s, infections resistant to multiple antibiotics, i.e., multidrug resistance, has increasingly become a human and animal health concern [9,10]. Bacterial species with multiple antimicrobial resistance clades have been discovered, such as E. coli, Salmonella typhi, Clostridium difficile, and Staphylococcus aureus [11]. In recent years, the increase in antimicrobial resistance has superseded the pace of research and development of novel antibiotics [11,12]. This phenomenon, unless addressed in a timely and targeted manner, could pose significant public health concerns due to decreasing options for effective antimicrobial therapy, and could reverse decades of advances since the advent of antibiotics.
In 2014, more than 700,000 human deaths occurred globally attributed to antibiotic resistant infections, and the cumulative economic damage in healthcare and reduced productivity would reach 100 trillion USD by 2050 [13]. Based on a report from the US. Centers for Disease Control and Prevention (CDC), it is estimated that more than 2.8 million antibiotic-resistant infections and 35,000 deaths occur annually due to antibiotic-resistance (CDC, 2019). At the present rate, it is predicted that by 2050 more than 10 million people may die annually due to antibiotic-resistant infections in the world [13].
The role of the environment is critical towards the pathogen’s ability to gain antibiotic resistance [14,15]. Antibiotic drugs are widely, and sometimes, indiscriminately used in animal farms for the treatment and prevention of bacterial diseases and occasionally, as a growth supplement [16]. Previous research has shown that extensive and indiscriminate use of antibiotics in animal husbandry can result in the creation of antibiotic resistant genes (ARGs) in livestock manure [17,18]. Treated livestock manure is used to fertilize cropland, which could aid in the subsequent spread of ARGs into the environment, leading to human and animal health challenges [19]. The goal of this article is to summarize and review previous studies on the presence, distribution, fate, and transport of ARGs in dairy manure, and the impacts of various manure treatment methods towards the reduction of such ARGs. Figure 1 shows the flow of ARGs from livestock waste and potential consequences on human health.
Livestock manure, manure application to cropland, and potential transfer of antibiotic resistances from manure to the ambient water and environment, and consequential public health risks.
2 Classification of antibiotics and antibiotic resistance
2.1 Classification of antibiotics
Antibiotic agents can be classified into different groups based on their mechanism of action, and classification based on mechanisms’ clinical purposes are shown in Table 1. Depending on the mechanism of action, antibiotics affect bacteria in many ways, such as the inhibition of cell wall synthesis, cell membrane function, protein synthesis, nucleic acid synthesis, and/or other metabolic processes [20,21,22]. For example, β-lactam antibiotics target the penicillin-binding proteins (PBPs), which are responsible for the synthesis of the peptidoglycan layer of bacterial cell walls. Failure to form bacterial cell wall leads to bacterial death due to autolytic hydrolases.
Different classes of antibiotics and clinical use for dairy animals
| Mechanism | Classes | Spectrum of activity | Effect on bacteria | Clinical use for dairy animals | Reference |
|---|---|---|---|---|---|
| Inhibition of cell wall synthesis | β-lactam antibiotics | Broad-spectrum/narrow-spectrum | Bactericidal | Mastitis, respiratory disease, diarrhea, uterine, metritis, foot rot, black leg, rhinitis, pneumonia, cellulitis, bursitis, and navel infection | [59,60,65,206] |
| Glycopeptides | Narrow-spectrum | Bactericidal | |||
| Inhibition of cell membrane function | Polymixins | Narrow-spectrum | Bactericidal | Diarrhea and uveitis | [59,60] |
| Lipopeptides | Broad-Spectrum | Bactericidal | |||
| Inhibition of protein synthesis (30 s Subunit) | Aminoglycosides | Narrow-spectrum | Bactericidal | Mastitis, diarrhea, locomotion, and bacterial enteritis | [60,206] |
| Tetracyclines | Broad-spectrum | Bacteriostatic | Respiratory disease, uterine, enteritis, weight gain, pneumonia, foot rot, metritis, and arthritis | [59,60,206] | |
| Inhibition of protein synthesis (50 s Subunit) | Amphenicols | Broad-spectrum | Bacteriostatic | Respiratory disease, pneumonia, and foot rot | [60,65,206] |
| Macrolides | Narrow-spectrum | Bacteriostatic | Mastitis and respiratory disease | [60] | |
| Lincosamides | Narrow-spectrum | Bacteriostatic | Mastitis | [206] | |
| Streptogramins | Narrow-spectrum | Group A or Group B – Bacteriostatic; Group A & Group B – Bactericidal | |||
| Oxazolidinones | Broad-spectrum | Bacteriostatic | |||
| Inhibition of nucleic acid synthesis | Quinolones | Broad-spectrum | Bactericidal | Respiratory disease, diarrhea, and mastitis | [59,60] |
| Aminocoumarin | Narrow-spectrum | Bacteriostatic/bactericidal | Mastitis | [206] | |
| Ansamycins | Broad-spectrum | Bactericidal | Mastitis (limited use) | [207] | |
| Inhibition of folic acid synthesis | Sulfonamides | Broad-spectrum | Bacteriostatic | Fever, bacterial pneumonia, calf diphtheria, diarrhea/digestive, and foot rot | [65,206] |
| Diaminopyrimidines (trimethoprim) | Broad-spectrum | Bacteriostatic | Diarrhea, coccidiosis, and systemic infections of newborn ruminants | [59] |
According to their spectrum of activity, antibiotics are classified as broad spectrum and narrow spectrum agents [23,24]. Broad spectrum antibiotics, such as tetracyclines, chloramphenicols, and cephalosporins (3rd, 4th, and 5th generation), can act against different classes of bacteria, including gram-positive and gram-negative bacteria. Narrow spectrum antibiotics such as penicillin, lincosamides, glycopeptides, streptogramins, and rifamycin [23] affect only a limited number of bacterial species. While antibiotics such as glycopeptides, lincosamides, macrolides, and streptogramins are used against gram-positive bacteria, other antibiotics such as aminoglycosides are only effective against gram-negative aerobic and facultative anaerobic bacilli [25]. In 2019, the United States Department of Agriculture in association with the World Organization for Animal Health, organized the Second International Symposium on “Alternative to Antibiotics.” Various studies have shown that vaccines can be a good alternative to antibiotics in food animals.
