Bovine mastitis: An appraisal of its alternative herbal cure

Microbial Pathogenesis Volume 114, January 2018, Pages 357-361 Microbial Pathogenesis Author links open overlay panelSaleemMushtaqabAabid ManzoorShahaAiyatullahShahaSajad AhmadLoneaAehteshamHussainaQazi ParvaizHassanaMd NiamatAlib https://doi.org/10.1016/j.micpath.2017.12.024 Get rights and content Highlights • Bovine mastitis is the most common and costly disease affecting dairy herds. • Antibacterial agents are associated with the problem of antibiotic resistance. • Herbal cure is an alternative therapeutic option for the treatment of bovine mastitis. • An overview of different medicinal plants used against mastitis is presented. • It highlights the logic and precedence behind mining this natural product resource. Abstract Bovine mastitis is globally recognized as the most common and costly disease affecting dairy herds. The disease causes huge financial losses to dairy industries by reduced yield and milk quality, deaths and culling of affected cows and also by associated treatment costs. The disease occurs due to invasion of the mammary glands by pathogenic bacteria followed by their multiplication in the milk producing tissues. The most common treatment method available against bovine mastitis is the intra-mammary infusion of antibiotics. However, their use is associated with the problem of antimicrobial resistance. This scenario has made search for alternative treatment approaches necessary. Medicinal plants with their well-established history are an excellent natural product resource used as an alternative therapy. Antibacterial agents from plants can act as important sources of novel antibiotics, efflux pump inhibitors, compounds that target bacterial virulence or can be used in combination with existing drugs. The plants form an essential component of ethno-veterinary medicine used in the treatment of different diseases like bovine mastitis. This review article attempts to provide an overview of the different medicinal plants used in the treatment of bovine mastitis. Antimicrobial studies of these plant species and some of their isolated constituents have been reviewed in detail. It highlights the logic and precedence behind mining this important natural product resource. Our own research findings in this direction and future scope of research are also discussed briefly. Previous article Next article Keywords Bovine mastitis Antibiotic resistance Medicinal plants Dairy Antibacterial 1. Introduction Bovine mastitis is the inflammation of the mammary glands in dairy cows, caused by invasion and destruction of the milk producing tissues by pathogenic microorganisms [1]. About 137 species of microorganisms including bacteria, yeasts and algae are known to cause mastitis [2,3]. Mastitis causes financial losses to dairy industries through reduced milk yield, poor milk quality, increased culling and also due to additional expenses on treatment and extra labor [4]. India is the world's largest milk producer, with 16% of global production [5]. The annual economic losses due to mastitis in India, United States, UK and worldwide have been estimated at $1.1 billion [6], $2 billion [7,8], $371 million [9] and $35 billion [10,11], respectively. The prominent bacteria responsible for causing mastitis include both gram-positive and gram-negative bacteria like staphylococci, streptococci, Escherichia coli and Klebsiella pneumoniae[12]. Coagulase-negative staphylococci (CNS) are opportunistic pathogens that have also emerged as important mastitis pathogens [13]. Antibiotics are used for the treatment of bovine mastitis, but these are associated with the problem of antibiotic resistance. The prevalence of mastitis pathogens and their antimicrobial resistance have been investigated in numerous studies around the world. For example, studies from Ethiopia and Estonia have reported a high prevalence of penicillin resistant S. aureus and CNS strains in these countries [14,15]. Similarly, in West Bengal, India, Gram-negative bacteria have been recently found to be resistant to antibiotics like β-lactams and tetracyclines [16]. In Central Mexico, antimicrobial investigations revealed that the isolated mastitis pathogens were resistant to penicillin, clindamycin and cefotaxime [17]. Antimicrobial studies from Canada have also exhibited that subclinical isolates of two important mastitis pathogens, Streptococcus uberis and Streptococcus dysgalactiae harbour antimicrobial resistance genes and should be considered as potential propagators of antimicrobial resistance [18]. In Southern Taiwan, E. coli isolates from milk samples of mastitis affected cows were fluoroquinolone-resistant and extended-spectrum β-lactamase-producing strains [19]. Therefore, there is a need to explore alternative approaches for the treatment of mastitis. This review article is an overview of the different medicinal plants used in the treatment of bovine mastitis and highlights their importance as an alternative natural product therapeutic resource. 