Harnessing Nanominerals for Managing Subclinical Mastitis in Cattle: An Innovative Approach

Abstract

Mastitis is a problem associated with mammary gland and results in drop in milk production. The significance is more in milch animals as milk is the primary product. Use of antibiotics for treating mastitis is not only adds to expenses but also raises the concern of antimicrobial resistance among the consumers. Use of nano-minerals may be a good alternative for treating mastitis in domestic animals. Nano-minerals can be defined as minerals of 1-100 nm range. The nano-minerals have unique properties as compared to their counterparts. Due to the biocidal properties, mineral nanoparticles of Ag, Au, Se, Cu, Zn, etc., in the diet as feed additive can control or reduce the subclinical mastitis, and thus can be a potential alternative of antibiotics. The nano-minerals act efficiently against mastitis causing agents, thanks to their anti-microbial, anti-oxidant, anti-inflammatory, and immunomodulatory properties. Though the results are encouraging, use of nano-minerals as a preventive and curative to subclinical mastitis is in its infancy. Further studies are warranted to validate the route of administration and evaluate its efficacy in long-term use in varied animal species. Moreover, the side effects of application of nano-minerals have to be studied before recommending in commercial scale.

1. Introduction

Mastitis is the most prevalent and expensive condition that affects dairy cattle in India [1] and worldwide [2], causing severe losses in the dairy industry. Next to foot and mouth disease, mastitis is regarded as one of the costliest and economically devastating diseases influencing the profitability of Indian dairy farmers and industries [3] through reduced milk production, milk quality, treatment, and culling cost [4]. Mastitis poses the risk that the bacterial contamination of milk from affected cows will render it unfit for human consumption by causing food poisoning or interfering with the production process or, in rare situations, providing a route for disease transmission to people [5].

The inflammation of the mammary gland is called mastitis, which can be observed in all mammals. This is an important disease in dairy animals as it affects their productivity with the potential to affect the health of humans and animals consuming it. In the majority of cases, an infection caused by bacteria causes this condition. Attempts are being made worldwide to manage bovine mastitis because of its significant impact on cattle and public health and the altered composition of milk from mastitis-affected cows. These could have an adverse impact on the suitability of milk processing as well as the quality of processed goods made from it. The loss in the dairy industry does not only refer to economic issues including milk quality and quantity, antibiotic usage, or extra labor but also in addition to the disease significantly affecting animal welfare and public health [6].

Mastitis may have different etiological factors, namely, bacteria, viruses, fungi, and algae-like infectious factors [7] coupled with the genotype, environmental conditions, immune status, and feed composition (dietary supplement addition) such as noninfectious factors [8]. Furthermore, the noninfectious factors may contribute directly or indirectly to the occurrence and severity of mastitis [6]. Depending on the source of infection, mastitis can be divided into two subcategories: contagious and environmental. Environmental mastitis is caused by pathogens from the environment, whereas contagious mastitis spreads from other infected quarters [9]. Among the bacteria, the most common bacteria that cause intramammary infection are Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli, and Streptococcus uberis [6, 10, 11, 12].

Among the noninfectious factors contributing to the onset of mastitis, mineral deficiencies are forerunners. Any nutritional deficiency will result in a weakened immune response, which will increase the risk of udder inflammation, and thus contribute as a predisposing factor for udder inflammation. Minerals are a group of nutrients that have been reported to influence udder health status since they strongly impact the immune system. Consequently, these deficiencies result in weakened immunity, which increases the risk of any infectious disease. The minerals such as Cu, Zn, Se, and Mn play a vital role in enhancing the immunity of cattle. Moreover, deficiencies of some minerals are associated with metabolic disorders such as milk fever, hypophosphatemia, and hypomagnesemia. Every mineral deficiency leads to immunosuppression [13] that can predispose the cows to mastitis [6]. Furthermore, cows with sound immune system can deal with microbial invasion and avoid the inflammation process, and thus prevent the occurrence of mastitis [6].