Based on the effect on bacteria, antibiotics are defined as bactericidal and bacteriostatic [23]. Antibiotics which prevent the growth of bacteria are considered bacteriostatic, whereas antibiotics which kill bacteria are known as bactericidal [26]. Bactericidal antibiotics such as β-lactams, aminoglycosides, glycopeptides, and quinolones cause bacterial cell death. Bacteriostatic drugs, such as chloramphenicol, oxazolidinones, sulfonamides, tetracyclines, and macrolides, inhibit bacterial growth. Some antibiotics possess both bactericidal and bacteriostatic abilities depending on the dose, duration of exposure, bacterial species, and other factors. For example, chloramphenicol triggers bactericidal activity against S. pneumoniae, and also initiates bacteriostatic activity against S. aureus [27,28].
2.2 Classification of antibiotic resistance mechanisms
There are four major types of bacterial resistance mechanisms. Bacteria may develop antibiotic resistance by reduction in permeability of cell membrane, enhancement of efflux pump efficiency, degradation of antibiotics, or/and modification of antibiotic targets. Antibiotic resistance mechanisms and corresponding bacteria genera is described in Table 2.
Antibiotic resistance mechanisms and bacteria genera
| Antibiotic classes | Resistance type | Bacteria genera | Common mechanism | Reference |
|---|---|---|---|---|
| Aminoglycoside | Reduced permeability | Gram-negative bacteria (e.g., Salmonella, Pseudomonas, Escherichia) and Mycobacterium | Innate mechanism of resistance due to multi-layered cell walls, down regulation of porins | [208] |
| Efflux pump | Many gram-negative bacteria (e.g., Enterobacteriaceae, Salmonella, Pseudomonas, and Escherichia) | Intrinsic AcrAD-TolC-type efflux pumps | [209] | |
| Degradation of antibiotics | Staphylococcus, Pseudomonas, Serratia, and Mycobacterium | AG-modifying enzymes | [210] | |
| Target modification | Pseudomonas, Klebsiella, and Citrobacter | 16S ribosomal RNA methyltransferases (RMTases) | [211] | |
| β-lactams | Degradation of antibiotics | Escherichia, Klebsiella, Enterobacteriaceae, Pseudomonas, Serratia, Enterobacter, and Staphylococcus | β-lactamases (ESBLs, plasmid-mediated AmpC enzymes, and carbapenemases) | [212,213,214] |
| Target modification | Staphylococcus, Enterococcus, Streptococcus, and Neisseria | Low-affinity PBP2a encoded by SCCmec, low-affinity PBP5 | [215] | |
| Chloramphenicol | Reduced permeability | Haemophilus, Burkholderia, and Salmonella | Loss of an outer membrane protein | [216] |
| Efflux pump | Pseudomonas, Escherichia, Salmonella, Klebsiella, Staphylococcus, and Bacillus | Specific exporters, E-1–E-8, multidrug transporter (MdfA, AcrAB-TolC) | [216] | |
| Target modification | Escherichia and Bacillus | Mutations in the major ribosomal protein gene | [216] | |
| Degradation of antibiotics | Escherichia, Enterococcus, Staphylococcus, Bacillus, and Salmonella | Chloramphenicol acetyltransferases | [216] | |
| Glycopeptide | Target modification | Enterococcus and Staphylococcus | Reducing binding affinity by substituting terminal D-lactate or D-serine for D-alanine | [215] |
| MLSB | Efflux pump | Corynebacterium, Enterobacter, Enterococcus, Gemella, Pseudomonas, and Streptococcus | ATP-transporters or major facilitator transporters | [217] |
| Degradation of antibiotics | Pseudomonas, Serratia, Staphylococcus, Clostridium, Streptococcus, Enterobacter, Escherichia, and Klebsiella | Inactivating enzymes including esterases, lyases, transferases, and phosphorylases | [217] | |
| Target modification | Bacteroides, Enterococcus, Shigella, Staphylococcus, Salmonella, and Mycobacterium | rRNA methylases | [217] | |
| Quinolone | Reduced permeability | Escherichia, Proteus, and Salmonella | Altering expression of outer membrane porin proteins (OmpA, OmpF, and OmpC) | [218,219] |
| Efflux pump | Escherichia, Pseudomonas, Staphylococcus, Acinetobacter, and Stenotrophomonas | Efflux systems (e.g., MdfA, NorA, MexXY, MexAB, MexCD, or MexEF) | [219,220] | |
| Target modification | Escherichia, Klebsiella, Salmonella, Enterobacter, Citrobacter, Proteus, and Shigella | Mutations in gyrA, gyrB, parC, and parE encoding the subunits of DNA gyrase and topoisomerase IV | [219,220] | |
| Sulfonamide | Target modification | Escherichia, Staphylococcus, Pneumocystis, Streptococcus, Campylobacter, Mycobacterium, and Neisseria | Chromosomal mutations in the folP gene encoding DHPS, plasmid-borne resistance encoding DHPS variants | [221] |
| Tetracycline | Target modification | Actinobacillus, Aerococcus, Streptococcus, Enterococcus, Psychrobacter, Staphylococcus, and Veillonella | tet and otr genes code for ribosomal protection proteins (RPPs) | [222] |
| Efflux pump | Mycobacterium, Streptomyces, Acinetobacter, Clostridium, Escherichia, and Bacillus | tet, otr, and tcr genes code for efflux pumps | [222] | |
| Degradation of antibiotics | Escherichia and Bacteroides | NADPH-requiring oxidoreductases | [222] |
2.3 Reduction in the permeability of antibiotics
One of the major strategies adapted by bacteria against antibiotics is to modify porin channels. While a cytoplasmic membrane in the gram-positive bacteria cell is surrounded by a thick layer of cell wall, a gram-negative bacteria cell consists of a thin cell wall, which is surrounded by a second lipid membrane [21]. This lipid membrane contains porins channels, which enables the passing of various molecules such as antibiotics [29,30]. The ability of bacteria to change porin channels allows them to protect themselves against antibiotics [31,32]. By modification of the expression/functionality of porin channels, bacteria may reduce the uptake of antibiotics. Many gram-negative bacteria resistant to β-lactams, fluoroquinolones, tetracycline, and chloramphenicol are known to modify protein channel to create resistance against antibiotics [33,34].