2. Bioprospecting medicinal plants Bioprospecting is the discovery of natural products that have a useful pharmacological or biological application [20]. In many cases, bioprospecting involves the search for useful organic compounds in natural products like microorganisms, plants, and fungi that grow in extreme environments, such as rainforests, deserts, and hot springs [21]. Natural products traditionally acted as primary source for more than 80% of the drug substances and even today hold an important place in the drug discovery process [22,23]. A data analysis of the literature available from 1981 to 2006 showed that more than 50% of the drugs approved by FDA were natural products or natural products derivatives [24]. Natural products have proved to be the primary source for antibacterial drug discovery also. About 66% of all the drugs currently approved as antibacterial agents are natural products or natural product derivatives [25]. Pressure to find novel antibacterial products with new modes of action that target non-essential cell processes has driven exploitation of plant sources for the identification of new and effective antibacterial agents [26]. The mechanisms of action of phytochemicals may be different from those of routine antibiotics and this feature could be of vital importance in the treatment of resistant bacteria. Combining phytochemical antibacterials with already existing drugs offers another field for application of phytochemicals and should be pursued extensively. While there are no plant-derived single chemical entity antibacterial drugs available on the market yet, this natural source is worth exploration due to several important reasons as has been excellently reviewed by several authors [27–30]. Plants can serve as a novel and alternative source of antibiotics [31]. Several phytochemicals, either with promising antibacterial activity such as horminone, pyrithione, gossypol, plumbagin and rhein, or as efflux pump inhibitors like 5′-methoxyhydnocarpin (5′-MHC) have been isolated from different plant species [32,33]. Plant antibacterial agents can also target bacterial virulence and this class of antibacterial agents remains largely untapped [34]. Antibiotic resistance can also develop against plant based antibacterial agents. However, during the course of evolution, plants may have evolved some different chemical strategy for the control of microbial infections in order to decrease the selective pressure for developing antibiotic resistance. For example, plant antibacterials usually act in combinations and have little efficacy alone [34]. Medicinal plants used against mastitis: In organic dairy farming, farmers replace antimicrobials with non-traditional herbal therapies. Herbal therapies are an essential component of ethnoveterinary medicine (EVM). EVM is particularly important in animal health care in developing countries [35]. It has become a recognized field of research that includes traditional veterinary theory, medicines, surgical methods, diagnostic procedures and animal husbandry practices [36]. Farmers and pastoralists in several countries use medicinal plants in the maintenance and conservation of the healthcare of livestock. Approximately, 75% of rural livestock owners in the Eastern Cape province of South Africa use plants or plant-based remedies to treat their livestock [37]. In India, EVM is used for primary health care treatment to make domestic animals productive and healthy [38]. The indigenous knowledge of the veterinary health care system acquired by traditional herbal healers is orally transformed from one generation to the other. Herbal therapy is also used in the treatment of mastitis in different parts of the world. For example, in the United States, organic farmers treat clinical mastitis using a variety of alternative therapies including whey based products, botanicals, vitamin supplements, and homeopathy [39]. Similarly, a number of plant species like Spathodea campanulata and Tridax procumbens are used to cure mastitis in India [40]. In British Columbia, Canada, mastitis is treated with Achillea millefolium, Arctium lappa, Salix alba, Teucrium scorodonia and Galium aparine[41]. Organic dairy farmers in different parts of the world use a variety of nontraditional methods to cure mastitis. Medicinal plants used against bovine mastitis may have different biological properties. However, there is limited efficacy data to support the use of these alternative treatments. Therefore, it is important to scientifically validate different traditional plant remedies. Although different alternative treatment approaches are used in the control of mastitis, the goal here is to highlight only those medicinal plants which have been investigated for antimicrobial potential against mastitis pathogens. 