Nucleotides in Animal Feed

The last 40 years of livestock industry have been marked by considerable progress in genetics, nutrition, bioenergetics and metabolism, as well veterinary medicine. Better diagnostic tools, improved vaccination programmes, more efficient drugs, and, even more important, improved communication (e.g. in epidemiology) helped farmers in successfully running their business. Nevertheless, the increasing susceptibility of animals to stress or various diseases and the consumer-friendly ban of AGPs as well as restricted use of medication aggravate the economic difficulties on farms.

Effective control of diseases is especially important in intensive animal management, where prevention must be given highest priority. This includes hygienic measures, immunisation programmes and disinfection. The increase of immunosuppressive diseases makes vaccination unavoidable. However, no pharmaceutical intervention can be invariably successful if an animal's immune system is not simultaneously enhanced in order to increase resistance to diseases. In addition, stress decreases the replication of special and crucial white blood cells, thereby negatively interfering with the body's natural immune defence.

High Quality Feed

The Use of Nucleotides in Animal Feed - Image 1

Performance in livestock industry is controlled by different parameters. Besides environmental factors, external stressors and the genetic of the animals, various types of nutrients are triggering performance. An imbalance of the different nutrients in a feed has similar adverse effects on performance than elevated stress or hostile environmental factors. But in contrast to genetics, environment and stressors, which usually can not be influenced by farmers, the feed must be regarded as a target to optimise performance of the animals. Well balanced feeds taking into account the nutritional needs of animals in different stages of development or growth are a prerequisite of economical performance. Nutritionists and feed producers know very well about the feasibility to assemble well balance feeds including all essential as well as minor nutrients. Nevertheless there is always the imponderability of lacking nutrients in a given diet. In most case the missing nutrients are not classified as being essential for performance. However, under specific conditions some of these non-classified nutrients may switch in their importance quite drastically. Therefore these nutrients are called conditionally essential nutrients.

Impact of nutrients on the development of tissues and regulatory systems

The development of newborn animals is not completely finished with birth. Although most of the organs and molecular mechanisms are basically installed, their functionality is still limited and needs extensive fine-tuning. For instance, the colonisation with microorganisms in the intestinal tract starts with birth, the formation of intestinal structures must e.g. adapt from liquid to solid feeding and innate (non-specific) as well as acquired (specific) immunity have to be developed. A functional immune system needs to be developed in early stages of life to enable the animal to react on environmental disturbances and health challenges. The defence against microbes or parasites in newborn mammals is achieved by maternal antibodies present in colostrum and milk. The concentration is lowering over time thereby forcing the proprietary immunity to be developed. The gradual decrease of maternal antibodies and the simultaneous increase of internal immune defence are antidromic processes associated with e.g. the development of the alimentary system in young animals.

The supply of nutrients for the newborn mammals, which is well balanced and comprises the nutritional needs to handle all the different processes during post-natal development, is stopped suddenly at weaning. Weaning is determined by technological, hygienically and commercial aspects. The conversion from liquid to solid feed associated with stress caused by abrupt rearrangement of groups and changed housing, leads to increased susceptibility to diseases. The former trend to prepone the weaning age aggravated the problems unless the diets were adjusted to the animals needs. This applies likewise for other non mammals or invertebrates used in livestock or aquaculture. Boosting and supporting the development in early stages is retained during the whole life of the animals reimbursed by enhanced quality and performance.

Processes involved in the development of organs or regulatory systems (e.g. the immune system) as well as growth or overall performance require the formation of new, specialised cells. Cells can not be assembled from nonentity; new cells are copies of already existing cells. The process of formation of new cells is called proliferation or cell division. During this process a given parent cell divides into two daughter cells. This requires sufficient amounts of nutrients available to form organelles and membranes. But the initial step for cell division is the duplication of the genetic material. The genes are kind of a library for the cells storing all information required for their functionality. Dependent on the organism examined, this library contains different numbers of books (chromosomes). The books have different numbers of chapters (genes) and different numbers of pages (nucleotides). In average a living organism contains approximately 3x10⁹ nucleotides. This information needs to be passed from parental to daughter cells. The whole circle of cell division takes several hours in which the majority of the time is used to accurately duplicate the genetic material. During this time the need for nucleotides is tremendously high.

