GROWTH PROMOTERS IN ANIMAL PRODUCTION : STATUS AND PROSPECTS I.G. PARTRIDGE
SUMMARY
Sub-therapeutic levels of in-feed antibiotics remain the most widely used growth promoters in animal production. They are generally cost-effective and current Iicencing regulations appear to be adequate in ensuring efficacy and safety. Probiotics are also quite widely used and may have a niche when there is a particular need to avoid medicinal additives.
However, there are doubts about the consistency of their effects.
Methods of manipulating the physiological control of growth are under intensive investigation and may yield a new generation of growth promoters during the 1990s. Porcine somatotrophin is particularly effective in increasing lean tissue growth rate and feed efficiency but at present is impracticable due to the lack of an appropriate delivery system to replace the need for daily injections. The more practical alternative of increasing endogenous somatotrophin release by immunisation against somatostatin shows promise, but further development is needed to improve its efficacy. The use of P-adrenergic agonists is effective in increasing lean deposition at the expense of fat but raises questions about possible side-effects and consumer safety.
INTRODUCTION
Growth promoters, notably the anabolic steroids and antimicrobial agents have been extremely valuable in enhancing the efficiency of animal production for many years. It now appears that the industry has reached a transitional phase. Whilst the use of anabolic steroids has been severely curtailed in many countries because of concerns about safety and because of “political ambiguity” (Lamming and Peters, 1987) antimicrobial feed additives continue to play a vital role, particularly in poultry and pigs and to a lesser extent in cattle. The use of antibiotics . in animals is big business. Armstrong (1981) estimated that the value of the world feed additive market at that time was $1.69 billion of which $460 million consisted of growth promoters.
MacGregor (1983) refers to projections which suggested that the world market for antibiotic feed additives in 1990 would amount to between $1.13 and $1.38 billion. This explosion in the use of antibiotics has given rise to fears concerning transfer of resistance and tissue residues and their potential threat to human health. These fears in turn have led to the development of the probiotic feed additives which aim to enhance performance by modifying the gut flora without the use of chemical agents.
There have also been tremendous developments in recent years in the search for methods of influencing growth rate and carcass composition by manipulation of the physiological control mechanisms. These efforts have centred upon the potential use of exogenous somatotrophin (growth hormone) and those factors such as somatomedins which influence the effects of growth hormone. The potential use of immunological methods to
suppress the endogenous compounds which limit growth has also been studied. The use of p- adrenergic agonists (re-partitioning agents) to decrease the rate of fat deposition and/or increase lean deposition has also received considerable attention.
Colborn-Dawes Australia (Pty) Limited, P.O. Box 279, South Wagga. NSW 2650.
The financial investment by pharmaceutical companies and research centres involved in these investigations has been enormous and it seems likely that several of these approaches will result in the development of commercial growth promoters within the next few years.
This paper will discuss the status and prospects for antimicrobial growth promoters and probiotics and the potential development of new products aimed at modifying the physiological control of growth and development. Whilst much of the discussion will be relevant across several animal species, attention will be focussed mainly on the pig.
ANTIBACTERIAL GROWTH PROMOTERS Mode of action
Antibiotics and other antimicrobial agents have been widely used as feed additives since the 1950s. Such products are commonly used at sub-therapeutic levels to enhance the efficiency of animal production through increased growth rate and reduced feed:gain ratio.
In general terms, it seems likely that the observed growth responses are due to modifications of the bacterial population of the digestive tract. Antibiotic growth promoters are mainly effective against Gram positive bacteria through various modes of action. For example virginiamycin owes its bacteriocidal effect to a mixture of two peptolides which act at the ribosomal level to inhibit protein synthesis within the bacterial cell. Tylosin and erythromycin are described as macrolide antibiotics which also inhibit protein synthesis. In contrast, bacitracin is a mixture of polypeptides which inhibit the synthesis of bacterial cell wall peptidoglycan compounds. Avoparcin and flavomycin act in a similar manner. Monovalent ionophores such as monensin and divalent ionophores such as lasalocid disrupt bacterial cells by facilitating the passage of inorganic ions across membranes.
