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Digestion and absorbtion of dietary nucleoprotein

Nucleotides and young animal health: can we enhance intestinal tract development and immune function?

Published: April 13, 2007
By: C.D. MATEO and H.H. STEIN - Alltech Inc.
The development of antibiotic resistance in humans has led to a growing interest in antibiotic-free animal production worldwide (Bager et al., 2000).

Unconventional management, feeding practices, and additives that act as alternatives to antibiotics have been tested (Turner et al., 2001; Stein, 2002). Research in human nutrition has demonstrated that the inclusion of nucleotides in parenteral formulas and infant milk formulas improves intestinal health and the development of the immune system in infants.

Because of their role in maintaining intestinal health, dietary nucleotides may act as an alternative to antibiotics in the feeding of young animals. If this were true it would provide the livestock industry with an alternative when looking to formulate antibioticfree feeds. This would be helpful in particular in diets for young animals where in-feed antibiotics are most efficient. However, very little data relative to the young animal’s need for nucleotides exist; and only limited information is available about the role of nucleotides in the development of the immune system and intestinal health. The objective of the current contribution is to give an update on the current understanding of the roles and functions of nucleotides in young animal feeding.


Nucleotide biochemistry and nomenclature

Nucleotides are ubiquitous molecules with considerable structural diversity. They are composed of a nitrogenous base linked to a pentose sugar to which at least one phosphate group is attached (Figure 1). The pentose sugar may either be a ribose for a ribonucleic acid (RNA) or a 2´-deoxyribose for a deoxyribonucleic acid (DNA). The nitrogenous base can be either a purine or a pyrimidine. Pyrimidine bases are composed of six-membered rings and comprise uridine, cytosine, and thymine (Table 1).

Purine bases have an additional five-membered ring and comprise adenine, guanine, and hypoxanthine. The phosphate group may be in a mono-, di-, or tri phosphate form, and is commonly esterified to the C-5′ hydroxyl group of the pentose sugar (Rudolph, 1994).


Nucleotides and young animal health: can we enhance intestinal tract development and immune function? - Image 1

Figure 1. Structure of a nucleotide.


When the phosphate group is absent, the compound is known as a nucleoside. Nucleosides are formed by a nitrogenous base attached to a pentose sugar through a glycosidic linkage between the N-1 nitrogen of a pyrimidine or the N-3 nitrogen of a purine, and the C-1 carbon of the pentose sugar (Voet and Voet, 1995). A chain of nucleotides attached together via a phosphodiester linkage at the 3C and 5C positions of neighboring ribose units are called polynucleotides or nucleic acids. Nucleic acids conjugated to proteins are called nucleoproteins. Sources of nucleotides in food and feed Nucleotides, particularly IMP, are mainly found in food rich in protein (Carver and Walker, 1995). Generally, feed or food ingredients containing cellular elements are potential dietary sources of nucleotides in the form of nucleoproteins. Organ meats, poultry, and seafood are good sources of nucleoproteins (Kojima, 1974; Clifford and Story, 1976; Barness, 1994). Yeast protein sources, baker’s or brewer’s yeast and yeast extract, are ingredients that have a relatively high concentration of nucleotides (Maloney, 1998; Ingledew, 1999; Tibbets, 2002). Feed ingredients are not routinely analyzed for nucleotide concentrations, but data are available for a few ingredients (Table 2). Most commonly used feed ingredients contain relatively low amounts of nucleotides.


Table 1. Nucleotide nomenclature.

Nucleotides and young animal health: can we enhance intestinal tract development and immune function? - Image 2
aAMP = adenosine 5′-monophosphate; GMP = guanosine 5′-monophosphate; IMP = inosine 5′-monophosphate; CMP = cytidine 5′- monophosphate; UMP = uridine 5′-monophosphate
bdAMP = deoxyadenosine 5′-monophosphate; dGMP = deoxyguanosine 5′-monophosphate; dCMP = deoxycytidine 5′-monophosphate; dUMP = deoxyuridine 5′-monophosphate; dTMP = deoxythymidine 5′-monophosphate
cADP = adenosine 5′-diphosphate; dADP = deoxyadenosine 5′-diphosphate; GDP = guanosine 5′-diphosphate; dGDP = deoxyguanosine 5′-diphosphate; CDP = cytidine 5′-diphosphate; dCDP = deoxycytidine 5′-diphosphate; UDP = uridine 5′-diphosphate; dUDP = deoxyuridine 5′-diphosphate; dTDP = deoxythymidine 5′diphosphate
dATP = adenosine 5′-triphosphate; dATP = deoxyadenosine 5′-triphosphate; GTP = guanosine 5′-triphosphate; dGTP = deoxyguanosine 5′- triphosphate; CTP = cytidine 5′-triphosphate; dCTP = deoxycytidine 5′-triphosphate; UTP = uridine 5′-triphosphate; dTTP = deoxythymidine 5′-triphosphate


Table 2. Nucleotide concentration in some commonly used feed ingredients (as is basis)a.