Supply of nucleotides

For years, nucleotides were not considered essential nutrients for use in any dietary programmes. It was thought that all organisms can supply sufficient amounts of nucleotides to meet their physiological demands via de novo synthesis or a so called "salvage pathway", the recycling of nucleotides from dead cells. However, some research over the past several years indicates that both mechanisms may not always supply enough nucleotides for the animal organism. Moreover it was found that some cells e.g. cells of the intestinal tract or immunocompetent cells lack the ability to produce sufficient amounts of nucleotides. When considering that most animals and humans must produce millions of new cells every second in order to simply maintain a status quo, it makes sense that during times of extraordinary stress (such as growth, reproduction, environmental change or challenge, combating disease and recovery from injury) trillions of additional nucleotides must be readily available for cell proliferation. This increased demand for nucleotides usually can not be covered by the internal supply mechanism. The inefficient extraction of nucleotides from the diet contributes only little to elevate the level of available nucleotides. As a result the affected or compromised animals need to reduce their performance or slow down development. This is what producers usually realize on their farms or in their wallets. Therefore this increased demand in combination with the relatively slow supply of nucleotides by the animal itself may result in the need for extra nucleotides added directly to the animal's diet.

The Use of Nucleotides in Animal Feed - Image 2

The Use of Nucleotides in Animal Feed - Image 3

Benefits upon fortification of feed with nucleotides

Supplementing feed with nucleotides has massive positive impact on cellular systems or tissues with low or no capability to produce nucleotides. Amongst those are cells of the intestinal tract, immunocompetent cells and blood cells. Balanced formulations of purified dietary RNA and nucleotides at least partially fill the gap in animal nutrition, supplying sufficient amounts of basic modules for cell proliferation and development, thereby meeting the physiological demand of the organism.

- improved development of the intestinal tract

The development of the intestinal tract upon dietary RNA and nucleotides was studied in various species. Most striking was the elongation of intestinal villi structures thereby increasing the active surface of the gastro-intestinal tract and the effectivity of intestinal enzymes. Day-old chicks feed a diet containing nucleotides for 10 days showed an advance of four days in the development of intestinal villi structures compared to control animals. Similar observations are reported from piglets, fish and mice. It seems that balanced formulations of dietary nucleotides likewise improve intestinal development in a wide variety of species. The increase in the active surface in the gastro-intestinal tract facilitates the uptake of nutrients which is reflected in the improvement of feed conversion ratios. Moreover the faster adaptation to changes in feeding strategies e.g. liquid feeding to solid feeding is assured, reducing the number and severity of diarrhoea problems post-weaning.

The Use of Nucleotides in Animal Feed - Image 4

- improved development of the intestinal microflora

Part of the development of the intestinal tract is its colonisation with a healthy and balanced population of microorganisms. In pigs it was demonstrated that upon dietary nucleotides the ratio of coliformal bacteria to lactobacilli was shifted, favouring the beneficial microorganisms. The mechanism is not completely elucidated but it seems that lactobacilli and bifidobacteria prefer the utilisation of dietary nucleotides for proliferation whereas coliformal germs rely on their internal supply. This advantageous unhindered proliferation of lactobacilli and bifidobacteria helps to establish a beneficial microflora in the gastro-intestinal tract.

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- improved immune response

One of the reasons for the success of nucleotide-supplemented diets is the fact that the nucleotides facilitate an accelerated immune response. An immune response is simply the ability of an organism to mount an effective defence against malignancies and invading micro-organisms (antigens) by producing immunoglobulins (antibodies). In general, the immune response is activated through the production of millions of specialised antibody producing cells. Unfortunately, cells of the immune system lack the potential to synthesize nucleotides. Since the proliferation of immunocompetent cells depends on the readily available nucleotides, it becomes clear why the immune response is accelerated when more nucleotides are made available. A strong immune system is equally important in an organism's ability to respond to other stress factors, such as injury, sudden environmental changes, physical exertion and growth. Moreover, challenges of the immune system reduce the ability to maintain or improve performance and productivity in livestock. Supplementary nucleotides have been demonstrated to affect a number of immune functions, including reversing malnutrition and starvation-induced immunosuppression, enhancing T-cell maturation and function, enhancing natural killer cell activity, improving delayed cutaneous hypersensitivity, aiding in resistance to such infectious agents as Staphylococcus aureus and Candida albicans.