2. Types of mastitis

Mastitis can be classified into two types: clinical and subclinical form. In the clinical form, signs may vary depending on the causative agent; whereas in the subclinical form, there are no visible changes in the aspect of the udder or milk, although it can limit milk output. However, subclinical mastitis is regarded to be the most economically significant type of mastitis for many cattle farms because of its high prevalence (19–78%), being a chronic source of infection for herd mates, its difficulty of detection and possibility to convert into clinical form [4, 14]. In India, Varshney and Naresh [15] reported that subclinical mastitis (SCM) had a higher incidence (10–50%) than clinical mastitis (1–10%). It reduces the milk production and causes changes in the composition and quality of the milk, as well as shortens lifetime of the affected cows and causes significant damage of the milk secretory cells [16]. Monitoring the number of somatic cells is a widely used practice in the European Union (EU) for assessing milk quality [17, 18] that increases in mastitis.

3. Economic implications

The economic implication of mastitis can be attributed directly through the loss in milk production and indirectly through the cost of treatment of animals [19, 20, 21]. Moreover, in subclinical mastitis, the owners fail to detect the disease; thus, there is an obvious delay in treating the cows. Despite the possibility of the consumption of infected milk causing health issues in humans and animals, it is still being consumed. Nevertheless, the prevention and treatment of mastitis, as well as the costs associated with preventive measures, also incur additional expenses for the farmer. To create the right economic interventions to prevent and cure mastitis, accurate information of the disease status is required, allowing feasibility of preventive measures for one dairy cow or for the entire herd [22].

Again, the costs of mastitis are divided into two broad groups: those that occur directly and those imparts indirectly. Veterinary services, diagnoses, therapies, additional labor needs, and milk wasted during treatment are considered as direct expenditures. The term “indirect costs,” often known as “hidden costs,” refers to expenses that are not always apparent to the producer of milk. Many farmers are unaware of the indirect costs associated with subclinical mastitis (SCM), which include decreased milk production, premature culling losses, and decreased quality premiums [23]. Education is essential in this area, since failing to detect indirect losses could make it harder to introduce mastitis control measures [22].

Most economic expenditures associated with mastitis are believed to be primarily attributable to SCM. Besides, the Indian diary industry lost more than 2.37 billion rupees each year as a result of mastitis, with SCM responsible for roughly 70%. According to some research, SCM is more common and causes greater economic loss in India than CM (28–42%: 1700–3000 crores annually vs. 58–72%: 4150–4365 crores; [24]). Rathod et al. [25] reported that depending on the cow’s health, the overall economic losses caused by SCM each lactation period ranged from INR 21,677 to 88,340. Singh et al. [26] reported that high-yielding crossbred cows suffered greater financial losses per lactation than native cows and buffaloes (INR 868.34 and INR 1, 272.36, respectively).

4. Problems in the recent treatment regimen

In bacteria, Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli, and Streptococcus uberis are predominant pathogens attributed towards mastitis [6, 10, 11, 12]. Thus, antibiotics are used for treating mastitis. However, indiscriminate use of antibiotics threaten the emerging issues such as antibiotic resistance in humans and cattle consuming such contaminated milk (Figure 1). Similarly, Pol and Ruegg [27] stated that mastitis is the prime cause of antibiotic use in dairy animals, and this can be a potent threat to the public’s health in terms of antibiotic resistance development. For instance, antibiotics are used to treat S. aureus infections causing mastitis, and beta-lactam antibiotics, that is, methicillin has been reported ineffective as a result of resistance to methicilin [28], known as methicillin resistant S. aureus, which has the mec gene [29].

Figure 1.

Compact antibiotic resistance by the use of nanominerals and phytochemicals.