Nucleotides and young animal health: can we enhance intestinal tract development and immune function? - Image 3
aData from Mateo et al. (2004a)


The nucleotide concentration in the milk of lactating mammals is species-specific and the concentration of most nucleotides changes during the lactation period (Table 3) (Johke, 1963; Gil and Sanchez- Medina, 1981; Gil and Sanchez-Medina, 1982; Mateo et al., 2004). In a recent experiment in our laboratory, we demonstrated that the concentration of 5′AMP, 5′CMP, 5′GMP, 5′IMP, and 5′UMP in porcine milk changed during the initial two weeks of lactation, but was relatively constant after that (Mateo et al., 2004b).

Because of the species differences in milk nucleotide concentration, it is possible that the nucleotide requirement may also vary among species, but at this point there are no data available on the nucleotide requirements of animals. The demand for nucleotides increases during periods of stress and rapid growth. Therefore, the requirement may be elevated during the immediate post-weaning period of livestock species. Current research in our laboratory is addressing this hypothesis.


Digestion, absorption and metabolism of nucleotides

Dietary nucleoproteins, nucleic acids, and nucleotides need to be enzymatically hydrolyzed prior to absorption because only nucleosides, bases, and small amounts of nucleotides are absorbed. This process takes place in the small intestine. Endonucleases, phosphodiesterases, and nucleoside phosphorylase are the major enzymes involved in this process (Figure 2). These enzymes originate from the brush border epithelium (Markiewicz, 1983; Morley et al., 1987), pancreatic juice (Weickman et al., 1981), and bile (Holdsworth and Coleman, 1975). In contrast to adults, the exact metabolism of nucleic acids ingested by infants is unknown (Carver and Walker, 1995).

However, an attempt to evaluate the capability of infants to metabolize nucleic acids and nucleotides was made by Thorell et al. (1996), who suggested that enzymes for nucleotide catabolism are present in the fetal small intestine and act on the nucleotide containing substrates.


Table 3. Concentration of adenosine 5′-monophosphate (AMP), guanosine 5′-monophosphate (GMP), inosine 5′-monophosphate (IMP), citidine 5′-monophosphate (CMP), and uridine 5′-monophosphate (UMP) in milk from different species (μmoles/100ml)ab.

Nucleotides and young animal health: can we enhance intestinal tract development and immune function? - Image 4
a Number of samples analyzed varied between 4 and 12
b Nucleotide analysis via enzymatic analysis or HPLC.
c Data from Johke (1963)
d Data from Gil and Sanchez-Medina (1981)
e Data from Gil and Sanchez-Medina (1982)
f Data from Mateo et al. (2004b)



Nucleotides and young animal health: can we enhance intestinal tract development and immune function? - Image 5

Figure 2. Digestion and absorption of nucleic acids and their related products (adapted from Quan and Uauy, 1991).


The duodenum has the greatest absorptive capacity (Bronk and Hastewell, 1987). Differences in the efficiency of uptake among nucleosides have been reported with guanosine being taken up most rapidly (Sanderson and He, 1994). Under physiological conditions, nucleotides have a limited capacity to pass through cell membranes (Sanderson and He, 1994).

This may be due to the absence of a nucleotide transport system. Nucleotides also have a high negatively charged phosphate group that hinders absorption. Therefore, the nucleoside form is the major vehicle for entry of purines and pyrimidines into the epithelial cells. More than 90% of dietary and endogenous nucleosides and bases are absorbed into the enterocyte (Salati et al., 1984; Uauy, 1989).

Nucleoside transport into the enterocyte occurs by facilitated diffusion and by specific Na+-dependent carrier mediated mechanisms (Bronk and Hastewell, 1987).

From the enterocyte, partial metabolic products of dietary and endogenous nucleotides and nucleosides enter the hepatic portal vein. These molecules are carried to the hepatocytes for further metabolism.