2.4 Expulsion of the antibiotics from the cell by efflux pumps
Efflux pumps are considered to be transport proteins. These transport proteins are found in the cytoplasmic membrane of both gram-positive and gram-negative bacteria [35]. The efflux pumps expel selective antibiotics and toxic substrates including lincosamides, macrolides, streptogramins, and tetracyclines from within cells into the external environment [36,37]. In some cases, mutations trigger amino acid changes which improve efflux pump efficiency in terms of extrusion of toxic substances such as antibiotics. For instance, Vettoretti et al. [38] described an amino acid mutation of MexXY efflux pump in P. aeruginosa, which results in an increased resistance to aminoglycosides, fluoroquinolones, and the β-lactam cefepime.
2.5 Modification and degradation of antibiotics
In addition to the use of efflux pumps, and modified porin channels, bacteria also develop other mechanisms such as the direct inactivation of antibiotics to protect themselves. Major classes of enzymes that inactivate antibiotics include β-lactamases, aminoglycoside-modifying enzymes, and chloramphenicol acetyltransferases [39]. β-lactamase is also known as penicillinase and was discovered in the 1940s [40]. Enzymes such as the β-lactamase break the β-lactam ring by hydrolysis, and inactivate the antibacterial properties of penicillin, cephalosporins, monobactams, and carbapenems [21,41]. The inactivated β-lactams are unable to bind to PBPs and thereby the process of cell wall synthesis is protected [41,42].
2.6 Modification of target sites in bacteria cells
The change in target sites of antimicrobials is another mechanism used by bacteria to prevent drug binding and resist against antibiotics [43]. Modification of critical target sites of antimicrobials generally leads to the inhibition of binding [21,44,45]. Studies have shown that changes in the ribosomes of Mycobacterium spp. resulted in a reduced affinity of streptomycin to target sites [46]. The presence of mutation in penicillin binding proteins in methicillin-resistant S. aureus and Listeria monocytogenes creates resistance to β-lactams [47,48]. Alterations in cell wall precursor components in staphylococcus and enterococci inhibit the binding of vancomycin and teicoplanin [49,50]. Mutations in DNA gyrase and topoisomerase IV in S. aureus and S. pneumoniae lead to reduced activity of fluoroquinolones [51,52,53], and mutations in RNA polymerases of Mycobacterium tuberculosis lead to resistance to rifampicin [54,55,56].
3 Antibiotics in food animal
Antibiotics have been globally used in food animals to prevent, restrict, and treat infectious diseases in both developed and developing countries [13,57]. A potential pathway of ARGs in animal waste is shown in Figure 2. Examples of commonly used antibiotics include trimethoprim/sulfonamides, tetracycline, β-lactams, and polymyxin B (Table 1) [58,59,60]. In 2010, global antimicrobial use in food animal production was 63,151 tons, which is estimated to increase to 105,596 tons by 2030 [61]. More than 6 million kilograms of medically important antibiotics and 5.3 million kilograms of not-medically important antibiotics in the U.S. were used in animals to prevent, control, or treat diseases in 2019 [62]. The majority (41%) of medically important antibiotics (i.e., important for treating human disease) used in animal agriculture in the US were administered to beef and dairy cattle [62], although the swine and poultry industries are estimated to be major consumers of antibiotics [61]. Cattle production was the third largest livestock industry in the world after the swine and poultry (approximately 80 million tons) in 2019 [63]. Currently, there are more than 60,000 dairy operations (≈17.5 million dairy herds) in the United States [64], and most operations use antibiotics for the treatment, control, and prevention of diseases. In 2013, about 87% of US dairy farms used antibiotics to treat cow mastitis, whereas 25 and 4% of farms used medically important antibiotics to prevent disease or promote growth for weaned heifers and pregnant heifers, respectively [65].
A potential pathway of ARGs recycling in dairy manure management system.
The administration of antibiotics in animals can be for various purposes: therapeutic, metaphylaxtic, prophylaxtic, or as growth promotors [59]. For therapeutic purposes, antibiotic drugs are administered to clinically ill animals. For example, around 16% of lactating dairy cows in the US receive antibiotics to treat mastitis every year [66,67], while 15% of beef calves in feedlots receive antibiotics therapy for clinical respiratory disease [68]. Metaphylaxis applications involve the pre-administration of antibiotics to the whole herd after the diagnosis of infection in one or more animals, in order to reduce the spread of the infectious disease [69,70]. Prophylaxis applications involve the administration of antibiotics to an individual animal or animal group as a preventive measure, prior to the appearance of clinical signs or infectious disease [71,72,73]. For example, prophylactic intramammary antibiotics are infused in the teat canal at the end of the lactation period to prevent and control future mastitis. Prophylactic antibiotics include penicillin, cephalosporins, and other beta-lactam drugs [66,67], amongst others. In addition, prophylactic antibiotics are used in 10% of healthy calves to reduce the risk of anticipated respiratory disease outbreaks [68]. In swine and cattle feeding, the prophylactic use of antibiotics occurs most often during the weaning period [71,72].
In addition to the use of antibiotics for reducing infections, antibiotics are also used as growth promotors [74,75]. In US, the use of medically important antimicrobials for growth promotion in food-producing animals has been eliminated by the US Food and Drug Administration (FDA) since 2017. However, 45 out of 155 countries are still using antimicrobials as a growth promoter according to the World Organization for Animal Health (OIE 2019). It is reported that low and subtherapeutic doses (1/10 to 1/100 of the curative dose) of antibiotics (such as penicillin, procaine, and tetracycline) are administered to animals via food or water to increase the rate of growth in animals [76]. Kirchhelle [57] highlights the long history of regulatory failures that has led to global antibiotic crisis.
It is important that remaining 45 countries follow suit on the ban on use of antibiotics as growth regulators. Several potential modes of action are proposed by the use of antibiotics as growth promotors [77]. The growth promotors are considered to be responsible for inhibition of nonspecific subclinical disease and gut microbiota, increasing availability of nutrition supply, reduction in harmful metabolites produced by intestinal bacteria, and improvement in absorption of dietary nutrients caused by thinning the intestinal wall [77,78,79,80]. Better understanding the mechanism of action might be helpful in developing effective alternatives [81].
At present, there is an increasing trend toward restricted use of antibiotics in food animals. In a meta-analysis conducted by Tang et al. [82] which included 81 animal studies, they found that reduction in the use of antibiotics lead to a decrease in the prevalence of antibiotic resistant bacteria by about 15% and multi drug resistant bacteria by 24–32%. In a similar meta-analysis study, Scott et al. [83] found that limiting antibiotic use in food animals reduced antibiotic resistant microbes, but the magnitude of the effectiveness were not quantified. In another interesting meta-analysis, Smith-Spangler et al. [84] found that the risk of isolating bacteria resistant to three or more antibiotics was higher in conventional chicken compared to organic chicken.
3.1 Excretion of antibiotic residues and presence of ARGs in dairy manure
From one health perspective, an approach to find optimal health for humans, animals, plant, and environment, it is important to find a solution for antibiotics crisis [85]. The major concern is that antibiotics critical for humans are used as mass medication for animals at very high dose. Though antibiotics could be effective at very low levels, large doses are normally administered to animals to facilitate drug delivery [86]. A major portion of this increased dose (up to 90%) is excreted in active form through feces [87]. Antibiotic residues such as the residues of tetracycline, chlortetracycline, and oxytetracycline are the most commonly detected antibiotics in dairy manure [88]. A study by Wallace and Aga [88] detected tetracycline residues in dairy feces and found that the majority of residues were primarily attached to fecal solids. In contrast, the widely used β-lactams are relatively more soluble and appear to be less persistent in manure [18]. To illustrate, a study that collected more than 80 fresh manure samples from 11 dairy farms in the northeastern United States, which commonly used penicillin and cephalosporins in their animals, showed no detection of β-lactam residues in any of their manure samples [18]. At low concentrations, sulfonamide, macrolide, and lincosamide residues have also been detected in dairy manure samples [18]. The presence of antibiotic residue in manure has been shown to negatively impact several downstream processes.
Prevalence of ARGs in animal feces are associated with the extensive and indiscriminate use of antibiotics in food animals [17,89]. Under antibiotic selection pressure, antibiotic resistant bacteria can be selected in the animal gut. Antibiotic resistance can develop by gene mutations (vertical gene transfer) or acquire exotic genes (horizontal gene transfer) in the animal gut from other species, strains, or extracellular DNA [90]. Feeding milk with residual concentrations of antibiotics has been shown to result in increased antibiotic resistance in E. coli isolates in the fecal samples of pre-weaned calves [91]. Since dairy manure is considered to be a reservoir for more than 60 types of ARGs [92], ARGs are frequently detected in livestock waste including manure, wastewater, lagoon slurries, and sediments [93,94,95]. For example, fecal samples collected from three large commercial pig farms in China yielded tens of thousands of times more ARGs than those not exposed to antibiotics [96].
ARGs detected in animal manure include various types of genes: bla for the β-lactams [97,98]; van for glycopeptides [97,99], erm gene for macrolide-lincosamide-streptogramin B (MLSB) [97,98,100], sul genes for sulfonamides [97,98,100], tet genes for tetracyclines [97,98,100], satA/satG for streptogramin [101], fexA, cfr, cmlA, and floR for chloramphenicols [102], acc for aminoglycosides [97,98], fca for FCA (quinolone, florfenicol, chloramphenicol, and amphenicol) [97,100], mcr for colistin [94], van for vancomycin [97], and mdr for multidrug [92,97]. The most commonly detected ARG categories in animal waste included tet, sul, erm, fca, and bla, which correspond to the most commonly used antibiotic types in animal agriculture [95]. Among these five ARG categories, tet and sul genes were generally most abundant, present in almost all livestock wastes [95]. The considerable variation in ARGs may result from different usage of antibiotics across livestock types and farm locations [95].
3.1.1 Transfer of AR and ARGs into the environment
The presence of antibiotics and ARGs in animal manure is a concern, because the majority of manure produced in animal-agriculture system is used as fertilizers in croplands. The elevated levels of antibiotics in manure, and its subsequent use in cropland could potentially contaminate the environment. Horizontal gene transfer is mainly responsible for the spread of ARGs in the environment, including transformation, transduction, and conjugation [103]. ARGs are classified as two forms: intracellular DNA transmitted by conjugation and/or transduction [104,105] and extracellular DNA transferred through transformation [106]. Transformation involves the direct passage of free DNA conferring antibiotic resistance from nearby dead cells [107]. Transduction involves the transfer of DNA from one bacteria cell to another via phagocytosis [108]. Bacteriophages containing ARGs infect the cell and introduce genes into the receiving bacteria [108,109]. Conjugation is the major way of transport of ARGs [110,111,112]. About 80.8% of all tested strains are considered to transmit ARGs by conjugation [112]. This mechanism is mediated by plasmids and involves the transfer of circular DNA by sexual pilus which requires cell-to-cell contact.
ARGs may be associated with bacteriophages and prophages, plasmids, and transposable factors [113], which contribute to the spread of ARGs. A large number of mobile genetic elements (MGEs) such as integrons, transposons, and plasmids are detected in animal manure [96,114,115]. The abundance of ARGs in swine farms in China were found to be significantly correlated with intI1 (class 1 integrase gene) and IS6100-type transposons in manure samples [114].
The overuse of antibiotics in animal-agriculture system and the subsequent application of animal wastes into soil systems (e.g., through land application of manure) introduces antibiotic residues, antibiotic-resistant bacteria, and ARGs into this environment [116]. The soil environment is considered one of the largest reservoirs of microbial communities, and it plays a crucial role in the emergence and spread of ARGs (Figure 1). Agricultural soil is considered to be a hotspot for bacteria to exchange genetic material by horizontal gene transfer [117]. Studies have shown that extracellular ARGs are able to persist in soil and sediments for long periods of time, up to years [118]. Subinhibitory concentrations of antibiotics in soil could cause selection pressure, and bacteria expedite their genetic material exchange rates to enhance horizontal transfer of ARGs [119,120,121]. Besides antibiotic residues, environmental conditions can also trigger horizontal gene transfer via stress response mechanisms [120,122]. For example, heavy metals in animal feed as alternative biocides or animal growth promotors [123] can cause stress on bacteria and select for ARGs through co-resistance or cross-resistance [124].
