Chapter 16

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Alternatives to antimicrobial growth promoters in animal feeds, Chapter 17. In .... research activities with the following objectives: 1) pathogen reduction, ... (leaves, buds, barks, bulbs, roots), extracts or decoction of plants where neither the ..... disturbance in farm animals. ... grouped into direct and indirect mechanisms.
Burel, C. (2012). Alternatives to antimicrobial growth promoters in animal feeds, Chapter 17. In Animal feed contamination: Effects on livestock and food safety, J.Fink-Gremmels (Ed.), Woodhead Publishing Series in Food Science, Technology and Nutrition, N°215, Sawston Cambridge, UK, pp 432448.

Chapter 17 ALTERNATIVES TO ANTIMICROBIAL GROWTH PROMOTERS (AGPs) IN ANIMAL FEEDS C. BUREL, French Agency for Food, Environmental and Occupational Health and Safety (Anses), France

Abstract: Antimicrobial growth promoters (AGPs) are antibiotics used to both protect animal health and stimulate growth. The ban on their use means there is an urgent need to find more acceptable alternatives. This chapter reviews research into the range of alternatives such as veterinary homeopathy, isotherapy, phytotherapy and the use of novel feedstuffs.

Key words: Antibiotics, antimicrobial growth promoters; animal farming, alternative feed additives.

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17.1 Introduction

The ban on antimicrobial growth promoters (AGPs) has given rise to a number of practical problems in animal husbandry in Europe. These antibiotics were used to protect the health of the animals but also had a positive effect on their growth rate, as well as on feed efficiency. The ban on these molecules has therefore resulted in a reduction in animal performance and thus also in economic losses. In addition, the withdrawal of AGPs makes the animals more sensitive to infections and they may consequently develop severe diseases that require veterinary care, and that can cause reduced weight gain and even mortality in some cases. All these deleterious effects have a significant economic impact (Kjeldsen, 2005). Hence, finding alternatives to AGPs is of crucial importance for European farming.

17.2 Chronology of the ban on Antimicrobial Growth Factors (AGPs) in Europe

Antibiotic growth promotion in agricultural animal production, particularly for monogastric animals, has been practised for about 50 years as reviewed by Dibner and Richards (2005). Antibiotic growth promoters have been in the process of being phased out in the European Union (EU) for some time, but a complete ban on their use was only implemented in July 2003. The use of the remaining four growth promoters was gradually reduced until, in January 2006, the ban became fully effective.

17.3 Main consequences of the ban on Antimicrobial Growth Factors (AGPs) in Europe

As mentioned above, animals whose diet does not contain AGPs often become more sensitive to infections and as consequence may develop severe diseases requiring veterinary care. In many countries this resulted in an increase in the use of therapeutic antibiotics after AGPs were banned. This increased use of the same or similar molecules could actually increase the likelihood of the

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emergence of resistant bacteria, which is a source of increasing public health concern, especially when zoonotic pathogens are involved.

Dibner and Richards (2005) provides an excellent overview of the consequences of the AGP ban in Denmark, indicating that the significant reduction (54%) in the total use of antibiotics in foodproducing animals was accompanied only by an increase of 5% in the use of antibiotics licensed for therapeutic use. An undesirable side effect of the AGP ban was an increase of the prevalence of necrotic enteritis in poultry, which was counteracted by a significant increase in the use of the ionophoric coccidiostat salinomycin, which is known to be active also against Clostridium perfringens. In addition, Kjeldsen (2005) demonstrated that in Denmark, the use of therapeutic antimicrobials in pig production increased after the ban on AGPs was put into place, due to increasing problems with diarrhoea in weaned animals when AGPs ceased to be used. At the same time, average daily weight gain in pigs decreased and mortality rates increased from 2.7 to 3.5% (Callesen, 2003, Dibner and Richards, 2005). This data will be an interesting tool in future years, as it will allow the effect of the ban on AGP to be assessed (Dibner and Richards, 2005). The observations made in Denmark could also prove to hold true in other European countries, i.e. the AGP ban would be followed by an overall increase in total antibiotic consumption, presumably as a result of the greater need to treat clinical disease outbreaks which would previously have been suppressed through the use of AGPs