From the liver, partial metabolic products of dietary and endogenous nucleotides and nucleosides are released into systemic circulation and enter muscle tissue. If these products are not re-utilized for nucleotide production or are unabsorbed, the purine and pyrimidine bases are catabolized into uric acid and ß-alanine or ß-aminoisobutyrate (Rudolph, 1994; Carver and Walker, 1995; Thorell et al., 1996). In mammals except for primates, uric acid is further catabolized into allantoin via the enzyme uricase.

Allantoin is then excreted into the urine. In avian species and primates, uric acid is excreted via the urine. The catabolic products of pyrimidine bases (i.e., ß-alanine and ß-aminoisobutyrate) are further metabolized into ammonia, carbon dioxide and acetyl CoA.


Synthesis of nucleotides

Humans and animals can synthesize nucleotides de novo provided that the precursors are available. This process takes place in the cytosol of hepatocytes where all the enzymes for purine and pyrimidine synthesis are available. The purine IMP is synthesized from α-D-ribose-5-phosphate via a process involving 11 reactions. In the first reaction, α-D-ribose-5- phosphate is phosphorylated at C1 by a phosphate group donated by ATP to form 5-phosphoribosyl-1- pyrophosphate (PRPP). In the second reaction, an N-glycosidic bond is formed to synthesize 5-phospho-ß-D-ribosylamine. Glutamine is the Ndonor in this reaction. Glycine, aspartate, and tetrahydrofolate derivatives are other precursors needed in the synthesis of IMP. Both AMP and GMP are subsequently formed from IMP via adenylosuccinate and xanthosine monophoshate, respectively (Rodwell, 2000). The precursors for pyrimidine synthesis are carbamoyl phosphate and aspartate. The pyrimidine UMP is formed in a process involving six reactions. A dephosphorylation of UMP yields UDP, which is subsequently turned into CMP or TMP. Glutamine and N5N10-methylene-folate are needed in the synthesis of CMP and TMP, respectively (Rodwell, 2000). The de novo synthesis of both purine and pyrimidine nucleotides is a metabolically costly process requiring a significant amount of energy in the form of ATP.

Synthesis of a nucleotide from a nucleoside and an inorganic phosphate group is accomplished via the Salvage Pathway. The nucleosides used in the Salvage Pathway may originate from dietary sources because most dietary nucleotides are changed to nucleosides prior to absorption. The Salvage Pathway may also be used to re-synthesize nucleotides via phosphoribosylation of purines and pyrimidines formed during the catabolism of nucleotides. This pathway may spare energy and allow cells (i.e., leukocytes, erythrocytes, bone marrow cells, intestinal mucosal cells and lymphocytes), which are incapable of de novo synthesis, to maintain their nucleotide pools (Sanderson and He, 1994).

Purines and pyrimidines are synthesized in equal amounts on a molar basis. The synthesis is strictly regulated via feedback and allosteric regulations (Rodwell, 2000).


Storage of nucleotides

Nucleotide metabolism is characterized by constant synthesis and catabolism. Tracer studies in animals indicate that 2 to 5% of dietary nucleotides are retained in the small intestine, liver, and skeletal muscle tissue pools (Saviano and Clifford, 1978). Increased tissue retention has been reported in young animals (Kobota, 1969) and during fasting (Saviano and Clifford, 1978; Gross and Saviano, 1991). This may be a manifestation of a physiological requirement.

Nucleotide pools are larger in differentiated (i.e., cancerous) cells than in undifferentiated (i.e., nonmalignant) cells (Sanderson and He, 1994). This suggests that undifferentiated cells are more dependent on the dietary supply of nucleotides.


Physiological roles of nucleotides

The concentration of ribonucleotides is relatively constant in all cells, while the concentration of deoxyribonucleotides varies with the stage of the cell cycle (Barness, 1994). Nucleotides are the building blocks for nucleic acids (i.e., DNA and RNA).

However, nucleotides also have physiological roles in the body such as being a source of energy (i.e., ATP and GTP), functioning as cofactors in oxidation and reduction reactions (i.e., FAD, NAD+, and NADP+), serving as physiological regulators (i.e., cAMP and cGMP), and carrying activated intermediates (i.e., UDP-glucose, CMP-sialic acid, and CDP-choline) and acyl groups (i.e., CoA).

Rapidly dividing tissues have increased DNA replication and RNA synthesis (Cory, 1992). Because of the role of nucleotides in RNA synthesis, regeneration of new tissue after injury or relative nutrient deficiency is accelerated (Iwasa et al., 1997; Yamauchi et al., 1998). Replication of DNA occurs during the S phase of the cell cycle, and during this time, the enzyme activity is increased for purine and pyrimidine synthesis and nucleotide interconversion (Carver and Walker, 1995). Therefore, there is an increase in demand for nucleotides during cell division and growth (Tsujinaka et al., 1999).