3. Antimicrobial studies of plants or plant derived molecules against mastitis Although plants are widely used against different animal diseases including bovine mastitis, there are limited reports available on the pharmacological study of medicinal plants used in the control of mastitis. Below we present a brief compilation of some of the literature reports available on the exploration of medicinal plants for their potential use against bovine mastitis. Hase et al., evaluated and compared the therapeutic efficacy of topical herbal spray (AV/AMS/15) with Mastilep gel against subclinical mastitis [42]. The phytochemical constituents of plant species Cedrus deodara, Curcuma longa, Glycyrrhiza glabra and Eucalyptus globulus are used in alternative medicine for their antibacterial, anti-inflammatory, analgesic, anti-histaminic and immunomodulatory properties. These herbal ingredients at various concentrations form the basis of Mastilep gel and herbal spray (AV/AMS/15). For experimental purposes, cows detected with subclinical mastitis were divided into three groups: one control group and two treatments. Group A i.e., control group was not given any treatment. However, first and second treatment groups i.e., Group B and Group C were treated with herbal spray (AV/AMS/15) and topical application of Mastilep gel, respectively. Both the herbal formulations were sprayed and gently applied to the cow udders twice a day after every milking for five consecutive days. The authors claimed that use of this herbal spray on test animals led to an improvement in milk yield and milk fat content and reduced SCC by boosting the udder immunity in comparison to the control group. Thus the herbal spray not only eliminated the udder infection in sub clinical mastitis but also helped in the control of mastitis without any side effects. The study proved that the overall cure rate and prophylactic efficacy of AV/AMS/15 topical herbal spray was good and at par to Mastilep gel. Since mastitis reduces milk yield and significantly alters milk composition depending on the severity and duration of the infection and the pathogens involved, therefore, changes in milk composition are used to assess udder health. Generally, mastitis is characterized by an increase in the blood constituents in milk and a decrease of normal milk constituents. While assessing such effects, Sunder et al., 2013 analyzed the effect of Morinda citrifolia fruit juice on milk characteristics of 13 healthy and 12 mastitis-affected dairy cows. The fruit juice was fed orally to the animals at the rate of 100 ml/day/animal. The authors noticed that the administration of the fruit juice significantly lowered the pH of mastitis affected milk from 7.2 ± 0.17 to 6.54 ± 0.07. The electrical conductivity of mastitis-affected milk also lowered significantly from 5.97 ± 0.81 × 105 mS/cm to 4.77 ± 0.14 × 105 mS/cm. It was further observed that the fruit juice reduced the total bacterial count in the mastitis milk to a significant level from 5.15 ± 0.03 × 108 to 2.54 ± 0.03 × 108 CFU/ml. The fruit juice feeding also decreased the total protein concentration in the mastitis milk from 41.83 ± 6.56 μg/ml to 21.13 ± 0.93 μg/ml. No significant change for these parameters was observed in the treated group of healthy animals. Although, the milk yield was not significantly changed in both the treatment groups but the mastitis affected animals showed some increase in milk yield after feeding of the fruit juice. Therefore, the overall results showed that feeding of M. citrifolia fruit juice to mastitis affected cows resulted in the positive change in the milk composition and thereby improving the udder health [43]. Ocimum sanctum (Tulsi) is an important plant species used in the treatment of various animal diseases. It possesses immuno-modulatory and anti-inflammatory properties attributed to its active constituents such as volatile oil (eugenol, 80%), flavonoids, and triterpene. Shafi et al., 2016 evaluated the immunotherapeutic potential of this important medicinal herb against mastitis affected dairy cows [44]. Twenty Holstein Friesian × Sahiwal lactating dairy cows were selected for this study. The cows were divided into two equal groups: a control group and a group orally administered the leaf powder of tulsi at a concentration of 600 mg/kg body weight on a daily basis for 7 days. It was found that the treatment reduced 69.23% of intramammary infections and also resulted in a significant reduction in somatic cell count and ceruloplasmin concentration, therefore decreasing udder inflammation and improving milk quality. The significant increase in phagocytic activity of milk neutrophils and enhanced lactoperoxidase and myeloperoxidase activities proved that the herb possesses immune-modulatory potential. Therefore, the study proved the immunotherapeutic potential of tulsi in the treatment of subclinical mastitis. Reshi et al., 2017 demonstrated the antibacterial activity of Fumaria indica and Adiantum capillus against subclinical mastitis by intra-mammary infusion of these plant extracts [45]. This was