17.4 Mode of action of the Antimicrobial Growth Factors (AGPs) in animal production and possible alternatives

The characteristics of AGPs help to explain their previous position as the additives of choice for growth promotion. In general they are effective at remarkably low doses and are relatively cheap, thus yielding significant return on investment. The search for replacements has been severely hampered by a lack of understanding of how AGPs work. It is widely assumed that AGPs act mainly through their effect on intestinal microflora. With less than 10% of intestinal microflora so far identified, there has been little chance of fully explore the specific effects of AGPs. It is postulated that AGPs benefit livestock by reducing the total number of intestinal microorganisms, including pathogenic microorganisms, and/or by creating a more favourable balance between beneficial and non-beneficial microorganisms. The intestinal microflora have important and differing effects on animals, including regulation of epithelial cell turnover, competition for ingested nutrients, 3

modification of digestion, competitive exclusion of pathogens, metabolism of mucus secretions and modulation of mucosal immunity. The best attempts at explaining the mode of action of AGPs are summarised in the study by Bikker and van der Aar (2005). However, responses to AGPs are subject to significant variation and may, to a large extent, be dependent upon the environment in which the animals are raised and the diet offered to them. AGPs have proved to be an effective method of enhancing animal health, uniformity and production efficiency. Their removal has had a number of consequences, and will therefore be a difficult obstacle to overcome, particularly if European animal production is to remain competitive with that of the rest of the world, where such products are likely to remain in use. In addition to this, regulation regarding zoonotic diseases (EC 2160/2003b) requires that member states better control, or even eradicate, zoonotic pathogens. The combination of these factors has led to various new research activities with the following objectives: 1) pathogen reduction, 2) augmentation of the immune response of the animals, and 3) development of nutritional strategies and/or use of feed additives that either improve performance in their own right, or directly modify the microbial flora of the gut. Aspects of pathogen reduction have been already discussed in this book and thus will not be further developed in this chapter. We just want to mention that since the ban on AGPs, new management practices and strategies developed today all aim to achieve improved hygienic conditions at the level of farms and feed mills.

17.5 Traditional

therapeutic

approaches

as

an

alternative

to

Antimicrobial Growth Factors (AGPs)

Improvement of the animal’s inherent immune response is one of the objectives of recent studies in the field (Berghman et al., 2005). Tailored vaccination programmes combined with the development of improved vaccine delivery may provide opportunities for minimizing feed medications. At the same time, knowledge is increasing of how to control the negative effects on performance that the immune response causes. It seems that the systemic, acute phase response of the animal to disease challenge involves a significant nutrient requirement, meaning that fewer nutrients are available for metabolic use. Conjugated linoleic acid is one compound that has been investigated for its apparent abilities to alleviate the immune-associated anorexic response (Klasing, 1998).

