Commercial poultry farming is expanding day by day and contributing in the provision of affordable and high quality proteins (Ahmad et al., 2010; Ghafoor et al., 2010). However, this sector is still confronted with many enteric diseases like coccidiosis which are hindering its progress (Saima et al., 2010; Hafez, 2011).
Avian coccidiosis in an intestinal protozoan disease caused by various species belonging to genus Eimeria. According to a recent estimate (Chapman, 2009), the United States poultry industry costs about US$127 million annual losses just because of coccidiosis and proportionally similar losses may be faced by the poultry producers in various parts of the world. Thus, in commercial poultry systems, coccidiosis is thought to be the one of the most expensive infectious diseases. Thus far, chemoprophylaxis and anticoccidial feed additives have controlled the disease but situation has been complicated by the emergence of drug resistant strains against commonly used drugs (Abbas et al., 2008; Abbas et al., 2011a).
Vaccination by using live coccidial oocysts has been another effective approach for coccidiosis control (Shirley & Lillehoj, 2012), but, in poorly managed production systems particularly in case of broiler birds, live vaccines may result in the onset of severe reactions ultimately affecting the performance and production of flocks (Chapman, 2000). As a result of this drawback of live vaccines, attenuated vaccines, having reduced pathogenicity, have been developed, but these are expensive to produce. The other draw back of using vaccines is diversity of Eimeria strains in different geographical distributions. Therefore, vaccine strain, effective in one geographical area may not be effective in the other area.
Because of development of drug resistance and pathogenicity associated problems with live vaccines, poultry producers all over the world are moving towards alternative control of avian coccidiosis. Cost effective alternative strategies are being sought for more effective and safer control of avian coccidiosis (Abbas et al., 2011b, 2011c; Abbas et al., 2012; Arczewska-Wlosek & Swiatkiewicz, 2012; Zaman et al., 2011) which are discussed in the following sections.
Acids: Acids are known to have antibacterial, antifungal, and antiprotozoal activity particularly at low pH. Many acids like formic acid, butyric acid, anacardic acid, acetic acid and hydrochloric acid are found effective in controlling avian coccidiosis (Shobha & Ravindranath, 1991; Garcia et al., 2007; Abbas et al., 2011b, c). In an experimental study, Garcia et al. (2007) found formic acid to have positive effects like increase in height of villus, depth of crypt and surface area of villus in broiler chickens experimentally challenged with E. tenella. The broiler growth performance and immune response were determined by using different doses of liquid dl-2-hydroxy-4-methylthio butanoic acid (LMA). In an arrangement of LMA with 4 graded levels 140%, 120%, 100% and 80% of methionine, broiler requirements were suggested by Chinese feeding standards for chickens; humoral immunity, cellular immunity and growth performance were determined. It was observed (Zhang & Guo, 2008) that in broiler chickens, methionine deficiency led to decrease in feed utilization; humoral and nonspecific immuno-competence were also decreased. However, use of LMA for methionine deficiency corrected these problems.
Organic acids like acetic acid have also been reported to have antimicrobial and anticoccidial effects (Chaveerach et al., 2004; Van Immerseel et al., 2004; Abbas et al., 2011b). Acetic acid is a weak organic acid which gives vinegar and is a partially dissociated acid in an aqueous solution. Only a few reports are available regarding the protective effects of acetic acid against avian coccidiosis (Abbas et al., 2011b). Organic acids showed promise in altering bacterial activities and cecal environment in chicken. Furthermore, a number of reports (Manickam et al., 1994; Runho et al., 1997; Yeo & Kim, 1997; Gunes et al., 2001; Abbas et al., 2011b) also showed the positive effects of organic acids on performance parameters such as weight gains and feed consumption. Recently, Abbas et al. (2011b) has shown the anticoccidial effect of acetic acid both in terms of improved performance (weight gain and feed consumption ratio) and pathological parameters (lesion scores, oocyst scores & mortality).