There are many diagnostic tools for the detection of mastitis in cows. However, their efficacy and time required for the characterization and identification of mastitis causes the significant difficulty and delay in the effective treatment of diseases. The majority of diagnostic procedures are often used widely, even though many lack the required accuracy. Some are time-consuming and expensive, whereas others can only identify the clinical mastitis when the cow is severely affected. For example, CMT has been used as a cowside test for a long time [30]. Errors can occur while interpreting SCC data because of the influence of several factors such as the presence of bacteria, diurnal variation, age, stage of lactation, and storage of the milk sample [31].

Because of the rise in antibiotic resistance and the public demand for high-quality milk, mastitis in cows need to be properly prevented and treated with non-antibiotic alternatives. For instance, in a study in the Transylvanian area (Romania), Staphylococcus aureus, isolated from the milk of the mastitis affected cows, were resistant to penicillin and tetracycline [32]. The detection of subclinical mastitis and adequate treatment are added challenges for veterinary professionals, dairy farmers, and scientists. Some reports suggest that nanominerals could be a good alternative to antibiotics for treatment (Figure 1) and prevention of mastitis in dairy cows [33, 34]. Though scanty, the literature indicates a lot of promise in the utilization of nanominerals, particularly Ag, Se, Zn, and Au, used to control mastitis in cows.

5. Nanotechnology

The era can be conferred as the era of nanoscience, thanks to its use in various fields such as science and technology. However, nanotechnology keeps surprising the researchers by virtue of its new phenomenon and unexpected outcomes. Though not limited to medicine, cosmetics, agriculture, scarce science, nanoscience has proved its mantle in many fields. The use of nanotechnology in veterinary medicine and as an animal feed supplement is relatively new but found promising applications [35, 36, 37, 38]. The quantum of research in nanotechnology, particularly nanomineral feeding, indicates its essence and opportunities in the field of veterinary science [4, 37, 39, 40]. Nanotechnology is a potential option for novel treatment for bovine mastitis [33, 35].

The science dealing with the materials studied in nanoscale is referred to as nanotechnology. More precisely, the materials having a size in the range of 1–100 nm scale are called nanomaterials [41]. For instance, nano-zinc denotes zinc particles that are engineered and processed to have dimensions in the nanoscale, which can potentially improve its bioavailability and cellular uptake compared to traditional zinc supplements.

6. Preparation and properties of nanominerals

The huge opportunities in nanominerals have popularized the technology, which is evident from the quantum of research done on nanominerals. The huge requirement warrants the scientists to standardize and make economical the synthesis of targeted nanominerals. The nanominerals can be synthesized by either physical, chemical, or biological methods (Figure 2). An application of physical forces such as ball mill to reduce the particle size is physical synthesis, whereas the use of chemicals to reduce the particle size is a chemical method of nanoparticle synthesis [42]. The use of live organisms to reduce the particle size is a biological synthesis of nanominerals [42]. The biological methods are reported to be environmentally friendly. However, chemical synthesis of nanominerals is economical and tends to produce uniform nanominerals [42].

Figure 2.

Preparation of nanominerals by various methods.

In another way, Neculai-Valeanu et al. [35] classified the synthesis of nanominerals into top-down (e.g., laser ablation, ball milling and chemical etching) and bottom-up approaches (e.g., sol-gel process, chemical vapor deposition, spray pyrolysis, green synthesis). In the top-down method, the bulk material is converted into nanometer-sized structures using different reagents and physical treatments. In the bottom-up approach, nanoparticles are developed to a specific size and shape from simpler molecules [35]. The size of nanoparticles can be altered to produce nanoparticles of the desired shape and size by altering pH, temperature, and reaction time [43, 44].

Nanominerals are synthesized with a size ranging from 1 to 100 nm [41]. Nanominerals are reported to portray novel physical, chemical, and biological activities [42, 45], and thus produces unexpected biological responses when fed to cows [38, 39, 46]. Thanks to the superior bioavailability of nanominerals as compared to their conventional inorganic counterpart, they result in better cow health and production at even reduced doses [34, 47]. Being nanometer size, zinc nanoparticles are easily absorbed in the gastrointestinal tract of animals, and thus are more effective than the larger size ZnO even at lower doses [41] and simultaneously less toxic as compared to the conventional inorganic salts [48]. Nanominerals had the capability of crossing the animals’ small intestines and entering easily into blood, brain, lung, heart, kidney, spleen, liver, intestines, and stomach [49]. However, nanoparticle absorption and metabolism are affected by many factors, namely, size, shape, zeta potential, other ligands, surface chemistry, age and species of animal, intestinal health, and dose of use [50, 51]. Desai et al. [52] reported that the translocation of 100-nm nanoparticles is 15–250 times more than that of micromolecules. Nanominerals interact more effectively with organic and inorganic substances in animal bodies that may be attributed to their large surface area [53]. Similarly, Rosi and Mirkin [54] stated that the chemical, catalytic, or biological effects of nanominerals are highly influenced by the particle size of the mineral. For instance, CuO nanoparticles are transported quickly into cells compared with CuSO4 and CuO microparticles [55].

7. Nanominerals as alternatives to antibiotics

Among the beneficiary effect of nanominerals, the antibiotic effect is realized and documented by many researchers [36, 46, 56, 57, 58]. The incidence of mastitis is found to reduce by the application of nanominerals. This may have been achieved either by directly killing bacteria and/or by improved immunity of the animal [36, 57]. Elkloub et al. [59] reported a decrease in E. coli count as a result of supplementing birds with Ag nanoparticles, demonstrating the antimicrobial effect of Ag nanoparticles.

Mineral nanoparticles of Zn, Ag, and Au can be used as a replacement for antibiotic drugs and without any drug residues in milk and animal products. Reports [36, 57] denote the antimicrobial effect of Nano Ag at the intestine level along with the immunomodulatory effect. Similarly, the somatic cell count in mastitis milk of Holstein Friesian cows was greatly reduced by the supplementation of Zn nanoparticles [34]. Moreover, Zn nanoparticles are found to be effective against both Gram-positive and Gram-negative bacteria [56]. Rosi and Mirkin [54] reported that the nanoparticles are effective against spores that are resistant to high temperature and high pressure.

Antibacterial activity means the reagent that locally kills the bacteria or slows down their growth, without being toxic to surrounding tissues [58]. The antimicrobial effect of ZnO is related to their electromagnetic effects as microorganisms are negatively charged, and thus get attracted towards positively charged metal oxides, resulting in oxidization and subsequent death of microbes [56]. The large surface area of metal nanoparticles can be the reason behind the antimicrobial effect as compared to the large-sized particles [60]. Minerals in nanoform also retard bacterial adhesion and biofilm formation [61], which may be the reason behind the antimicrobial effect. Padmavathy and Vijayaraghavan [61] studied the effect of various nano-Zn particle sizes (20–40 nm, 12 nm, 45 nm) against E. coli and observed that nano-Zn has better bactericidal activity than bigger ZnO particles. These results contribute to the abrasiveness and the surface oxygen species of ZnO nanoparticles promoting its bactericidal effects. According to Rajendran et al. [62], ZnO nanoparticles inactivate the proteins responsible for nutrient transport; hence, decreasing the membrane permeability leads to cellular death. Similarly, Au nanoparticles promote innate immunity at <1 mg/kg dose in chicken [63].

Negatively charged bacterial membranes are pulled to positively charged metal nanoparticles resulting in leakage and bacterial cell lysis Gahlawat et al., [64]. Kim et al. [65] discovered that Ag nanoparticles could stop the development of yeast isolated from a case of bovine mastitis and hemorrhagic enteritis-instigating E. coli O157:H7 with an estimated MIC value of 3.3–6.6 nmol/L and 6.6–13.2 nmol/L, respectively. Mineral nanoparticles act as biocides that may be ideal alternatives to antibiotic drugs and prevention of contagious diseases, including mastitis, limiting the burning issue of antimicrobial resistance in animals and humans [66].

8. Nanominerals and mastitis

Bacteria are the main cause of mastitis in dairy cows, and the agents that act against them will also be helpful in the prevention and cure of mastitis. Thanks to the antimicrobial effects, nanominerals may be good and healthy alternatives of antibiotic drugs in treating and controlling mastitis. The antimicrobial effects of metal nanoparticles are mainly because of the release of metal ions, disruption of the cell membrane and cell wall, reactive oxygen species production, and inhibition of appropriate DNA replication [35]. Many researchers [67, 68, 69] have found metal nanoparticles to be effective against bovine mastitis pathogens [70, 71] and bacteria that are resistant to methicillin as well [35]. Similarly, Rajendran et al. [34] observed an improvement in milk production by the supplementation of nano-ZnO in cows affected with subclinical mastitis. The increases in milk production were attributed to the suppression of subclinical mastitis evident from the reduction of somatic cell count [33, 34]. The use of nanoparticles as a therapeutic alternative for bovine mastitis controls the gaining importance attributed to their improved antimicrobial activity and low cytotoxicity and opens the window for organic farming [35, 70, 71]. Furthermore, Se nanoparticles prevent the growth of common mastitis-causing bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus, and E. coli at a concentration of 1 mM [72]. Studies conducted by Soni and Yadav [73], Krishna et al. [74]; Mohsenabadi et al. [75], and Vasile et al. [76] have documented the efficiency of nanogels against intracellular pathogens such as Staphylococcus aureus, and thus opened new possible method to address the therapeutic challenges caused by mastitis in animals. Debata et al. [72] studied the in vitro antibacterial activity of nanominerals on mastitis-causing bacteria using the well diffusion method and reported that nano-Se particles were able to inhibit Escherichia coli and Staphylococcus aureus and Pseudomonas aeruginosa. Zhang et al. [77] postulated that the antibacterial activity of nanoparticles may be because of the generation of reactive oxygen species, malondialdehyde (MDA), and leakage of proteins and sugars in bacterial cells. Wernicki et al. [78] and Kalinska et al. [79] observed that silver and copper nanoparticles exhibit the highest antimicrobial activity against bacteria isolated from inflamed udders. Thus, antimastitic effect of nano-minerals is an additional benefit along with its environment friendly effect [40, 80], augmentation of animal productivity [58, 81] and improved mineral retention [40, 82] which may be proved vital in maintaining the productivity and profitable farming.

9. Conclusions

Mastitis has long been a problem that has not been fully resolved. This issue also affects organized farms that are run efficiently as well as unorganized farms. Mastitis not only reduces the production of animals but also incurs financial loss directly though treatment and reduction in milk production. Even though in a smaller number of incidences, mastitis threatens to cease the milk production completely, and thus directly governs the economic importance of dairy animals. Apart from that, the use of nonspecific use of antibiotics to control and treat mastitis in dairy animals is a potential reason for the development of antibiotic resistance in human as well as animals. Hence, in this context, the literature survey indicated that the use of mineral nanoparticles of Ag, Au, Se, Cu, and Zn in the diet as feed additives can control or reduce subclinical mastitis, and it can be used in place of antibiotics, thanks to their biocidal properties. The mechanism of action is not only restricted to antimicrobial properties but also as a potent antioxidant, anti-inflammatory, and immunomodulatory agent that acts collectively to prevent subclinical mastitis. The antibacterial properties particularly in mastitis animals are studied for so long, and encouraging responses are also recorded by many. However, more systematic studies are warranted to establish their effect as a substitute for antibiotic drugs. Moreover, the duration of application and probable toxicity to the animal under treatment and, in a remote sense, those who are consuming the products keep knocking the minds of the researchers and are to be addressed.