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In the meantime, alternative methods are being developed in the field, such as homeopathy, isotherapy, and phytotherapy. Homeopathy is a therapy based on the practice of treating like with like. A disease is treated using an agent or substance that produces symptoms in a healthy individual similar to those experienced by a sick individual. Homeopathic medicines contain often very small quantities (high dilutions) of the agent/substance prepared in a special way. In the organic livestock sector, homeopathy is the alternative therapeutic approach commonly used to replace antibiotics. Homeopathy has demonstrated its effectiveness in practice in a range of medical areas, but scientific evidence is lacking. The research literature that looks at veterinary homeopathy consists of fewer than 20 published, peer-reviewed randomised controlled trials (Mathie et al., 2007). The research data available relate to the treatment of mastitis and infertility in cattle, infectious diseases including colibacilloses in pigs, growth rate in pigs and salmonella in chickens (Camerlink et al., 2010). Homeopathic remedies may offer some benefits as no residues remain in the animal products, nor does homeopathy generate resistant microorganisms. Homeopathy aims to activate the self-healing mechanisms of the body. The healing process could therefore take longer, and more attention might need to be paid to determining the correct remedy. A lack of knowledge and understanding of homeopathy could account for its currently limited use in the livestock sector. In addition, research in the field of homeopathy is often subject to criticism. One reason for this is that at the molecular level no actual substance can be detected in some highly diluted homeopathic medicines. Detractors claim that veterinary practitioners who use homeopathic remedies are using their position of authority to convince the owner that the animal being treated by homeopathic methods is getting better (Camerlink et al., 2010). Isotherapy is the specialized application of homeopathic theory and therapy. An isotherapic remedy is prepared from the blood or other secretion of an infected individual, diluted to the same extent as in regular homeopathic medicine. As for homeopathy, the research literature on isotherapy is scarse. A systematic analysis of selected papers where animal models are used for studying isotherapy showed that methodological rigor is generally adequate, even if some particular aspects could be still improved (Bonamin and Endler, 2010). Phytotherapy is the treatment of a disease using natural plants or plant extracts. Some involved in animal production claim that these alternative methods give satisfying results in the field for the control of diseases such as coccidiosis; however, in many cases the lack of coherent information about product composition, as well as about the experimental design used in some studies, hinders a scientific evaluation of their efficiency. Indeed, while an abundant bibliography suggests that various plants or plant extracts, either pure or in combination, may improve the animal’s health and/or performance, most of the studies are performed on mixtures of whole plants or parts of plants 5

(leaves, buds, barks, bulbs, roots), extracts or decoction of plants where neither the proportion nor the mode of extraction are indicated. It is difficult, then, to disclose the nature of the extracts and the active ingredients that are exerting the reported beneficial effects. In addition, the experimental conditions (animal types, rearing conditions, dietary ingredients, feed formulation, production levels, heath status, current diseases, and so on) are not always indicated, are extremely diverse and are often not reflecting European rearing systems. Subsequently, the claimed beneficial effects are not reproducible or the observed effects are very limited lacking statistical significance (AFSSA, 2007).

17.6 Novel nutritional strategies and feed additives

The link between diet and the incidence of enteric disease in monogastric animals is well known. The following sections describe some nutritional strategies and/or feed additives that are either able to improve performance in their own right, or help to directly modify the gut microbial flora.

17.6.1 Feed formulation and preparation

In the absence of antimicrobial growth promoters ingredients that potentially increase the risk of adverse health effects must be used with greater caution. For instance, diets based on rye and barley, and to a lesser extent wheat, seem to lead to greater susceptibility to necrotic enteritis (Riddell and Kong, 1992). Indeed, these feedstuffs have long been known to be of poorer nutritive quality than corn, probably because of the presence of large quantities of soluble, viscous arabinoxylans and -glucans, which significantly reduce the rate of digestion. A reduced rate of digestion causes greater substrate provision for microflora resident in both the lower small intestine and the large intestine/caecum. In turn, a high substrate availability in the lower gastrointestinal tract increases the risk of bacterial overgrowth (the bacterial population has been shown to be 100 to 1000 times larger with rye compared to corn-based diets), including the growth of pathogenic bacteria (Apajalathi and Kettunen, 2003).Gut health and enteric disease resistance are thus often dependent upon the digestibility of feed components and feed formulation, and any approach that improves digestibility is typically beneficial for the animals. The cereal base can affect not only total numbers of bacteria in the gut, but also the profile of the gut microflora (review of Burel and Valat, 2009). For instance, when rye is used instead of wheat in the