The digestive tract is virtually sterile at birth but rapidly acquires a gut flora which tends to be characteristic for a given species. The,bacterial population of the gut consists of two distinct groups, one of which exists free within the lumen and its contents, the other being intimately associated with the epithelium. Studies with gnotobiotic animals have indicated the effects of these bacterial populations on the functional activity of the gut epithelium (Yokota and Coates, 1982). In these germ-free animals there are changes in the histology of the absorptive surface of the small intestine. Specifically the rate of movement of enterocyte cells up the villi is reduced. There is some evidence that the effect of antibiotic growth promoters may be similar, resulting in reduced demand for epithelial cell renewal, increased brush-border surface area and enhanced absorption of nutrients (Armstrong and Parker, 1989).
It has also been widely observed that sub-therapeutic levels of antibiotics reduce the mass of the small intestine due to a thinning of the intestinal wall (eg Yen et al., 1987). It has been suggested by Parker and Armstrong (1987) that in view of the very highte of metabolic activity of the intestinal tissues, this reduction in mass represents a significantly reduced maintenance energy cost. These authors also reviewed other reported actions of antibiotics, such as changes in digestive enzyme activities, alterations in bile acid metabolism and fat absorption, which may also contribute to the growth-enhancing effect. It is also generally supposed that sub-therapeutic levels of antibiotics suppress the effects of sub-clinical diseases.
Efficacy
The continuing widespread use of antibiotics as growth promoters for pigs and poultry is perhaps testimony in itself to the efficacy and, more importantly, the cost-effectiveness of the commercial products currently licenced for use in Australia and elsewhere.
Indeed, the licencing procedure itself requires manufacturers to demonstrate beneficial effects on animal performance. Cromwell (1987) has combined survey data presented by Hays (1977) and Zimmerman (1986) to show the average responses of large numbers of pigs to antibiotic supplementation. The results are given in Table 1. An important observation from these results is the much greater response in the younger animals.
TABLE 1. The efficacy of antibiotics as growth promoters for pigs?
An important principle of growth promotion is that products such as antibiotics which contribute to an improvement in the environment (in its widest sense) may be regarded as growth permitters, since they allow the animal more completely to achieve its potential. These are most effective when the animal is in the early growth acceleration phase and as its most susceptible to environmental deviations. On the otherhand, the majority of new growth promoters which aim to manipulate the physiology of the animal are in effect altering the potential for growth of body tissues.
The pharmaceutical companies continue to develop new antibiotics that could serve as growth promoters. Data relating to the efficacy of some of the more recent products have been reviewed by Cromwell (1987).
Copper sulphate remains the most widely used growth promoter for pigs. Although its mode of action is not fully understood, in many ways it is similar to an antibiotic. At an inclusion level of 2509 of copper per tonne the average improvement in performance over a large number of trials was reported to be 8.1 per cent for growth rate and 5.4 per cent for feed:gain ratio.
(Braude, 1967). Several trials have indicated synergism between copper and at least some of the antibiotic growth promoters (Braude, 1975).
Safety
There has been considerable opposition to the continued use of antibiotics as feed additives. This opposition is based on two premises; firstly the danger of residues in meat products and secondly the danger of developing antibiotic-resistant strains of pathogenic micro- organisms, particularly those pathogenic in humans.
With regard to residues it appears that appropriate screening of products by the licensing process has largely eliminated the problem: testing for residues in the U.K. showed positive results for antibiotics in only one percent of samples taken during 1980-3 (Food Surveillance Paper No. 22, HMSO London:cited by Dean, 1990). The danger which might result from the development of resistant pathogens can be avoided firstly by selection of antibiotics which have no major application in humans. Secondly, by choosing those which are mainly active against Gram positive bacteria, there is little risk of resistance transfer, a phenomenon limited in practice to the Gram negative Enterobacteriaceae.
PROBIOTICS
A probiotic has been precisely defined by Fuller and Cole (1988) as “a live microbial feed supplement which beneficially affects the host by improving its intestinal microbial balance”. This definition emphasises the importance of live cells and distinguishes probiotics from chemical modifiers of the gut environment.
It has been amply demonstrated that the natural microflora of the gut imparts a protective action on the host against a variety of pathogens (for reviews see Fuller et al. 1986;
Snoeyenbos, 1989). The imposition of stress such as weaning, overcrowding, env=ental fluctuations, diet changes; handling and transportation induces changes in the intestinal environment medicated through the release of adrenocorticoid hormones. These changes upset the population balance of the intestinal microflora and tend to favour the development of pathogens (Ewing and Haresign, 1989). The aim of probiotics is to maintain the population balance in favour of beneficial or protective bacteria by supplementing these orally.
A wide range of products has been offered onto the market (Haresign and Ewing, 1988). These are predominantly based on Streptococcus faecium, Lactobacillus acidophilus and Bacillus subtilis. A number of mechanisms has been proposed to explain their protective action. These have been reviewed by Partridge (1990) and include:
competitive exclusion of pathogens from sites of adhesion production of antibiotics
modification of pH by production of acids
metabolic inhibition of toxin production by pathogens systemic effects on the immune system
For these effects to be manifest in practice the commercial probiotic preparation must provide an appropriate strain of organism capable of colonising the gut of the target species. In addition, they must be presented in a form in which they remain viable during storage before and after incorporation in the feed. For many applications they must also be capable of surviving the pelleting process.
The efficacy of commercial probiotics in practical feeding trials has been extensively reviewed in both pigs (e.g. Thacker, 1988) and poultry (e.g. Partridge, 1990). In some trials probiotics have given economic responses similar to those expected with sub-therapeutic levels of antibiotics. However, in many trials no response has been seen and in some cases negative effects have been reported.
This inconsistency should not in itself discourage the use of probiotics. The response to any factor which has the potential to improve health is bound to vary according to the degree of challenge imposed.
Several factors continue to discourage the widespread use of probiotics. There is no reliable evidence to suggest that probiotics give additive benefits in conjunction with antibiotics.
Assuming that the industry continues to be allowed to choose, antibiotics are likely to remain more attractive because individual products are more clearly defined with regard to efficacy, potency, stability, dose-response relationships and appropriate inclusion levels as a result of independent regulatory procedures.
MANIPULATION OF PHYSIOLOGICAL CONTROL MECHANISMS Porcine somatotrobhin
Much has been learned in recent years about the neuro-endocrine regulation of growth and the partitioning of nutrients between lean tissue and fat deposition. These studies have led to the identification of several possible ways of modifying the processes exogenously, with potential benefits in growth rate, efficiency of feed use and improved carcass composition.
Somatotrophin produced by the pituitary gland is the principle hormone involved in stimulating growth. It is an anabolic agent and its release has been implicated as a possible mode of action of the anabolic steroids (Lamming and Peters, 1987). Although the mechanisms by which somatotrophin exerts its effects are not clear, it has been shown to stimulate hepatic synthesis of DNA, RNA and protein, to increase the concentration of plasma free fatty acids and to decrease amino acid catabolism (Welsh, 1985).
During early studies on the effects of exogenous somatotrophin injection in pigs, progress was slow due to the difficulty of extracting sufficient quantities of the hormone from pig pituitary glands. It is now a historic fact that these problems were overcome by the use of recombinant-DNA technology to modify bacteria genetically enabling them to produce large quantities of species-specific somatotrophins (Goeddel et al., 1979).
The response of growing pigs to porcine somatotrophin injection has been discussed in a number of reviews (Steele et al., 1987; Thacker, 1988; Thornton and Tume, 1988). The dose-dependent nature of the response was demonstrated by Ether-ton el al. (1987), who observed stepwise improvements in performance from daily injections of 0, 10, 30 and 70 pg somatotrophin per kg Iiveweight, per day. An example of the magnitude of improvement which can be achieved is given in Table 2.
Table 2. Effects of exogenous porcine somatotrophin injection on the performance of pigs from 60 to 100 kg Iiveweight (Campbell, 1987).
At present the major factor limiting the practical application of exogenous somatotrophin is the need for frequent injections throughout the growing period. It seems likely that the tremendous financial benefits at stake will encourage the development of appropriate delivery systems. A major advantage of somatotrophin is that it is not deposited in the body tissues.
Furthermore, it has a half-life in plasma of only about 9 minutes (Althen and Gerrits, 1976) eliminating the need for a withdrawal period. Safety is further ensured by the fact that it is a protein; if ingested it would be harmlessly broken down by the normal process of protein digestion.
Immunological techniques
Somatotrophin secretion from the pituitary is controlled by two hormones secreted by the hypothalamus; growth hormone releasing factor has a stimulating effect and somatostatin an inhibitory effect. Thus, the rationale for immunisation against somatostatin is to reduce its inhibiting effect on somatotrophin release. The procedure is similar to other immunisation techniques. Somatostatin is coupled with a foreign carrier protein and combined with a suitable adjuvant before injection. A major advantage of the technique is that it requires only two injections, a few weeks apart, in contrast to the present need for daily injections of somatotrophin.