Some strong acids like hydrochloric acid, in low concentrations, are also being used for the control and treatment of avian coccidiosis (Abbas et al., 2011c). Furthermore, the acids when used at low concentrations also result in better performance by improving the solubility of the feed ingredients, digestion and absorption of nutrients but higher concentrations result in negative impact on weight gains and feed intake (Owings et al., 1990; Adams, 1999; Vesteggh, 1999).
Anacardic acid shows antimicrobial (Himejima & Kubo, 1991) and antitumor (Kubo et al., 1993) activities in addition to having effective molluscicidal (Kubo et al., 1986) effects. The feed supplementation with 0.4% cashew nut shell oil and 0.2% anacardic acid was found to be effective in controlling coccidial infection. Furthermore, it was also reported that anacardic acids with four concentrations C15:3, C15:2, C15:1 or C15:0 showed uncoupling effects of alkyl side chains (similar to the classical uncoupler 2,4-dinitrophenol) on the ADP/O ratio, state 4 and respiratory control ratio in succinate-oxidizing rat liver mitochondria (Toyomizu et al., 2000). Considering that proton electrochemical potential mediats the oxidative phosphorylation, as chemiosmotic hypothesis described, in mitochondria anacardic acids could act as ionophores and/or as protonophores (Toyomizu et al., 2003). Anacardic acids administration has dual effect as anticoccidial and/or antiinflammatory drugs due to its possible protonophores/ ionophore properties.
So far, the exact anticoccidial mode of action of acids is not fully understood but it is thought that after entering into the microbial cell, the acids ionize to release H+ ions, resulting in a decrease of intracellular pH. This influences microbial metabolism, inhibiting the action of important microbial enzymes and forces the cell to use energy to export the excess of protons H+ , ultimately resulting death by starvation. In the same matter, the protons H+ can denature acid sensitive proteins and DNA of the microbial cell (Russell & Diez-Gonzalez, 1998).
Vitamins: Vitamins play a significant role in the development of chicken immune system and thus enabling them to fight against various stresses (Khan et al., 2010; Ajakaiye et al., 2011). Essential nutrients such as vitamins may affect both humoral and cell-mediated immune responses. Vitamin A differentiates the epithelial cells, which is highly essential for maintaining the integrity of mucosal surface of intestine (Chew & Park, 2004). Deficiency of vitamin A increases the chances of enteric diseases like coccidiosis and it also impaires the local immune defences within the gut lymphoid tissues of broiler chickens (Dalloul et al., 2002). Due to this effect, there was a significant reduction in intraepithelial lymphocyte subpopulations, mainly CD4+ T cells. The alteration in intraepithelial lymphocyte subpopulation leads to lower the ability of resistance against E. acervulina. Furthermore, it was reported (Dalloul et al., 2002) that the deficiency of vitamin A also affects the systemic immune system by reducing the ability of splenic T lymphocytes to respond to in vitro mitogen stimulation, which resulted in lower IFNgamma secretion. In fact dietary vitamin A levels can affect gut immunity in broiler chickens, and its deficiency may lead to immunosuppression at those sites that make the birds more susceptible to coccidiosis.
Probiotics: Probiotics are 'live microorganisms, which when administrated in adequate amounts confer a health benefit on the host' (FAO, 2002). In poultry production, probiotics are identified for their ability to reinstate the intestinal microflora after being disrupted by antibiotic treatment or enteric infections (Line et al., 1998; Pascual et al., 1999). In addition, they are also known for their capacity to enhance the immune system and used against allergies and other immune diseases (Dalloul et al., 2003a, b; Kabir et al., 2004; Koenen et al., 2004).