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diet of broiler chickens, the relative abundance of Streptococcus/Enterococcus group and E. coli increases, whereas the abundance of Lactobacillus group drops dramatically (Apajalathi and Kettunen, 2003), and when wheat and barley are used in the diet instead of corn, facultative anaerobic bacterial populations increase, including those of lactobacilli and coliforms (Mathlouti et al., 2002). According to Apajalathi and Kettunen (2003), it seems that corn selects bacteria other than bifidobacteria. Indeed, corn, as well as sorghum, stimulates enterococci. But the strongest effect seems to be the stimulation of streptococci by rye-based diets. An increase in streptococci, enterococci and coliform populations is likely to cause additional stresses that affect the performance and health of the animals. In other respects, poorly digested protein meals cause the proliferation of putrefying bacteria in the hindgut, which increases toxic metabolites that compromise gut health. In general, antibiotics are most effective in animals fed diets containing high levels of non-digestible proteins (Smulders et al, 2000). The digestive microflora can also be modified by the form in which the diet is fed (whole grains, meals, pellets), the grain type and particle size (Santos et al., 2008, review of Burel and Valat, 2009). Pelleting contributes to an increase in coliforms and enterococci in the ileum, and a reduction of Clostridium perfringens and lactobacilli in the distal parts of the digestive tract (Engberget al., 2002). Feeding whole or coarsely ground grains decreased caecal Salmonella populations in 42-day-old broiler chickens (Santos et al., 2008). The consumption of a whole wheat-based diet compared to a ground wheat-based diet also caused a change in the microflora: a decrease of the ileal population of coliforms and lactobacilli at the beginning of the rearing period of broiler chickens (Gabriel et al., 2003). This is extremely significant, as there has recently been an increasing interest in the use of whole grain in the feed of poultry in order to decrease feed cost and also to meet consumer demands for a more “natural” feeding system and improved animal welfare. But more generally, it seems that feed processing significantly affects the characteristics of the feed as a substrate for the bacterial community. The temperature of the conditioning process, the pressure of the steam and so on may all add to the characteristic structure of the bacterial community. Thus, the manufacturing process itself could be used to control and manage the GI microflora of animals (Apajalathi and Kettunen, 2003). The immune system of an animal is also affected by nutrition, as discussed in details in the works of Klasing (2007), Kogut (2009), Kogut and Klasing (2009) and Bao and Choct (2010). The commensal microflora plays a role in competitively excluding pathogens, thus provide significant benefits to the intestinal immune system. The composition of the diet can provide the basis for the establishment of the commensal microflora and thus also the development of the intestinal immune system in young

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animals. However, some cereals contain high proportions of non-starch-polysaccharides (NSPs) and oligosaccharides, the effect of which on the immune system of animals has not yet been definitively established. Choct (1997) reported that the amount of fermentative microflora in the small intestine of chickens is significantly reduced by the depolymerisation of soluble NSPs. Given that nutritionists are increasingly forced to introduce plant-based by-products in their diet formulations for farm animals, it has become even more important for researchers and animal producers to gain an understanding of the mechanisms through which NSP and its associate substrates influence the intestinal immune system, and thus the overall health of the animals (Bao and Choct (2010). It seems that NSPs might not only provide substrates for beneficial bacteria but could play an important role in removing free radicals, and act as antioxidants. Given that the criteria used to formulate animal feeds do not usually take into account the importance of nutrition in maintaining animal health, the modification of nutrition for farm animals to improve their intestinal health has an important role to play in modern agriculture.