The application of Lipopolysaccharide (LPS), thereby mimicking a bacterial infection, significantly accelerated the production of IgG in pigs. Instead of 8 hours in controls an increase in IgG was already observed after 2 or 1-2 hours respectively dependent on the concentration of dietary nucleotides. This acceleration of the immune response is due to the unhindered and unlimited supply of all nutrients including nucleotides to produce new antibody-producing cells. It is very important to keep in mind that nucleotides are not immune-stimulators as such. The unhindered and unlimited supply of nucleotides just facilitates natural processes leading to the formation of new antibody-producing cells.

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- improved vaccination

Vaccination is a widespread tool to control diseases. It is more frequently used in livestock compared to aquaculture. Vaccination at first stimulates innate immunity and thereafter the acquired immune system, leading to the memory effect which constitutes rapid and reliable defence against pathogens upon a second challenge. The response of the immune system upon vaccinations is accelerated and at the same time shows an increase in the antibody titres.

- improved stress resistance

Stabilisation or sustain of general health of animals in livestock or aquaculture is a prerequisite of performance and return of investment for the farmer. Modern livestock farming needs to exhaust the genetic potential but problems are often exacerbated due to stressful conditions on the farms. Stress is known to induce genotoxic effects and disturbs regulatory systems on molecular and cellular levels. As a consequence the immune system is suppressed and the performance must be biologically reduced to retain the health status of the animals.

When inducing a dietary oxidative stress in pigs by feeding high concentrations of polyunsaturated fatty acids (PUFA) the damages in lymphocytes on the level of DNA were reduced upon fortification of the feed with nucleotides. The level of damages was close to the control while the lymphocytes in animals not receiving the fortified diet showed a significant increase in the damage-level. The results indicate that nucleotide supplementation prevents DNA damaging induced by high oxidative loads. Similar results were obtained in experiments with Mycotoxins. Most likely the improved supply of nucleotides facilitates excision and repair of damaged parts of the DNA of immune and possibly other cells. Oxidative stress or stress in general increases the demand for dietary nucleotides over the endogenous supply to ensure repair on cellular and molecular levels. This is most likely not only important for optimisation of immune system functionality but may be generalised for every tissue or organ somehow affected by environmental or health challenges.

The Use of Nucleotides in Animal Feed - Image 7

The Use of Nucleotides in Animal Feed - Image 7

- improved performance

Most of the trials in livestock and aquaculture focused on determining the overall performance of the animals, as this was of critical importance to farmers. Under standard farming conditions, without evident abnormalities, there was a significant and visible improvement in performance. In a dose response trial with piglets, a linear increase in growth was established along with simultaneous improvement of the feed conversion ratio. Based upon the results from this trial, the inclusion of nucleotides in post weaning piglet diets statistically increases the technical and financial gain. The level of response was linear from 500 ppm to 2000 ppm inclusion.

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This trial clearly demonstrated that the inclusion of nucleotides resulted in a more positive response in smaller (lighter weight and younger age) than in heavier and older piglets. Farmers buying weaned piglets from other farms for breeding or fattening, report similar findings. The difference in uniformity of the piglets usually triggers the problems, as the bigger and stronger piglets suppress the development of the smaller and weaker ones. In these trials, the addition of nucleotides to the feed showed a significant improvement in average daily weight gain and feed conversion ratio. Moreover, it resulted in greater size uniformity. The reformation of groups of piglets on farms typically leads to stress. Additionally, the simultaneous conversion from liquid to solid feeding often overburdens the young animals and leads to increased mortalities or retarded development. Nucleotides tend to compensate the cellular and biochemical effects of stress. At this stage of growth, this reduces e.g. the occurrence of diarrhoea and other diseases and also reduces mortality.

Conclusion

The universally valid use and the diverse functionality of nucleotides in every living organism predestine them to be regarded as a management tool to control stress, performance and diseases in livestock industry and aquaculture. Purified dietary nucleotides are not restricted to species or applications. Besides boosting the development of regulatory systems or organs they participate in cellular and molecular repair mechanisms. Compared to other feed additives they support or facilitate immune reactions by unhindered proliferation of immuno competent cells, gene expression of factors involved in immune response and signalling. Other simultaneously proceeding processes in the organism e.g. growth, development or reproduction need not to be suppresses upon health challenges.

Know more about the use of Nucleotides in pig nutrition watching this video: