Research in infants and animal models clearly demonstrates that the body has a need for nucleotides but whether a constant exogenous supply is needed or whether salvage from degradation of nuclear material and de novo synthesis can be completely relied upon to meet nucleotide needs is poorly understood and hotly debated. It has been estimated that human milk provides about one-third of the neonate’s requirements¹.

Measuring whole body nucleotide status/flux is impractical on a routine basis and the complexities are beyond the scope of this review but it seems clear that understanding this complex issue could hold the key to how the body uses nucleotides and whether exogenous nucleotides really are essential.

Dietary nucleotides are not considered essential in the traditional sense because they can be synthesised by the body².  However, a number of investigators have described dietary nucleotides as conditionally essential in a variety of clinical situations and during development^2,3.

Dietary nucleotides could theoretically become conditionally essential under 3 circumstances:

• During periods of insufficient intake
• Where there is a high demand/high rate of growth
• In the presence of disease⁴ 

It has been demonstrated that enterocytes, whilst having a high demand for nucleotides, have a low capacity for de novo synthesis⁴. Thus it could be postulated that enterocytes rely more heavily on an exogenous supply of nucleotides from the diet. Further, if the dietary intake of nucleotides is low, due to a restrictive diet, these compounds could be considered conditionally essential.

In a study examining the effect of a nucleotide supplement on symptoms in Irritable Bowel Syndrome it was felt that dietary nucleotides were probably not essential in healthy people but under conditions of stress, illness or a poor diet nucleotides may well become semi-essential⁵.
 

No particular disease or classical deficiency syndrome has been related to nucleotide deficiency^6,7. But this may be because salvage pathways and de novo synthesis are up-regulated to compensate. Whilst this may be sufficient for most cells; for enterocytes and cells of the immune system, who synthetic capacity is lower, or perhaps tissue-specific injury or generalised illness this may result in minor problems that have not yet been detected.

Studies in rats have demonstrated that a diet devoid of nucleotides results in lower nucleotides levels in the liver⁸ and small intestine². It follows then that downstream processes, which rely on nucleotides, such as glycogen synthesis, and protein and lipid metabolism may be disrupted. Indeed, many studies have demonstrated a reduction in protein secretion including immunoglobulin’s⁹ and this may partially explain why dietary nucleotides are closely associated with immune function.

The supplementation of infant formula with nucleotides is considered beneficial since it has been found to influence lipid metabolism, immunity and tissue growth, development and repair¹⁰. The majority of standard infant formulas are now supplemented with nucleotides.

Studies have demonstrated that babies fed nucleotide supplemented infant formula have increased ‘friendly’ bifidobacteria counts in faeces compared to infants fed standard formula milk, but counts were still lower than found in breast fed babies¹¹. However in other studies, infants receiving a nucleotide supplemented formula had increased colonisation of Escherichia coli compared to infant fed standard formula milk¹². Counts of bifidobacteria were also lower in the infants receiving the supplemented formula. These authors did not support the addition of nucleotides to infant formula milk.

Nucleotide supplemented formulas have also decreased the prevalence and duration of diarrhoeal disease in infants but this was not associated with changes in faecal microflora¹³. Thus mechanisms other than the modification of faecal microflora, for example, effects on the immune system, might be responsible for the reduction in diarrhoeal disease.

Infant studies also suggest those receiving nucleotide supplemented formula have an improved antibody response following immunisation^14,15.

Investigations in animals suggest that dietary nucleotides influence several indices of immune function. Restriction of dietary nucleotides in mice decreases cell mediated immunity and decreases resistance when challenged with methicillin resistant Staphylococcus aureus¹⁶ and Candida albicans¹⁷. Further studies in mice have also demonstrated that a nucleotide-free diet suppressed immune function and this was only restored when nucleotides were re-introduced into the diet¹⁸.

Rats fed a diet devoid of nucleotides showed signs of reduced nuclear material, reduced endoplasmic reticulum and reduced ribosome numbers in hepatocytes¹⁹. The authors conclude that dietary nucleotides are essential for the normal functioning of the liver but overt deficiency or functional changes were not investigated. Feeding a nucleotide supplemented diet to rats has also demonstrated gastrointestinal benefits. Rats with experimentally induced ulcerative ileitis fed nucleotide supplemented enteral and parenteral feeds show accelerated healing of small-bowel ulcers compared with rats fed a standard formula²⁰. In another study, weanling rats fed a nucleoside-supplemented diet saw increased villus height and enhanced gut maturation compared to rats fed a standard diet²¹.

1. Maldonado, J., Navarro, J., Narbona, E. and Gil, A. (2001). The influence of dietary nucleotides on humoral and cell immunity in the neonate and lactating infant. Early Human Development 65S, S69-S74
2. Sanchez-Pozo, A. and Gil, A. (2002). Nucleotides as semiessential nutritional components. Br. J. Nutr. 87:1S, S135-S137
3. Maldonado, J., Navarro, J., Narbona, E. and Gil, A. (2001). The influence of dietary nucleotides on humoral and cell immunity in the neonate and lactating infant. Early Human Development 65S, S69-S74.
4. Yu, V. Y. H. (2002). Scientific rational and benefits of nucleotide supplementation of infant formula. J. Paediatr. Child Health 38, 543-549.
5. Dancey, C. P., Attree, E. A. and Brown, K. F. (2006). Nucleotide supplementation: a randomised double-blind placebo controlled trial of IntestAidIB in people with Irritable Bowel Syndrome. Nutrition Journal  5, 16
6. Gil, A. (2002). Modulation of the immune response mediated by dietary nucleotides. European Journal of Clinical Nutrition 56:S 3, S1-S4.
7. Carver, J. D. (1999). Dietary nucleotides: effects on the immune and gastrointestinal  systems. Acta Paediatr Suppl. 88:430,  83-8
8. Lopez-Navarro, A. T., Bueno, J. D., Gil, A. and Sanchez-Pozo, A. (1996). Morphological changes in hepatocytes of rats deprived of dietary Nucleotides. Br. J. Nutr. 76, 579-589.
9. Singhal, A., Macfarlane, G., Macfarlane, S., Lanigan, J., Kennedy, K., Elias-Jones, A., Stephenson, T.,  Dudek, P. and Lucas, A. (2008). Dietary nucleotides and fecal microbiota in formula-fed infants: a randomized controlled trial. Am. J. Clin. Nutr. 87: 6, 1785-1792.
10. Carver, J. D. and Walker, W. A. (1995). The role of nucleotides in human nutrition. J. Nutr. Biochem. 6:2, 58-72.
11. Gil, A., Pita, M., Martinez, A., Molina, J. A. and Sánchez Medina, F. (1986). Effect of dietary nucleotides on the plasma fatty acids in at-term neonates. Hum. Nutr. Clin. Nutr. 40:3, 185-95.
12. Balmer, S. E., Hanvey, L. S. and Wharton, B. A. (1994). Diet and faecal flora in the newborn: nucleotides. Archives of Disease in Childhood - Fetal and Neonatal Edition 70, F137-F140.
13. Brunser, O., Espinoza, J., Araya, M., Cruchet, S. and Gil, A. (1994). Effect of dietary nucleotide supplementation on diarrhoeal disease in infants. Acta Paediatrica 83:2, 188-91.
14. Hawkes, J. S., Gibson, R. A., Roberton, D. and Makrides, M. (2006). Effect of dietary nucleotide supplementation on growth and immune function in term infants: a randomized controlled trial. Eur. J. Clin. Nutr. 60:2, 254-64.
15. Schaller, J. P., Kuchan, M. J., Thomas, D. L., Cordle, C. T., Winship, T. R., Buck, R.H., Baggs, G. E. and Wheeler, J. G. (2004). Effect of dietary ribonucleotides on infant immune status. Part 1: Humoral responses. Pediatr Res. 56:6, 883-90
16. Adjei, A. A., Takamine, F., Yokoyama, H., Shiokawa, K., Matsumoto, Y., Asato, L., Shinjo, S., Imamura, T. and Yamamoto, S. (1993). The effects of oral RNA and intraperitoneal nucleoside-nucleotide administration on methicillin-resistant Staphylococcus aureus infection in mice. J. Parenteral Enteral Nutrition 17:2, 148-152.
17. Fanslow, W., Kulkarni, A., van Buren, C. and Rudolph, F. (1988). Effect of nucleotide restrictions and supplementation on resistance to experimentation murine Canidiasis. J. Parenteral Enteral Nutrition. 12:1, 49-52.
18. Kulkarni, A. D., Rudolph, F. B. and Van Buren, C. T. (1994). The role of dietary sources of nucleotides in immune function: A review.  J. Nutr. 124:8, 1442S-1446S.
19. Lopez-Navarro, A. T., Bueno, J. D., Gil, A. and Sanchez-Pozo, A. (1996). Morphological changes in hepatocytes of rats deprived of dietary Nucleotides. Br. J. Nutr. 76, 579-589.
20. Sukumar, P., Loo, A., Magur, E., Nandi, J., Oler, A. and Levine, R. A. (1997). Dietary supplementation of nucleotides and arginine promotes healing of small bowel ulcers in experimental ulcerative ileitis. Gastroenterology 42: 1530-1536.
21. Uauy, R., Stringel, G., Thomas, R. and Quan, R. (1990). Effect of dietary nucleosides on growth and maturation of the developing gut in the rat. Journal of Pediatric Gastroenterology and Nutrition 10:4, 497-503.

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