17.6.2 In-feed enzymes Feed enzymes also play an important role as feed additives. Typical examples are carbohydrases (αand ß-amylases, cellulose, α-galactosidase, ß-glucanase, ß-glucosidase, glucoamylase, hemicellulase, invertase, ß-mannanase, lactase, pectinase, pullulanase, xylanase), proteases (protease, bromelain, ficin, papain, pepsin, trypsin), lipase (lipase), oxidoreductase (catalase, glucose oxydase) and phosphatase (phytase). These enzymes can increase the digestibility of nutrients, decrease intestinal viscosity and inactivate antinutritional factors in monogastric animals, leading to greater feed efficiency and performance. At the same time they can help to minimize the negative environmental impact of increased animal production. However, the relative contribution of an enzyme preparation is greater when the quality of the feedstuff is lower. For instance, the digestibility of wheat, barley, rye, triticale and even corn-based diets can be significantly improved through the use of exogenous enzymes including xylanases, phytases and -glucanases (Rosen, 2001). In addition, young animals such as newly weaned piglets may lack the required amounts of certain enzymes to digest feed ingredients. Therefore, adding enzymes to their diet may be a useful strategy to increase feed digestibility, improve early growth performance and limit the occurrence of diarrhoea in recently weaned pigs. Because supplemental enzymes mediate their beneficial effects primarily by enhancing feed digestibility and nutrient availability to the host, they also influence the microbial ecosystem of the gut (Choct et al., 1996; Hock et al., 1997; Bedford, 2000; Rosen, 2001; Parker et al., 2007). When 8

fermentable substrates are removed from the ileum, ileal populations of microflora are reduced (Bedford and Schulze, 1998). While the addition of exogenous enzymes appears to limit microbial growth in the ileum, the opposite may be true in the caecal environment. Here, the products of enzymatic breakdown may provide fermentable substrates to the caecal flora. Increases in volatile fatty acid (VFA) production and changes in the VFA profile favour the beneficial organisms (Bifidobacteria for example) and suppress populations of deleterious organisms (Campylobacter, Salmonella, Clostridium). The use of these enzymes as feed additives is restricted in most countries pending approval by local authorities, or within the EU through authorization by EFSA’s FEEDAP (Feed and Feed Additives Panel) in accordance with Council Regulation 1831/2003.

17.6.3 Prebiotics

When specific carbohydrates are included in the diet, preferably fermented by beneficial microorganisms, they not only modify the availability of nutrients from raw ingredients for bacterial fermentation, but also have an osmotic effect and can positively influence the composition of the GI microflora. Prebiotics are defined as “non-digestible or low-digestible food ingredients that benefit the host organism by selectively stimulating the growth or activity of one or a limited number of beneficial bacteria in the distal part of the GI tract” (Crittenden and Playne, 1996). Indeed, specific species can be selected for prebiotics which escape digestion by the host, but are readily available to the metabolic machinery of the target microorganisms (bifidobacteria and some Gram-positive bacteria). Prebiotics are short chain carbohydrates that cannot be digested or absorbed by the animals and are therefore available to the intestinal microflora. They are also known as “dietary fibres”. The ileal digestibility of Inulin (a prebiotic) is only 7.5%, but none can be found in faeces, indicating total fermentation in the hindgut. The end products of fermentation are Short Chain Fatty Acids. There are two main types of prebiotics: the fructo-oligosaccharides (FOS) and the Mannan-oligosaccharides (MOS). Briefly, the FOS have been shown to influence the intestinal bacterial population by enhancing the growth of lactic acid bacteria (Lactobacillus species and Bifidobacterium) and to inhibit Escherichia coli and Salmonella growth in the large intestine (Hidaka et al., 1986; Mitsuoka et al., 1987; Roberfroidet al., 1998; Fukata, 1999; Xuet al., 2002). Beneficial bacteria such as Lactobacilli and Bifidobacteria benefit the host by improving gut efficiency through an increase in nutrient absorption and the acceleration of gut development (Yokota and Coates, 1982; Palmer and Rolls, 1983; Fureseet al., 1991). The MOS (mainly from the cell wall of yeast) seem to have two types of 9

activity: the adsorption of enteric pathogens and immunomodulation (Newman, 1994). MOS are thought to block the adhesion of pathogenic bacteria to the animal’s intestine, preventing the colonisation that may result in disease. They are also considered to stimulate the animal’s immune system, thus reducing the risk of diseases (Savage et al., 1996; Ijiet al., 2001; Patterson and Burkholder, 2003). When the relationship between the oligosaccharide structure and those effects is better understood, it should be possible to design novel prebiotics to maximize the protective effect. Another means of influencing animal health through carbohydrates is via cell-to-cell interactions. Carbohydrates from bacterial cell surfaces function in a variety of ways to influence cell-to-cell communication (quorum sensing), and influence bacterial attachment to the host tissues (Sperandio et al., 1999; Newman and Spring, 2004; Fujiya et al., 2007).However, while many authors consider prebiotics to be a promising alternative to AGPs for use in animal feeds, the experimental data are still inconsistent and their benefits have not been confirmed by all studies.

17.6.4 Competitive Exclusion (CE) and Probiotics

The phenomenon by which the normal GI microflora protect the host against invading pathogens is called competitive exclusion (CE). Numi and Rantala (1973) were the first to apply the CE concept to domestic animals, mainly to poultry. That is why CE is also called the “Numi concept”. These authors observed that the oral administration of gut content, containing viable bacteria and originating from adult pathogen-free birds, could protect young birds against Salmonella infections. Numerous articles have been published on this subject in the last 30 years. CE involves preventing the entry or establishment of one bacterial population into the GI tract through the presence of a competing bacterial population that already occupies potential attachment sites. To be able to succeed, a population must be better suited to establish or maintain itself in that environment or must produce inhibitory compounds against its competitors. The adhesion of beneficial bacteria to the GI wall is considered a prerequisite for the CE of pathogens and for the modulation of local and systemic immunological activities. The mechanisms involved in CE by which bacteria operate, i.e spatial exclusion, micro-environmental alterations, production of antimicrobial substances and epithelial barrier integrity, are very complex and little has so far been discovered about them. Specific adhesinreceptor interactions and non-specific hydrophobic group interactions have been identified as the major mechanisms for adhesion (Ofek and Doyle, 1994). The importance of Volatile Fatty Acids (VFA) as part of the mechanisms of CE has been reported by several researchers in recent years, while 10

others have suggested that protection is in the first instance a physical phenomenon rather than a process involving synthesis of VFA or other metabolites (Schneitz, 2005). Antibacterial lypophilic factors, antimicrobial compounds (peptides and proteins) and carbohydrates have all been shown to inhibit the adhesion of bacteria to the intestinal cell surface (Coconnier et al., 2000). In animal production, CE uses live, defined cultures of beneficial microorganisms. Gram-positive bacteria of the Lactobacillus, Enterococcus and Bacillus types are used, as are fungi of the Saccharomyces (yeast) genus (Revington, 2002). Such cultures are often included in feed as an adjunct to antibiotic therapy in order to re-introduce beneficial flora to the intestinal tract of infected animals. Supporters of CE claim that it is the most effective harmless method available to control GI disturbance in farm animals. This CE concept highlights the role of the GI microflora in ensuring animal health, as well as the importance of favouring the beneficial bacteria in the GI tract, particularly since these have been intentionally introduced into the gut of the animals. One possible means of favouring the proliferation of these beneficial bacteria is the manipulation of substrate availability in the GI tract so that it is able to feed these microflora (cf prebiotics). The modes of administration of live bacterial populations are mainly in novo, i.e. individual oral administration, spray (in hatchery for poultry), introduction into drinking water upon arrival on the farm, or spray on first feed (Schneitz, 2005). The treatment is fully biological and leaves no residues. The concept was originally designed for Salmonella reduction in growing chickens. Over the years, other pathogens such as pathogenic Escherichia coli, Clostridium perfringens (Hoang et al., 2008), and Listeria monocytogene have also been targeted,(Mojganiet al., 2007) and the practice has been extended to other farm animals too. Preliminary effects on Campylobacter and other members of the flora such as viruses and protozoa have been reported (Doyle et al., 2006; Schneitz, 2005). There are currently many commercially available CE products, all of which are mixed cultures derived from the caecal contents and/or mucosa-associated flora obtained from the caeca and/or the gut wall of farm animals. More recently, an extension of the CE principle has led to more routine administration of probiotics (lactobacilli, bifidobacteria, Aspergilla, yeast, etc) (Fuller, 1991, Rush, 2002). Because of the diversity of the mechanisms of action of probiotics, including immune regulation (Vila et al., 2010), they have recently been broadly defined as “live microorganisms, which when administered in adequate amount, confer a health benefit on the host” (Guarner and Schaafsman, 1998). Probiotics can play a preventive role by competing with pathogens or a curative role by repairing the changes that occur in the GI microflora as a result of stress: they can, at least partially, restore the animal’s resistance to some enteric disturbances. This curative effect depends on the level of infection. Moreover, and as a

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consequence, beneficial effects on body weight gain in farm animals can be achieved by the addition ofprobiotics in diets (Abazaet al., 2008). However, the factors that affect the colonization of a given probiotic culture are not clear. Difficulties arise in defining the specific culture that should be used, and in administering the cultures via the feed, since the heat treatments that are often involved in feed preparation (pelleting for example) are obviously harmful to live cell products. Moreover, it appears that most probiotics do not colonize the intestine, but simply pass through. Most of the proposed mechanisms of action (enhancement of the physical and functional mucosal barrier, competitive adhesion to epithelial receptors, reduction of intestinal pH by lactic acid production, modification of bile salt, competitive exclusion) remain hypothetical and much work remains to be done in order to refine the application of this approach (Crevieu-Gabriel and Naciri, 2001). Probiotics also have anti-inflammatory and cytoprotective effects (Canny and McCormick, 2008). In addition, a recent study showed that fermented soybean meal with Aspergillus influenced pancreatic and intestinal enzymatic activities and villus height differently according to the age of the animal (Fenget al., 2007). In conclusion, the mechanisms involved in potential beneficial effects of probiotics can broadly be grouped into direct and indirect mechanisms. Indirect mechanisms are the result of the normal microflora altering the physiological response of the host, which in turn affects the interaction between the host and the microorganisms (Rolfe, 1991). Direct mechanisms are exerted by different bacterial populations on each other. Regarding the use of probiotics in daily practice, a number of diverse factors need to be considered, including the dose, the health status of the farm, production conditions, and husbandry practices. In addition, the inherent anaerobic nature of intestinal bacteria has hindered the commercial development of many effective probiotics. Like AGPs, probiotics appear to have a pronounced effect on farms where the housing and hygiene conditions are suboptimal.

17.6.5 Synbiotics

The bacterial nutrient package will not succeed in the absence of the targeted, beneficial bacteria, and likewise the live microorganism product will not succeed if the environment into which it is introduced is unfavourable. Therefore so called “synbiotic products”, which contain both a probiotic strain and a prebiotic favouring the growth of that probiotic strain, are thought to offer a means of maintaining the correct balance of the GI microflora.

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17.6.6 Organic acids

Organic acids, which have antimicrobial activity, are the most frequently-used alternative to AGPs. However the mechanism of their impact on gut microflora is poorly documented. The use of acidifiers in piglet feeds has proven to be beneficial, and organic acids have been used as Salmonellacontrol agents in feed and water supplies for livestock and poultry. The success of acidifiers in piglet nutrition is typically a result of the high buffering capacity of the feeds coupled with the limited ability for hydrochloric acid production in piglets. Organic acids are particularly effective as preservatives thanks to their ability to enter a bacterial cell and to acidify its contents, thereby inhibiting microbial enzymes. The energy required to fight acidification is thought to weaken the already distressed bacteria, slowing growth and reproduction. A further benefit is that the acidification of the intestinal tract favours the acid producing bacteria (lactobacilli,bifidobacteria) and inhibits the acid-intolerant bacteria (Salmonella, E Coli, Campylobacter sp) (Dibner and Buttin, 2002). Dietary acidification brings other benefits including improvements in gastric proteolysis and protein digestibility, with consequent reduction in growth-restricting microbial metabolites (ammonia), reduction in the digestive pH, and increased pancreatic secretion. The acid anion can also form a complex with minerals, increasing their digestibility. Organic acids also serve as substrates in intermediary metabolism and therefore have an energy content (Revington, 2002). Finally, they have trophic effects on the gastrointestinal mucosa which vary with the formulation of the diet and the type of acid used.

17.6.7 Herbs, spices, essential oils and various plant extracts

Herbs, spices, essential oils and plant extracts have received increasing attention as potential replacements for AGPs. There is evidence to suggest that some of these components have appetite stimulating, anti-bacterial, anti-oxidant, coccidiostatic and even antiviral properties (Langhout, 2000; Wenk, 2003 ; Abbas and Ahmed, 2010). They have also been claimed to increase digestive enzyme secretion and to lead to improvements in immune functions. These compounds can probably only be effective on a practical scale if they are used in a more concentrated form than that found in nature. These substances are often claimed to be “all natural”; while this is true, from a feed safety perspective it could be somewhat misleading, as many conventional antibiotics are also “natural”, 13

being produced by Streptomyces or Penicillium species. It is likely, therefore, that the plant extracts that prove to be most beneficial in the modification of the microbial environment of the intestine will also ultimately be subject to regulatory approval (Revington 2002).

17.6.8 Specific antibodies

One alternative to antibiotics which offers promising potential involves the inclusion of specific antibodies in feed with the intention of neutralizing pathogenic organisms. To provide a straightforward example, hens may be exposed to specific antigens, stimulating their systems to produce immunoglobulins. These immune proteins are then harvested from the eggs and included in animal feed. The swine industry has used this method with a degree of success; however, there may be some problems with the mode of delivery, since both heat treatments and the digestive processes of the animal obviously have a detrimental effect on the functionality of protein (Revington, 2002).

17.6.9 Bacteriophages

Bacteriophages are viruses that infect bacterial cells and may destroy them by lysis. They can be very specific to certain pathogens. This idea of using bacteriophages in the treatment and prevention of diseases is not new and in fact dates back to the 1920s, but their use was stopped when the first chemotherapeutics (dyes and sulphonamides) and antibiotics became available. Recent work with poultry has suggested that bacteriophages may be useful replacements for antibiotics in the treatment of various diseases, particularly in those cases where pathogens are located on biological surfaces (Biswaset al., 2002; Joerger, 2003; Huff et al., 2005).

17.7 Conclusions

There are few alternative strategies and agents available today that can apparently offer the same benefits as the AGPs that they purport to replace. Indeed, any replacement for AGPs would have to provide an improvement in feed efficiency that is economically viable. If the AGP substitute does not have antimicrobial properties, other concerns, including the incidence of enteric diseases and

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airsacculitis, will have to be addressed through the continued use of ionophores, management changes, or both (Dibner and Richards, 2005). Rosen (2004) observed that it was necessary to study the efficiency of numerous candidates simultaneously, because combinations of potential replacements should prove more efficient as alternatives to AGPs. The ban on in-feed AGPs and its consequences for the animal industry is a textbook case for the impact of new regulations. Of course, most European livestock producers disagreed to this policy which was based on the precautionary principle were in total disagreement, and stressed the risks for animal health and the transfer of zoonotic pathogens from animals to humans as a consequence of the ban. In addition, reduced animal performance, especially in pig and poultry production has economic as well as ecologic consequences. However, the absence of an “antimicrobial net”has also led to increased efforts to improve good agricultural practice and hygienic conditions in animal husbandry. The ban on AGPs has also encouraged the scientific community to find alternatives, leading to new concepts and original ideas. However, it is important to emphasise that all these alternatives must be carefully investigated, in order to prevent new feed safety crises and to ensure that these proposed alternatives are indeed safe.

REFERENCES

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