These manure-associated ARGs can be transferred from cropping and grazing lands [125] to surface/ground waterways (Chee-Sanford et al. 2009) by rainfall and runoff. ARGs from the soil can enter the food chain via contaminated crops and groundwater and cycle back to humans [126,127]. A study found elevated levels of tetracycline resistance genes in groundwater underlying two swine operations [128]. Besides, ARGs from water and soil may also enter the air by physical movements [129]. Antibiotic resistant bacteria on airborne particles can be inhaled by humans through dust particles or can settle on skin surfaces [130,131,132]. ARGs in surface and ground water, soil, and air can proliferate by horizontal gene transfer to indigenous bacteria including pathogens, and eventually reach humans causing public health concerns [133,134,135]. One study stated that resistance genes can persist for over 10 years in the absence of the corresponding antibiotic agents [136]. Hill et al. [137] analyzed crop nutrients and environmental contaminants including antibiotics from nine uncomposted manure samples from Idaho dairies collected for over 2.5 years. Monensin was the most frequently detected antibiotics. They also investigated the relative abundance of several plasmids involved in the spread of ARGs and found that IncI, IncP, and IncQ1 in almost all the samples. Ruuskanen et al. [138] studied the effect of animal manure on dissemination of ARG to the farm environment in Finland. Their findings show that there was increased relative abundance of two ARGs (Sul1 and Tet m) in cow and swine manure that was stored in the farm for approximately 9 months. They hypothesized that the selection pressure could have been the reason for such an increase. The atmospheric environment of composting has been shown to harbor ARGs. Gao et al. [139] in their study found 22 ARGs and int1 in the air around composting. This necessitates the proper regulations for such a facility as the presence of ARGs in the air could pose risk of transfer to humans and animals in the vicinity of the facility breathing such contaminated air.
3.1.2 Transfer of AR and ARGs to crop plants
The time-tested healthy practice of using dairy waste as manure for crop plant has been challenged with the advent and use of antibiotics over the past 75 years. Animal manure is a rich source of essential organic nutrients for plant growth. The strategy of fertilizing plants with animal manure had a two-pronged advantage of using them as a cheap source of fertilizer and an economic way of disposing animal waste. Unfortunately, with the increasing use of antibiotics over the past 75 years and the emergence of antibiotic resistant microbes carrying ARGs in animal waste, regulatory agencies around the world have imposed restrictions on their use as fertilizer to several crops. The age-old healthy practice with two-pronged advantage has become a two-sided disadvantage. This has left us with a problem of finding alternatives for both disposing animal waste and reliance on inorganic fertilizer as a sole source of nutrients for many crops.
In a study to understand the effect of transfer of ARG to plants fertilized with manure-based amendments, Guron et al. [140] used controlled, integrated, and replicated greenhouse study. They used radish and lettuce, a leafy vegetable as their model plants. Radish, a root vegetable was found to carry a great load of ARG, and species richness compared to lettuce. Their finding on association shows that there is almost exclusive association between ARGs and MGEs in plants that receive raw manure amendments. Composting did alleviate the mobility of manure resistance derived traits. In another study, Zhang et al. [141] found that the absolute abundance of ARGs and MEGs on the rhizosphere and phyllosphere of soil fertilized with raw manure from poultry and cattle farms was significantly higher than the ones detected in root and shoot endophytes. Compared to the control samples, the number of ARGs and MEGs detected in shoot and root endophytes were significantly higher than the controls. This clearly shows that application of raw manure with ARGs and MEGs might affect the microbiome of vegetable crops.
In another study, Zhang et al. [142] found that manure application did not enrich ARGs in the root endophytes in cherry radish. Cattle manure application increased the ARG resistome of rhizosphere and phyllosphere microbiota but not the endophytic bacterial microbiota. Despite being buried in the soil, the endophytic microbiota was not significantly affected. This clearly shows that transfer of ARGs is crop dependent. More studies on transfer of ARGs from manure to different crops are required to precisely regulate the use of manure on different crops.
Zea mays (corn) is an economically important crop in the United States of America and around the world. Mullen et al. [143] found that antibiotic residues of sulfonamide and tetracycline bioaccumulated in plant shoots, when the plants were grown with dairy manure amended soil. When antibiotics spiked manure (1 mg/kg) was used, tetracycline and sulfamerazine were detected at concentrations of about 300 and 1,260 ng/g, respectively. Interestingly, no antimicrobial resistance genes were detected. Though, in this study, the presence of antibiotic residues in the shoot were studied, the accumulation of these residues in the corn cobs were not analyzed.
Zhu et al. [144], in their study on the phyllosphere of staple crops under pig manure fertilization, found that ARGs were prevalent in both of their crops of interest, rice and wheat. They were able to detect 162 unique ARGs and five MGEs from rice and wheat samples. They showed that cleaned (treated) pig manure led to lower enrichment of ARGs compared to raw manure. They also found that wheat samples had higher ARG diversity than rice.
Zhao et al. [145] studied the effect of long-term manure application on antibiotic uptake by crops. Peanuts on the field with long term (>15 years) manure application was studied. Antibiotics were found in all peanut tissues (root, stem, leaves, cells, and kernels). Consumption of those peanuts were considered to present moderate health risk to humans.
Due to the concern of pathogens, most farmers, growing leafy greens worldwide, currently refrain from using animal manure as fertilizer. Currently, the United States FDA has a regulation of 120 days interval between the application of raw manure and planting for the crops where the economically important part of the plant comes in contact with the soil and 90 days interval for the ones where it does not come in direct contact with the soil [146].
3.2 Treatment technologies to reduce ARGs
Manure is usually applied to agricultural land nearby due to its agronomic value. The application of manure as fertilizers may increase the spread of ARGs into the environment and eventually affect human health. Although existing manure management technologies used for treating manure are not designed to mitigate ARGs. Fate of ARGs during different treatments of manure are shown in Table 3.