Recently, Lee et al. (2007a) reported the increased resistance of birds against coccidiosis and a partial protection against growth retardation with a Pediococcusbased commercial probiotic (MitoGrow®). In another study, Pediococcus and Saccharomyces-based probiotic (MitoMax®) given to birds challenged with 5000 oocysts of either E. acervulina or E. tenella, less oocyst shedding and a better antibody response was found in probiotic fed birds compared to non-probiotic controls. These results suggest that MitoMax® when included in the diet, may improve the resistance against coccidiosis by enhancing the humoral immune response in birds (Lee et al., 2007b). Furthermore, Lactobacillus-based probiotic has optimistic influence on cellular immunity (Dalloul et al., 2005)
Mushrooms: Mushrooms contain antibacterial and antioxidant properties, thus, having the health-supporting bene?ts. Recently, Willis et al. (2007) conducted an experiment to determine the health and growth of broiler chicken by using the combination of probiotics (PrimaLac) and extract of Shiitake mushroom (Lentinus edodes). The results indicated that this combination was not effective for weight gain but showed positive effect on health enhancement. Furthermore, Guo et al. (2004, 2005) explored the immunoprotective effects of polysaccharide extracts of two mushrooms, Tremella fuciformis and Lentinus edodes, with an herb Astragalus membranaceus in the chickens infected with E. tenella. Both Lentinus edodes and Astragalus membranaceus fed groups showed lower cecal oocyst output. Likewise, it has been reported (Dalloul et al., 2006) that a mushroom lectin (FFrL) extracted from Fomitella fraxinea has the immuno-potentiating effect on cell-mediated immunity and subsequent protection against coccidiosis. As mushrooms have immunomodulatory activity, they can be used as effective growth promoting and immunostimulating agents in poultry.
Nonsteroidal anti-inflammatory drugs: The use of nonsteroidal anti-inflammatory drugs may be another effective approach for the control and treatment of avian coccidiosis but so far a very limited work has been done on this aspect. Ibuprofen is a nonsteroidal anti-inflammatory drug which inhibits the biosynthesis of prostaglandins with pro-inflammatory and immunosuppressive properties and is therefore proposed as a candidate molecule for the treatment of coccidiosis in broiler chickens (Vermeulen et al., 2004). A number of trials were performed to find out the anticoccidial activity of Ibuprofen. In all experiments, Ibuprofen was administered via drinking water and it was found that coccidial lesion scores and oocyst shedding were reduced when Ibuprofen was provided at a dose of 100 mg/kg body weight. However, at this dose, Ibuprofen did not show any significant effect on the degree of sporulation and infectivity of E. acervulina oocysts.
Natural feed stuffs: The use of natural feed additives has also been reported to provide protection against coccidiosis. Among natural products, fat rich diets such as fish oils, flaxseed and its oil, when fed to chickens from first day of age, are effective to control caecal coccidiosis (Allen et al., 1996a). Fat diets are a rich source of n-3 fatty acids (n-3 FA). Allen et al. (1996b) showed that n-3 FA rich diets (fish oil & flaxseed oil diets) significantly reduced the development of both sexual and asexual stages of E. tenella, characterized by cytoplasmic vacuolization, chromatin condensation within the nucleus, and lack of parasitophorous vacuole delineation (Danforth et al., 1997). Later, these findings were confirmed by the same effect of n-3 FA diets on other parasites (Allen et al., 1998). These diets (n-3 FA diets) are detrimental for the development of parasite because of inducing oxidativestress (due to the high concentration of easily oxidized double bonds). Therefore, the anticoccidial effect of n-3 FA against caecal coccidiosis (E. tenalla) is directly related to the concentrationsof double bonds in n-3 FA ethyl esters (Allen & Danforth, 1998). However, n-3 FA diets are particularly effective against E. tenella because the developmental stages, sporulated oocysts and sporozoites, of this Eimeria spp. are deficient in superoxide dismutase enzyme, which would protect them from reactive oxygen damage. Allen et al. (2000) further supported the oxidative-stress hypothesis and observed that the antioxidant-stabilized diets supplemented with up to 10% flaxseed could not protect against E. tenella. Sources of fats, such as n-3 FA, can be used in combination of anticoccidial drugs or vaccines for the effective control of E. tenella. But further research is needed to explore the knowledge about the missing information about their mode of action and immunomodulatory effects.
Glycine betaine or betaine is extensively originated in nature and has been in use as anticoccidial agent in broiler chickens (Boch et al., 1994). The cells are protected from osmotic stress by betain accumulation and permit them to carry on activities of regular metabolism, in situations that would generally deactivate the cell (Petronini et al., 1992; Ko et al., 1994). In avian species coccidia is related with an enteric disease, and ionic and osmotic disorders are associated with this disease (Virtanen, 1995). These disorders may be worsened by using ionophorous anticoccidial drugs (Virtanen, 1995). Betaine, because of its osmoprotectant effects against osmotic stress, stabilizes cell membranes and thus enabling the maintenance of osmotic pressure in cells and ultimately maintain and ensure normal metabolic activity (Ko et al., 1994). Because of this osmoprotection, a number of studies (Augustine et al., 1997; Allen et al., 1998; Fetter et al., 2003) have been conducted to find out protection against avian coccidiosis. Betain showed not only intestinal protection against coccidiosis but also showed improved weight gains. However, to get maximum protection, authors suggested to use betain in combination with anticoccidial drugs.
Essential oils: Essential oils (EOs) are the combination of fragrant, volatile compounds, named after the aromatic characteristics of plant materials from which they are isolated (Oyen & Dung, 1999). EOs have been reported to have immunomodulatory effects that play a vital role in treating infectious diseases, especially when these oils have no adverse effect on the host (Awaad et al., 2010). Most of the EOs inhibit nitric oxide production in macrophages (de Oliveira Mendes et al., 2003). Nitric oxide is a potent intracellular parasite killing mechanism in macrophages and it is well known fact that macrophages are pivotal in the innate immune response (Dogdan, 2001). Oregano EOs have shown an antioccidial effect both in terms of better production (weight gain & feed conversion ratio) and reduced pathogenic effects (mortality, lesion scores, oocyst excretion) against experimentally induced E. tenella infection in broiler chickens (Giannesnas et al., 2003). But, this anticoccidial effect was lower as compared to commercial anticoccidial drug 'laslalocid'. However, in another study (da Silva et al., 2009), the anticoccidial effect of Oregano EOs was similar to anticoccidial effect exerted by ionophores antibiotics. Later, Oregano EOs were used in combination with some other plants EOs and extracts. This combined use of Oregano EOs increased the spectrum of their activity against both bacteria and Eimeria species (Bona et al., 2012). The effect of EOs on improvement in feed effeciency and ultimately better weight gains could be attributed to their positive effects on nutrient digestibility (Hernandez et al., 2004; Jamroz et al., 2005).
The carvacrol and thymol compounds, the primary components of Oregano EOs, are thought to impart anticoccidial activity by maintaining the intestinal integrity (Greathead & Kamel, 2006; da Silva et al., 2009).
Prebiotics: Prebiotic is a non digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in colon, and thus improves host health (Gibson & Roberfroid, 1995). The positive influence of prebiotics on the intestinal flora has been confirmed by a number of studies (Van Loo et al., 1999). Mannanoligosaccharides (MOS), derived from the cell wall of the yeast Saccharomyces cerevisae, are widely used as prebiotics to promote gastrointestinal health and performance. Mode of action of MOS is thought to block the binding of pathogens to mannan receptors on the mucosal surface and stimulate the immune response (Spring et al., 2000). In poultry, MOS enhance the development of Bifidobacteria spp. and Lactobacillus spp. in the intestinal tract of young chickens and suppress the number of enterobacteriacea members (Fernandez et al., 2002). Dietary MOS (1 g/kg feed) were found effective against, artificially induced, light infection of E. tenella (Elmusharaf et al., 2006). Later on, it was also observed that a dietary supplementation of MOS, at a concentration of 10 g/kg feed, reduced the oocyst excretion and diminished the severity of lesions caused by E. acervulina. But this anticoccidial effect was also observed against light infection induced by subclinical doses of sporulated oocysts (Elmusharaf et al., 2007). However, further research is required to validate whether MOS has anticoccidial activity when used at higher concentrations in feed in combination with higher challenge doses.
Botanicals: Recently, research on botanicals is getting great attention for the control and treatment of enteric diseases caused by both microbes and parasites (Alawa et al., 2010; Jung et al., 2011; Badar et al., 2011). Several poultry scientists all over the world are also actively engaged in research into the use of plants and plant derived products to fight and reduce the heavy economic losses in poultry industry caused by coccidiosis. Recently, Abbas et al. (2012) has provided an excellent review on the anticoccidial effects of various botanicals, herbal complexes and commercially available botanical products, against avian coccidiosis, along with their doses, active compounds, and mechanism of action. A number of botanicals were discussed but the candidate plants with anticoccidial properties include Aloe spps. (Marizvikuru et al., 2006; Yim et al., 2011), Artemisia spp. (Allen et al., 1998; Arab et al., 2006; Brisibe et al., 2008; de Almeida et al., 2012), Azadirachta indica (Tipu et al., 2002; Abbas et al., 2006; Biu et al., 2006; Toulah et al., 2010), Beta vulgaris (Ko et al., 1994; Augustine et al., 1997; Kettunen et al., 2001; Klasing et al., 2002), Camellia sinensis (Jang et al., 2007); Curcuma longa (Allen et al., 1998; Abbas et al., 2010; Khalafalla et al., 2011), Echinacea purpure (Allen, 2003), Origanum vulgare (Giannesnas et al., 2003), Saccharum officinarum (El-Abasy et al., 2003), Triticum aestivum (Allen et al., 1998) and Yucca schidigera (Alfaro et al., 2007). Most recently an herbal complex containing Allium sativum, Salvia officinalis, Echinacea purpurea, Thymus vulgaris and Origanum vulgare has also been found effective against many species of Eimeria, in broiler chickens, in terms of reducing oocyst output (ArczewskaWlosek & Swiatkiewicz, 2012).
Most of the above mentioned plants have been reported to have antioxidant compounds like saponins, flavonoids, papaine, n-3 fatty acids, vernoside and tannins, and therefore may be lethal to the parasites by inducing oxidative stress.
Integrated coccidiosis control program: It is clear from the scientific literature that rapidly increasing problem of drug resistance and treatment failure will give rise to use of alternative control strategies in an integrated avian coccidiosis control program in future. Integrated control refers to the intelligent use of alternative control methods like; use of botanicals, vaccine, pre- and pro-biotics and immunemodulatory compounds in order to minimize the use of chemical compounds. In case of avian coccidiosis, alternation of drugs has been practiced with vaccines for many years. The suggestion that vaccination be combined with chemotherapy is not new, but efforts have not been made to develop an integrated control program by adopting other alternatives as well. Plant, bacterial, and other substances claimed to alleviate coccidiosis either directly or indirectly by improving health and immune status have been evaluated individually. So far, there is no data available on integration of these strategies into one coccidiosis control program. The future research in the area of botanicals and alternative control strategies should be focused on integration of already proven alternatives into an effective control program so that farmer could control coccidiosis in an effective manner with minimal use of drugs.
In the face of development of drug resistance almost all over the world and drug residues in food, there is an urgent need to take a shift towards alternative ways for the effective and long term control of avian coccidiosis. Using alternatives, mentioned in this review, provide a novel approach for controlling wide spread drug resistant Eimeria strains in intensive poultry production systems. Most of the alternates enhance the immunity of the birds and thus could play a vital role to minimize or eliminate the burden of anticoccidial chemotherapeutic agents in poultry production. Integration of the alternates proposed above for the treatment and control of avian coccidioisis may be one of the viable options. However, there is need of large scale experimental trials to establish the efficacy of alternative agents because most of these studies lack the sufficient replication, proper experimental designing and appropriate controls.
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