Early applications of this technique have produced variable results (for reviews see Spencer, 1986, 1987). A preliminary study by Spencer and Williamson (1981) gave a remarkable 76 per cent improvement in the growth rate of lambs, but subsequently improvements of 15 - 20 per cent have been more usual. .
The results of a preliminary experiment to determine the effects of somatostatin immunisation on weaner pig performance are shown in Table 3.
Table 3. Effect of somatostatin immunisation on the performance of weaner pigs from 4 to 9 weeks of age (Thacker, 1988).
During the four-week trial, pigs immunised against somatostatin grew approximately 12 per cent faster than the controls, with no effect on feed utilisation. Trials with other species have shown improvements in feed:gain ratio, both as a result of the shorter growing period and due to more efficient feed utilisation during the growing period (Spencer et al., 1983). The treatment does not appear to have any marked effect in reducing carcass fat,xcept perhaps as a result of animals being younger when killed at equal weight (Spencer, 1987).
The considerable practical advantages of this technique suggest that it is worthy of further development. There is reason to believe that improvements in the consistency of the response may be achieved by selection of more appropriate carrier proteins and adjuvants.
The group of compounds referred to as P-adrenergic agonists comprises synthetic chemicals which have a molecular structure similar to the naturally occurring catecholamines, adrenaline and noradrenaline. Current examples which may have applications in animal production are clenbuterol, cimaterol, salbutamol and ractopamine.
The mode of action of P-agonists and responses in various animal species have been discussed in a number of reviews (Convey, 1987; Fiems, 1988; Thacker, 1988; Thornton and Tume, 1988; Warriss, 1990). An agonist is a compound that occupies a receptor and mimics the activity of a natural endogenous mediator. It is often more potent than the natural compound. Whilst other hormones act via nuclear or cytoplasmic receptors, adrenergic receptors are associated with cell membranes. Stimulation of P-receptors promotes relaxation of involuntary muscle whilst a-receptors promote contraction. The P-receptors are further classified into pl and p2 according to the muscle types in which they predominate. However, both types of P-receptor are widespread in many tissues including skeletal muscle and adipose tissue.
The interest in P-agonists in animal production stems from their so-called “repartitioning”
potential. Like adrenaline and noradrenaline they stimulate lipolysis in adipose tissue and release fatty acids. They also have a positive effect on nitrogen retention. A major benefit of p- agonists is that they are orally active and can thus be given as feed additives.
The effects of cimaterol on the performance and carcass characteristics of pigs have been summarised by Fiems (1988), as illustrated in Table 4.
Table 4.
In general, it is seen that the fat content of the carcass is reduced without significant effects on growth rate. Feed efficiency may be improved as a result of reduced fat deposition. One might suppose that the magnitude of the reduction in carcass fatness would depend upon the genetic potential of the pig for protein deposition, vis a vis fat deposition. It is of interest therefore that improved pigs with a high lean potential also showed significant improvements in carcass characteristics as illustrated in Table 5.
Table 5. Effects of a P-agonist on carcass quality in lean pigs (Warriss, 1990)
These results clearly show the greater muscle development of treated animals and their improved conformation, with a greater proportion of body mass in the more valuable hind limb.
Some slight adverse effects of P-agonists have also been reported in relation to meat quality but their practical significance remains unclear (Warriss, 1990). There is a tendency for reduced post mortem glycolysis, with increased ultimate pH. This adversely affects keeping quality of the meat and its colour, particularly in cured products. Increased incidence of foot lesions in pigs (Jones et al., 1985; Cromwell et al., 1987) and transient increases in heart rate in cattle (Williams et al., 1986) have also been observed.
Since P-agonists have metabolic effects in humans there is some concern about the possibility of residues in meat. This raises the question concerning appropriate withdrawal times. Unfortunately, the withdrawal of cimaterol for as little as seven days has been shown to result in compensatory fat deposition, provoked by a marked increase in feed intake of some 0.31 kg per day in comparison with control animals (Jones et al., 1985).
Although the practical application of j3-agonists in pig production presents some difficulties, the potential benefits are great. ,No doubt there will be continuing efforts to develop more suitable products and methods of application.
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