Fate of antibiotic resistant genes during different treatments of manure
| Genes | Changes in gene abundance | Type of treatment | Scale | Feedstock | Reference |
|---|---|---|---|---|---|
| ermB, ermF, and tetW | Increased 0.2–1.5 log copies/g | Mesophilic anaerobic digestion | Laboratory-scale | Wastewater sludge | [180] |
| sulI, sulII, tetC, tetG, tetX, and intI1 | Decreased 0.5–1.5 log copies/g | ||||
| sulI, sulII, ermB, ermF, tetO, tetW, tetG, and intI1 | Decreased 0.5–1.5 log copies/g | Thermophilic anaerobic digestion | Laboratory-scale | Wastewater sludge | [180] |
| aphA2 | Decreased 2.2 log copies/g in summer and 1 log copies/g in winter | Ambient temperature anaerobic digestion (summer and winter) | Pilot-scale | Dairy manure | [190] |
| ermB | Decreased 1 log copies/g in both seasons | ||||
| bla TEM-1 | Decreased 2.2 log copies/g in summer and 0.84 log copies/g in winter | ||||
| tet (X, Q, W, G, C), erm (X, Q, F, B), and sul (1, 2) | Decreased 1.03–4.23 log in total (copies/16S rRNA) | Mesophilic anaerobic digestion | Laboratory-scale | Swine manure with wheat straw | [175] |
| tet and erm | Decreased 0.1–0.15 copies/16S rRNA | Anaerobic digestion | Field-scale | Swine manure | [177] |
| sul, fca, and aac | 1.4–52 times increase (copies/16S rRNA) | ||||
| sul2, intI1 and intI2, and gryA | Decreased 0.1–1.5 log copies/g | Moderate anaerobic digestion | Laboratory-scale | Dairy manure | [181] |
| tetC, tetM, tetQ, tetX, and sul1 | Increased 0.1–3.5 log copies/g | ||||
| sul1, sul2, intI1 and intI2, gryA | Decreased 0.1–1.5 log copies/g | Mesophilic anaerobic digestion | |||
| tetC, tetM, tetQ, and tetX | Increased 0.1–1 log copies/g | ||||
| sul1, sul2, intI1 and intI2, gryA, tetM, tetX, tetW | Decreased 0.1–1.5 log copies/g | Thermophilic anaerobic digestion | |||
| tetC | Increased 1 log copies/g | ||||
| tetG | Decreased <1 log copies/g | Stockpiled | Field-scale | Dairy manure | [223] |
| RPP tet | No change | ||||
| ermB, ermC, ermF, ermT, and ermX | Decreased 1–2 log copies/g | ||||
| tetA, tetC, and RPP tet | Decreased ∼4 log copies/g | Composted | Field-scale | Swine manure | [224] |
| tetG | No change | ||||
| tet, sul, aac, erm, bla, mdr, fca, and van | Reduced 5 times in total (copies/16S rRNA) | Composted | Field-scale | Dairy manure | [97] |
| erm genes (A, B, C, F, T, and X) | Decreased ∼2–3 log copies/g | Composted (55°C with aeration) | Laboratory-scale | Swine manure | [156] |
| tet genes (A/C, G, M, O, T, and W) | Decreased 1–4 log copies/g | ||||
| erm genes (A, B, C, F, T, and X) | Decreased < 1 log copies/g even increased slightly (ermF) | Lagoon (room temperature) | Laboratory-scale | Swine manure | [156] |
| tet genes (A/C, G, M, O, T, and W) | Decreased < 1 log copies/g even increased slightly (tet(A/C)) |
3.2.1 Solid–liquid separation (SLS)
SLS is applied in many US dairy farms to remove fibrous solids from manure slurries to prevent accumulation in long time storages [18]. The separated solids can be used as a renewable bedding source, or as a feedstock for digestion processes [65,147]. Antibiotic residues have different solubility and sorption properties, and thus there is distinct partitioning between solid and liquid portions after SLS [88,148]. However, there are only a few articles studying the effect of SLS on the attenuation of ARGs [18], and the results showed a higher abundance of ARGs in separated solids compared with raw manure. Wallace et al. [149] collected raw and separated dairy manure from an SLS system located on a dairy farm with 1800 cows, and SLS treatment resulted in increased quantities of sul1, sul2, and tetO in separated solids. This suggests that mechanical separation without subsequent processing is likely to concentrate on certain types of ARGs in separated solids. Tien et al. [98] collected soil samples in field plots amended with untreated and mechanically dewatered manure, and authors reported that the occurrences of ARGs were more frequent in soil receiving raw manure than that receiving dewatered manure. Gros et al. [150] investigated the fate of ARGs in a full scale on farm livestock waste treatment plant. The plant used SLS, anaerobic digestion, and reverse osmosis of liquid digestate. Their findings show that antibiotics mostly partitioned onto the solid fraction after SLA. Zhang et al. [151] explored the change in ARGs in liquid and solid fractions of dairy manure. Results show that high total solids enhanced ARG reduction in liquid fraction, while those in solid fraction increased. Post treatment of such solid waste where ARGs increase should be a mandatory step to prevent their spread into the environment. Figure 3 elaborates flow of ARGs in dairy manure, and potential treatment options to control ARGs dissemination.
Dairy manure management system and dairy waste management technologies for controlling the dissemination of ARGs into environment.
In another study, Wright and Gooch [152] measured the partitioning of ARGs in an on-farm screw press separation. They found that the majority of antibiotic residue were partitioned with liquid stream. Ray studied the impact of on-farm SLS followed by rotary drum composting on the fate of ARGs. The authors studied sul1, bla OXA-1 , int1, and tetO. They found that about 88% of tetO were partitioned into separate solids, while 70% or more of sul1, bla OXA-1 , and int1 were partitioned into liquid. Rotary digestion process was effective in reducing tet0, sul1, bla OXA-1 , and int1 at 98, 75, 87, and 60%, respectively.
3.2.2 Composting
Composting is used to convert organic material into a stable, humus-rich material, which could generate heat and deactivate pathogens in the process. The effect of composting on reducing ARGs varies among different studies [153,154,155,156,157]. It was reported that reduction in ARG in intensively managed composts is generally more effective than stockpiling [158,159]. A previous study showed that composted manure had the lowest abundance of ARGs compared to untreated, anaerobically digested, and mechanically dewatered dairy manure from farms [98]. Xie et al. [160] suggested a significant reduction in the total abundance of ARG in cattle and poultry manures after thermophilic composting in a commercial scale. ARGs that confer resistance to vancomycin, sulphonamides, beta-lactams, and MLSB were reduced by several folds to more than one order of magnitude in cattle and poultry manure [160]. However, genes such as tetL, aadA, and aadA2 were persistent in composted material. It was reported that thermophilic composting removes ARGs better than mesophilic composting [95,161]. Additives such as clay, biochar, superabsorbent polymers, zeolite, calcium, and superphosphate can promote the effects of composting on ARGs [102,162,163,164]. Cui et al. [102] stated that biochar could change the fate of ARGs during the composting process by reducing the bioavailability and mobility of heavy metals, which could provide a suitable habitat for microbial proliferation by increasing the temperature and shifting the bacterial community.