Dietary nucleotide supplementation has been associated with both humoral and cellular immunity, but the exact mechanism has not been elucidated. Nucleotide deprivation caused the arrest of T-cells in the G phase of the cell cycle, preventing a response to various immunological signals that occur by transition to the S phase (Kulkarni et al., 1994).

Nucleotide deprivations also caused a decrease in phagocytic activity, lymphokine production, and/or inhibited lymphocyte maturation (Paubert-Braquet et al., 1992). Dietary nucleotides contribute to the circulating pool of nucleosides available to stimulate leukocyte production (Kulkarni et al., 1994; Carver and Walker, 1995). Therefore, there is an elevated need for nucleotides indicated during periods of immunological challenges.

Dietary factors play a role in the antibody response to immunization of infants. Infants fed milk formula fortified with nucleotides had better responses to immunization as evidenced by an increase in humoral antibody response (Fanslow et al., 1988; Pickering et al., 1998) and increased cytokine production (Carver et al., 1991). In vivo studies in mice show similar results to nucleotide supplementation (Jyonouchi et al., 1993; Jyonouchi, 1994).

Nucleotide-free diets supplemented with single nucleotides (i.e., AMP, GMP, or UMP), have been shown to increase immunoglobulin concentration (Navarro et al., 1996). Dietary supplementation of purified nucleotides to milk replacers fed newborn bull calves challenged with lipopolysaccharide (LPS), resulted in a trend toward higher mean IgG levels in supplemented compared to the unsupplemented calves (Oliver et al., 2003). Nucleotide supplementation also increased lymphocyte stimulation to phytohaemagglutinin and concanavalin-A challenges in weanling piglets by 50 and 30%, respectively (Zomborsky- Kovacs et al., 1998). Similar results were observed to challenges by keyhole limpet hemocyanin (KLH) and non-specific T-cell mitogens in piglets fed yeast RNA (Cameron et al., 2001). Pigs with pathogenic E. coli infection fed diets supplemented with NuproTM, a yeast extract as a source of nucleotides, have reduced diarrhea and improved weight gain and feed conversion compared to pigs fed the control diet (Maribo, 2003). Results of these studies imply that dietary sources of nucleotides play a role in developing, maintaining, and enhancing the immune system.

Dietary nucleotides enhance intestinal absorption of iron, affect lipoprotein and long chain polyunsaturated fatty acid metabolism, have trophic effects on the intestinal mucosa and liver, and reduce the incidence of diarrhea (Cosgrove, 1998; Schlimme et al., 2000). Fecal flora of infants fed a nucleotidesupplemented commercial milk formula had a predominance of bifidobacteria (Tanaka and Mutai, 1980), while enterobacteria predominated in the fecal flora of infants fed a commercial formula without nucleotide supplementation (Uauy, 1994). These studies suggest that nucleotide supplementation may positively influence the microflora in the gastrointestinal tract, which leads to a lowering of gastric pH and hinders the proliferation of pathogenic bacterial species as evidenced by a lower rate of diarrhea (Yu, 1998).

Nucleotide supplementation increased bacterial resistance of mice inoculated with Candida albicans (Fanslow et al., 1988) and Staphylococcus aureus (Kulkarni et al., 1986; Carver, 1994). Intraperitoneal administration of nucleotides and nucleosides decreased bacterial translocation, number of colony forming units, and increased the survival of mice against methicillin-resistant S. aureus (Yamamoto et al., 1997). Therefore, nucleotides are capable of increasing resistance to a wide range of potentially pathogenic bacteria.

Dietary nucleotides from yeast extract supplemented in calf milk replacers improved intestinal health as demonstrated by improved feacal scores compared to the non-supplemented control group (Oliver et al., 2002). In piglets, nucleotides in concentrations similar to those in human milk exert a protective effect in the intestinal lumen against an inflammatory response to ischemia-reperfusion (Bustamante et al., 1994).

Dietary nucleosides enhance the growth and maturation of intestinal epithelial cells as evidenced by an increased formation of mucosal protein, DNA, taller villi in the small intestine and increased maltase:lactase enzyme ratio (Uauy et al., 1990; Carver, 1994). Dietary nucleotides may also stimulate differentiation (Sanderson and He, 1994). Parenteral supplementation of nucleic acids supports mucosal cell proliferation and function as demonstrated by increased mucosal wet weight, protein and DNA contents, villous height, but not crypt depth, and narrower tight junctions of the jejunal width (Kishibuchi et al., 1997; Tsujinaka et al., 1999). The development of the gastrointestinal tract directly affects the degree of nutrient absorption and ultimately, animal growth. Because of the role of nucleotides in maintaining intestinal morphology and maturation, dietary nucleotides may be needed during the immediate postweaning period to maintain the structure and growth of the intestinal tract.


Are dietary nucleotides needed in diets for weanling pigs?

The need for nucleotides is elevated during periods of rapid growth, during periods of stress, and in immuno-compromised animals. In newly weaned pigs, all of these factors are present – therefore, it is expected that they would have a high requirement for nucleotides during this period. Because nucleotide synthesis is an energy and glutamine-requiring process and because newly weaned pigs are often deficient in both energy and glutamine, it is possible that pigs are not able to synthesize sufficient quantities of nucleotides during the immediate post-weaning period. If this is correct, dietary nucleotides must be supplied.

In a typical starter diet for weanling pigs, the concentration of 5′CMP is close to the concentration found in sow’s milk during the last half of lactation, but the concentrations of 5′AMP, 5′GMP, 5′IMP, and 5′UMP are much lower than in sow’s milk (Table 4). Assuming that the concentrations of nucleotides in sow’s milk are representative of the requirement of the piglets, it is easily concluded that a starter diet for young pigs is deficient in four of the five nucleotides. It may, therefore, be beneficial to add additional nucleotides to such diets.

In a recent experiment in our laboratory, we added nucleosides to a deficient starter diet. We used nucleosides rather than nucleotides because dietary nucleotides need to be digested to nucleosides before absorption. Blood samples and fecal samples were collected from weanling pigs on the day of weaning, on day 7 postweaning and on day 14 post-weaning. Blood samples were analyzed for IgG concentrations, while the microbial flora was quantified in the samples. Results of the experiment showed that fecal counts of Clostridium perfringens were reduced in samples collected from pigs fed a nucleoside-supplemented diet as compared to the non-supplemented control diet. On day 14 post-weaning, the fecal counts of Lactobacillus acidophilus and Bifidobacterium spp. also were higher in pigs fed the nucleoside-containing diet (Mateo et al., 2004a). These results indicate that nucleoside supplementation during the immediate post-weaning period may positively influence the gastrointestinal microflora by decreasing Cl. perfringens and increasing L. acidophilus and Bifidobacterium spp. This observation was subsequently confirmed in an in vitro experiment that showed that nucleotides have antibacterial properties against Cl. perfringens and E. coli. The implication of this finding is that pigs fed diets supplemented with nucleosides may have improved intestinal health, less scouring, and improved performance. Although no improvement in serum IgG was observed in the above experiment, the improved intestinal health may also lead to an improvement in the immune system of animals fed diets supplemented with nucleotides.


Table 4. Calculated nucleotide concentration of a starter diet for weanling pigs a .

Nucleotides and young animal health: can we enhance intestinal tract development and immune function? - Image 6
aData from Mateo et al. (2004a)
bDiet formulated to contain the following feed ingredients: Corn, 49.32%; Whey powder, 20%, Soybean meal, 8%; Fish meal, 8%; spray dried protein plasma, 7.5%, vitamins, minerals, oil, and crystalline amino acids, 7.18%.
cData from Mateo et al. (2004b)



A reduced concentration of enterobacteria and an increased number of probiotic bacteria (i.e. L. acidophilus and Bifidobacterium spp.) may also result in improved intestinal morphology and improved nutrient uptake. This hypothesis is being tested in a current research project at South Dakota State University.


Conclusion

Nucleotides are molecules with considerable structural diversity. They are composed of a nitrogenous base linked to a pentose sugar to which at least one phosphate group is attached. Feed or food ingredients containing cellular elements are potential sources of nucleotides. Nucleotides have many important physiological, gastrointestinal, and immunological functions in the body. The exact metabolism of nucleic acids ingested by young animals is unknown. Synthesizing nucleotides de novo is metabolically costly compared to synthesis via the Salvage Pathway.

During periods of rapid growth and development, disease challenges, injury or stress, dietary nucleotide supplementation may be beneficial because of the role of nucleotides in developing and enhancing immunity, maintaining intestinal health, and preserving energy. However, more research is needed to verify this hypothesis.



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Authors: C.D. MATEO AND H.H. STEIN
Department of Animal and Range Sciences, South Dakota State University, Brookings, South Dakota, USA
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