done after preliminary screening of extracts from three plant species for their safety by carrying out cytotoxicity studies on HeLa cell line using MTT cell proliferation assay. The plant extracts were then assessed for their antibacterial activities against S. aureus, E. coli, S. agalactiae and K. pneumoniae by using disc diffusion method. It was found that Fumaria indica extract showed best antibacterial activity followed by Nepata cataria and Adiantum capillus. In order to further check their efficacy, in vivo studies were carried by intramammary infusion of aqueous extracts at a dosage of 750 mg/tube for 5 days in cows affected with subclinical mastitis. For this purpose, animals were placed into five groups: Group II, Group III and Group IV were treated with aqueous extracts of Fumaria indica, Adiantum capillus and Napeta cataria, respectively. Groups I and V served as negative and positive controls. Recovery was confirmed by correlating the California Mastitis Test score on day 5 with somatic cell count (SCC) as compared with day zero of therapy. Highest clinical recovery was reported in case of Fumaria indica followed by Adiantum capillus. Therefore, herbal preparations of Fumaria indica and Adiantum capillus can be considered as an alternative treatment for mastitis. A topical polyherbal formula known as Ya-Sa-Marn-Phlae (YSMP) has been traditionally used in Thailand for the treatment of wounds and inflammatory skin diseases. It consists of Curcuma longa (rhizome), Areca catechu (seed), Oryza sativa (seed), and Garcinia mangostana (pericarp). Chusri et al., evaluated the antibacterial potential of this polyherbal formula, its herbal components (Curcuma longa, Areca catechu, Oryza sativa, and Garcinia mangostana), and representative chemical constituents (catechin, α-mangostin, and curcumins) against both coagulase positive and coagulase negative staphylococci isolates [46]. The results showed that ethanol extracts of polyherbal formula, G. mangostana, and α-mangostin showed most promising antibacterial activities with MIC values of 1–32 μg/ml. When the test samples were investigated for their anti-biofilm activity, it was found that these significantly inhibited biofilm formation of the test isolates. Further studies revealed that the polyherbal formula showed similar results like that of α-mangostin and G. mangostana. Electron microscopic studies showed that the polyherbal formula and G. mangostana act by causing severe alterations in the bacterial cell wall by the formation of holes and morphological disorganization. The studies also proved that G. mangostana is the most active component of the YSMP. However further investigation are needed to correlate the activity of either YSMP, G. mangostana, or their constituents. While evaluating the antimicrobial potential of an indigenous polyherbal preparation on periparturient immunity and udder health of high yielding Karan-Fries crossbred cows, Sharma et al., 2014 noticed that the herbal preparation showed promising results [47]. The herbal product consists of Withania somnifera, Asparagus racemosus, Emblica officinalis, Ocimum sanctum, Tinospora cordifolia, Tribulus terrestris, and Nigella sativa. The preparation was given to the cows at the rate of 200–250 mg/kg body weight. It was observed that test product significantly reduced periparturient stress while enhancing immunity and improving the udder health in test animals. These primary studies suggest that the herbal product can be probably used as feed additive to reduce the incidence of mastitis. Leaves form an integral component of most natural pastures for ruminant diets and chemical investigations have shown that tree leaf components like tannins, essential oils, or other aromatic compounds have anti-nutritional or anti-microbial factors. Based on this hypothesis, researchers evaluated the preliminary antimicrobial activity of tannin extracts from eight plant species common to the Southern Great Plains of USA [48]. The evaluated plant species showed a dose dependent in vitro inhibition of S. aureus, in the following order: Shinnery oak > Post oak > Locust > Blackjack oak ≥ Skunk bush > Sericea lespedeza > commercial Quebracho ≥ Sumac > Plum. The extracts from two plant species i.e., Shinnery and Post oaks showed maximum growth inhibition of S. aureus. As the tannin extracts from leaves of these plant species were highly inhibitory to selected pathogens, the researchers recommended that these may provide alternatives and supplements to conventional antimicrobial feed additives. Different medicinal plants Symphythum officinale, Sambucus nigra, Mentha sp., Ocimum basilicum, Parapiptadenia rigida, Cuphea carthagenensis, Salmonella cholleraesuis, Alternanthera brasiliana, Achillea millefolium, Baccharis trimera and Solidago chilensis are used in the prevention and control of bovine mastitis in Southern Brazil [49]. Decoctions prepared from these plants were analyzed for their in vitro antimicrobial activity against S. aureus and Salmonella choleraesuis by the agar dilution method in order to scientifically validate the traditional practice. Extracts from Alternanthera brasiliana, Achillea millefolium, Baccharis trimera and Solidago chilensis inhibited the growth of S. aureus while Symphythum officinale, Sambucus nigra, Mentha sp., Ocimum basilicum, Parapiptadenia rigida and Cuphea carthagenensis extracts were active against both microorganisms. The results thus justified to some extent the traditional use of the above plant species against bovine mastitis. As part of the search for alternative therapeutic approaches to antibiotics for the treatment of mastitis, the efficacy of short chain fatty acids viz., caprylic acid and monocaprylin were examined for their ability to inhibit the growth of five common mastitis pathogens, i.e., S. agalactiae, S. dysgalactiae, S. uberis, S. aureus, and E. coli. The antimicrobial studies showed that both caprylic acid and monocaprylin were bactericidal against the above microorganims at the tested concentrations and reduced the growth of all pathogens by > 5.0 log CFU/ml after 6 h of incubation [50]. The streptococci species were found to be most sensitive while E. coli was most tolerant to the test samples. The results indicate that both caprylic acid and monocaprylin should be further evaluated as alternatives or adjuncts to antibiotics as intramammary infusion strategies to treat bovine mastitis. In another similar study, a research group explored the antimicrobial potential of four essential oil components Trans-cinnamaldehyde (TC), eugenol, carvacrol, and thymol against mastitis pathogens inoculated in milk samples [51]. These four essential components have been classified as GRAS (generally regarded as safe) by the United States Food and Drug Administration. The test antimicrobials were evaluated for minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) determination against major mastitis pathogens like S. agalactiae, S. dysgalactiae, S. uberis, S. aureus, and E. coli. The four molecules inhibited the growth of test pathogens but TC was most effective in reducing the bacterial growth. In time-kill assays, TC reduced the bacterial load in milk by 4.0–5.0 log CFU/ml and to undetectable levels within 12 and 24 h, respectively. Further, the antimicrobial effect of TC persisted for the duration of the experiment (14 d) without any loss of activity. These results suggest that among the test molecules, TC has the potential to be further evaluated as an alternative or adjunct to antibiotics as intramammary infusion to treat bovine mastitis. Similarly, a research team evaluated the antibacterial activity of three plant-derived diterpenes against a panel of microorganisms known to cause bovine mastitis [52]. From the three evaluated diterpenes, ent-Copalic acid (CA) was found to be the most active metabolite, with promising MIC values (from 1.56 to 6.25 μg ml) against S. aureus, S. epidermidis, S. agalactiae, and S. dysgalactiae. Time-kill assays of CA against S. aureus showed that it has a bactericidal effect. Therefore, the study concluded that CA could be of interest in the control of several Gram-positive bacteria associated with bovine mastitis. While assessing the antimicrobial activities of leaves of Spathodea campanulata and Tridax procumbens, Das et al., found that the methanol extract of S. campanulata inhibited the growth of S. agalactiae, S. uberis, E. coli and S. aureus[53]. However, the methanol extract of T. procumbens was only active against S. aureus. Further, phytochemical screening of the plant species revealed the presence of alkaloids, tannins, saponins, steroids, terpenoids and flavonoids. As tannins are well known antimicrobial agents and tannin-containing plants are used to treat diarrhoea, inflammatory disorders and skin problems, the research team used these points as the rationale behind using these plants as a natural remedy to cure mastitis in dairy cows. In search of natural alternatives for the treatment of mastitis, Montironi and coworkers [54] evaluated the antimicrobial efficacy of Minthostachys verticillata essential oil and one of its major constituents, limonene against S. uberis strains isolated from bovine mastitis. The MIC and MBC values ranged from 14.3 to 114.5 mg/ml and 114.5 and 229 mg/ml in case of the essential oil while the values for limonene were found to be 3.3–52.5 mg/ml and 210 mg/ml respectively against the different tested strains of S. uberis. Since S. uberis strains are considered to be strong biofilm formers, the test samples were also evaluated for their anti-biofilm activity and it was found that both these agents reduced biofilm formation. The biofilm inhibition of the essential oil MIC ranged from 88.25 ± 7.62% to 23.50 ± 16.26% while that of limonene from 92.18 ± 4.78% to 23.20 ± 16.05%. As Minthostachys verticillata essential oil and its major constituents have shown no toxic effects in both in vitro and in vivo assays, therefore the authors argue that these could be used as an alternative and/or complementary therapy for bovine mastitis caused by S. uberis in future after further evaluation studies. The leaf extracts of Liquidambar orientalis (L. orientalis) were evaluated for their antibacterial activity against different S. aureus strains and CNS responsible for causing subclinical mastitis in cows [55]. In addition, the extracts were also checked for their antioxidant potential. The results showed that acetone extract had best antibacterial activity against S. aureus isolate numbered −17 with zone of inhibition equal to 12 mm. However, all the three solvent extracts i.e., acetone, methanol and ethanol showed best MIC value of 3.2 mg/ml against the tested bacterial strains. Anti-oxidant activity was determined by ABTS [2, 2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid)] free radical assay where ethanol extract exhibited a strong anti-oxidant activity. Alves et al., 2016 reviewed some of the medicinal plants explored for their antimicrobial activity against mastitis pathogens. They observed that the antimicrobial potential of essential oils of plant species like oregano (Origanum vulgare), Mexican oregano (Lippia graveolens), thyme (Thymus vulgaris) and that of constituents like carvacrol, thymol and cinnamaldehyde are of importance [56]. Gomes and Henriques [57] provided an overview of some of the conventional and emerging approaches in the management of bovine mastitis infections. The list included bacteriophages, vaccines, nanoparticles, cytokines, and natural compounds from plants, animals, and bacteria as some of the valid substitutes to antibiotics. The review discusses about the positive results of plant based antimicrobials on important mastitis pathogens and suggests their potential use as an alternative treatment source to antibiotics. Pasca et al., 2017 investigated the antimicrobial efficacy of alcoholic extracts from eleven plant species and eight plant-derived products against a panel of 32 test microorganisms isolated from milk samples [58]. The eight herbal products were produced due to a combination of various plant extracts in different concentrations. The results showed that three plant species viz., Evernia prunastri, Artemisia absinthium, and Lavandula angustifolia inhibited the growth of test microorganisms to the maximum level. Similarly, from the eight evaluated plant products, only three samples R3, R4 and R7 showed best antimicrobial activity comparable to the standard antimicrobial drugs florfenicol and enrofloxacin. The plant products showed better activity than individual plant extracts possibly due to synergistic effect of the plant products. 4. Our studies In recent years, our research group has been working on the exploration of traditionally used medicinal plants of Kashmir Himalayas, India, in the control of bovine mastitis. During these preliminary studies, we have evaluated some medicinal plants for their antimicrobial potential against important mastitis pathogens. For example, while working on one plant species viz., Aquilegia fragrans, the crude methanol extract of the underground parts along with five isolated constituents exhibited moderate to weak antibacterial activities against mastitis pathogens [59]. Similarly, another plant species Thalictrum minus was pursued for alkaloid isolation because alkaloids are a large and structurally diverse group of compounds that serve as scaffolds for important antibacterial drugs such as metronidazole and the quinolones [60]. We isolated three bisbenzylisoquinoline alkaloids i.e.; Thalrugosaminine, O-Methylthalicberine and 5′-Hydroxythalidasine from Thalictrum minus that inhibited the growth of important mastitis pathogens [61]. 5. Future scope Extensive bioprospecting studies are needed in this direction to discover the tremendous medicinal potential of various plant species from biodiversity rich areas of the world. The medicinal plants used as an alternative therapeutic option against bovine mastitis can act as antibacterial, anti-inflammatory or immune-modulatory agents which need to be explored. As considerable oxidative damage occurs in the mammary glands during bacterial infection in mastitis, there are also likely opportunities for pharmacological intervention to block this proteolytic or oxidative cascade. Since plants are an excellent source of antioxidants, the use of plant antioxidants to prevent this oxidative stress in bovine mastitis offers another opportunity for exploration of medicinal plants in the control of this chronic disease. Acknowledgements The first author is thankful to University Grants Commission, New Delhi India for fellowship support. References [1] J.W. Schroeder Bovine mastitis and milking management NDSU Extention Serv., 1129 (2012), pp. 1-16 CrossRefView Record in Scopus [2] J.L. Watts Etiological agents of bovine mastitis Vet. 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