Liao et al. [165] in their study showed that hyperthermophilic composting removed ARGs and MEGs more efficiently than conventional composting at 89% and 49%, respectively. The reduction in ARGs and MEGs were associated with the reduction in bacterial abundance. Their modeling using partial-least square path shows that reduction in MEGs also play a key role in the reduction in ARGs. Cao et al. [166] studied the profiles of ARGs at different stages of composting. In their study, they found that ARGs increased during composting. The same group, in another study, found that inoculation of composting material with microbial agents was shown to promote the removal of ARGs in pig manure [167]. Aerobic combined anaerobic composting has been shown to significantly reduce the abundance of ARGs in swine manure [168]. Yu et al. [169] have shown that integration of bioelectrochemical system into conventional anaerobic composting could enhance the reduction in ARGs. The attenuation of ARGs was attributed to the combination of CaO2 and bioelectrogenesis. Co-composting of swine manure with cauliflower and corn straw as a bulking agent was shown to significantly decrease the absolute abundance of most ARGs [170]. In an industrial scale composting, Tang et al. [171] found that the abundance of ARGs and MGES increased during aerobic thermophilic stage. Firmicutes and Actinobacteria were identified as potential hosts. MGEs in the host were identified as a hindering factor in ARG removal. Zhang et al. [172] showed that aerobic composting of cow manure was effective in reducing ARGs. In their study they identified Acinetobacter and Pseudomonas as potential hosts. After 14 days of aerobic composting, the abundance of ARGs were reduced by over 83%.
3.2.3 Anaerobic digestion
Anaerobic digestion is a process of decomposition, where organic compounds are degraded by microbial community in the absence of oxygen. Recent studies have demonstrated that anaerobic digestion is a potential way to remove ARGs [173,174,175]. However, other studies have indicated that the reduction effect of anaerobic digestion could be gene specific [95,100,176,177]. Some ARG classes were even enriched by anaerobic digestion. The inconsistent effect of anaerobic digestion on ARG removal can be attributed to complicated interactions among ARGs, bacteria, digestion parameters, and associated metabolic pathways in the anaerobic digestion process, which requires additional research [178]. Wallace et al. [149] investigated the abundance of sulfonamide- and tetracycline-resistant ARGs (log(ARG Copies/16S rRNA)) through a full-scale advanced anaerobic digester, and the authors found that only sul1 and sul2 copies were significantly reduced (P < 0.001) by 5 and 10%, respectively. However, tetracyclines-related genes (tetW and tetO) were unchanged in this study.
Previous studies have investigated the reduction in ARGs during anaerobic digestion under various conditions such as temperature [174,179,180,181], retention time [180], pH [182], co-digestion [175,183], antibiotics [184,185,186], and pretreatments [180]. Temperature could shift the diversity, function, and interactions of the microbial community [187]. Bacterial communities can be one of the major drivers in ARG reduction during anaerobic digestion [175,181]. Some bacteria in livestock manure are potential hosts of ARGs. Anaerobic digestion has a different removal rate of ARG host bacteria compared to the other non-host bacteria. Anaerobic digestion also reduced the abundance of integrase genes because most aerobic hosts of integrons cannot withstand the anaerobic environment. The reduction in integrase genes mitigated the horizontal gene transfer of ARGs (Sun et al., 2016).
Both mesophilic (35–37°C) and thermophilic (53–55°C) anaerobic digesters are used for treating organic waste. Compared to mesophilic digestion, thermophilic anaerobic digestion is advantageous in waste stabilization, pathogen elimination, and rapid methane production. However, the operation cost is also higher [158]. The effect of temperature on ARG reduction in anaerobic digestion has been investigated mostly for wastewater sludge [174,179,180] but rarely for dairy manure [181]. Some studies suggest that the thermophilic digestion process [179,181,188] reduces the quantities of mesophilic bacteria that carry certain ARG types and favors the growth of thermophilic bacteria. Thus, the removal of certain ARGs was more efficient compared to the moderate and mesophilic conditions.
However, thermophilic digestion did not always achieve better removal of all ARGs [174,180,189,190]. Ma et al. (2011) conducted laboratory-scale sludge digestion processes, and found that thermophilic anaerobic digestion had a more effective reduction on ermB, ermF, tetO, and tetW, while mesophilic anaerobic digestion significantly reduced sulI, sulII, tetC, tetG, tetX, and intI1. Zhang et al. [174] studied the fate of ARGs through thermophilic and mesophilic anaerobic digestion of wastewater sludge using bench-scale reactors at 35 ± 2°C and 55 ± 2°C, respectively. They found mesophilic anaerobic digestion had more reductions on tetG, tetO, tetW, and ermB, but enriched aadA, macB, and sul1, while thermophilic anaerobic digestion more effectively removed sul2, but enriched erythromycin esterase type I, sul1, and tetM.
Anaerobic digestion can be done in two phases either based on temperature or on the nature of archaea growing in the reactor (acidogenic or methanogenic). Hameed et al. [191] studied anaerobic digestion at two different temperatures (thermophilic and mesophilic). Their findings show that their first phase anaerobic digestion at a thermophilic temperature of 45 and 55°C performed better in terms of methane production and the second phase operated at a mesophilic temperature of 35°C centigrade. They also reported that second phase mesophilic digestion improved the effluent quality by reducing volatile solids by 15–20%. Wu et al. [192] studied the fate of ARGs during two phase anaerobic digestion by metagenomic approach. They divided the anaerobic digestion into acidogenic and methanogenic phases. Their findings show that the acidogenic phase was effective in removing all the ARGs. In our recent study, we found that microwave treatment significantly reduced the ARGs [193]. ARGs such as sulII, intI1, and tnpA were reduced by two-order magnitude in less than 1 min of microwave treatment. Li et al. [194] explored the occurrence of ARGs in sledge samples during microwave-pretreatment and anaerobic digestion. Their results showed that the occurrence of ARGs were quite different. Tian et al. [195] found that the thermophilic anaerobic digestion of sludge under stirring conditions at 55°C led to 55–86% reduction in ARGs. The presence of antibiotic residue did not affect the biogas production.
Recently, Sun et al. [196] showed that biochar has a positive effect on nitrogen conservation during anaerobic digestion process and reduces the abundances of most ARGs in cattle farm wastewater. They found that adding 20 g/L of biochar reduced the rate of ARG spreading. The abundance of 5–7 among the 13 ARGs studied decreased with the addition of biochar. Zhang et al. [197] in their study found that iron nanoparticles not only promote anaerobic digestion and methane production, but also decreased the absolute abundance of total ARGs. Heavy metals have been used as feed additives in livestock feed. Copper is one of the heavy metals that is present in high concentration. Zhang found that in swine manure containing residual copper (75 and 227 mg/L) increased the abundance of ARGs and MGEs. In another study, the same group found that addition of graphene oxide resulted in reduction in ARGs and MEGs abundance [198]. Graphene oxide was found to interfere with the horizontal gene transfer thus limiting the ARG abundance.
3.2.4 Emerging alternate and modified treatment strategies
Electrodialysis reversal was shown to help in the removal of antibiotics, sulfadiazine, and tetracycline [199] from pig manure. The authors found that sulfadiazine was removed mainly due to elector migration and tetracycline was removed by membrane sorption. Li et al. [200] demonstrated that bio-electro-Fenton as a promising system for ARG degradation. They showed that degradation of erythromycin could reach up to 88%. The degradation rate of other genes studied like ermG, ermC, and ermB were 65, 77, and 100%, respectively. Pinecone biochar has been shown to enhance immobilization of SMZ, CIP, and OTC antibiotics [201]. They also found that the kinetics of sorption of these antibiotics were accelerated. Higher sorption to the surfaces led to less runoff of antibiotics.
Quejigo et al. [202] found that using electrode enhances sulfamethazine total bio degradation. In their study, they found that negative anode potential significantly increases antibiotic microbial mineralization. High anode potential enhances the microbial capacity to mineralize sulfamethazine. Li et al. [203] studied the fate of antibiotic-resistant bacteria and genes during electrokinetic treatment of antibiotic-polluted soil. Their findings show that average removal rate of tetracycline, oxytetracycline, and chlortetracycline after 7 days of treatment was 35–40%. They also found that the ARGs tetC, tetG, tetW, and tetM were reduced by an average ratio of 55.5, 12.4, 47.1, and 61.2%, respectively. Ma et al. [204] studied the effect of nano-zerovalent iron on degradation of ARG during anaerobic digestion of cattle manure. Their findings show that 160 mg/L of nano-zerovalent iron effectively removed ARGs. Staley et al. [205] investigated the effect of stockpiling manure on conductive concrete slabs in the removal of antibiotic resistant bacteria and genes. The authors observed a significant reduction in the number of ARGs. A field-based study on farms supplemented antibiotic residues containing manure would be more valuable. Also, it would be important to study the accumulation of antibiotic residues in corn cobs. This would be critical in evaluating the transfer of AR and ARGs if any to humans. Previous studies’ noteworthy findings are reported, when iron-based nanoparticles were used as additives. Iron nanoparticles promoted anaerobic digestion and methane production and decreased the absolute abundance of total ARGs, and the nano-zerovalent iron enhanced the degradation of ARG during anaerobic digestion of cattle manure [225,226]. While the presence of ARGs in manure are reported, how manure borne ARGs are affecting human health is yet to be established, and lack of knowledge in terms of exposure assessment and dose-response assessment data for multiple scenarios is a major challenge [227]. Toxicity data of target antibiotics and non-antibiotics provide comprehensive information about chemical environmental toxicity on aquatic and terrestrial species [228], which can help in approximating lethal concentrations of ARGs. In terms of global health risk, ARGs have accelerated microbial threats to human health in the last decade [229]. Metagenomics-based analysis detected 2,561 ARGs that showed resistance to 24 classes of antibiotics, and about 23.78% of the ARGs pose health risks. Further, extreme climate events such as dry periods followed by rain/flood are shown to increase 2–3 fold higher abundance of ARGs in runoff water [230]. Because of ARGs presence in ambient water flow, most likely ARGs can be transferred from non-organic farms to organic farms. Studies have shown that tetracycline and sulfonamide ARGs were found in soils from organic farms in Nebraska [231]. While ARG/bacteria is currently recognized as a growing problem, quantitative understanding of the direct risk posed by ARGs and antibiotic-resistant bacteria is lacking. Attempts on obtaining the dose-response at lethal and sub-lethal concentrations either through observed studies or mathematical simulation can help in determining the ARGs associated with direct public health risks.
4 Conclusion
The use of antibiotics in animal-agriculture systems is a common practice, and the development of antibiotic resistance acquired by bacteria/pathogens poses risks to animal and human health. Antibiotic resistance is a serious challenge towards the treatment of infectious diseases caused by antibiotic-resistant pathogens. While ARGs are already present in the environment, the excessive use of antibiotics in animal-agriculture systems has the potential to increase the ability of microbial communities to resist the effects of antibiotics. Animal waste borne bacteria are getting increasingly resistant to antibiotics, which could accelerate the emergence and spread of resistance genes in the environment. The study on the abundance of ARGs manure-based farming is a relatively new field of research, and the abundance of ARGs in agricultural soil prior to the application of manure is an important control factor that needs to be taken into account. Animal manure treatment processes such as aerobic digestion, anaerobic digestion, and composting have potential to reduce ARGs in manure. Studies have shown that iron-based addition such as nano-zerovalent iron, and iron nanoparticles promoted anaerobic process, improved methane production, and enhanced ARGs reduction and microbial community. Therefore, the dissemination of these technologies could help in controlling ARGs dissemination. In addition, recently, there has been an effort to find feasible alternatives to heavy use of antibiotics in food animals. While there is ongoing research to identify better alternatives to antibiotics, currently, there is a pressing need to find better ways of treatment to reduce the prevalence of antibiotic residue and ARG in dairy-based manure.
Acknowledgments
We would like to acknowledge the Division of Agriculture and Natural Resources (ANR) and School of Veterinary Medicine Extension, University of California, Davis for supporting this work.
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Funding information: The authors state no funding involved.
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Author contributions: Y.W. wrote the first draft of manuscript. B.D.S., S.K., and P.K.P. critically revised the manuscript. P.K.P. developed the idea and assisted Y.W. in writing the manuscript. P.K.P. revised the manuscript during review process. All authors read and approved the final manuscript.
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Conflict of interest: The authors state no conflict of interest.
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Data availability statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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