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 aureus¹ and Candida albicans². 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 diet³.

Infant studies suggest those receiving nucleotide supplemented formula have an improved antibody response following immunisation^4,5.

Nucleotide supplemented formulas have also decreased the prevalence and duration of diarrhoeal disease in infants but this was not associated with changes in faecal microflora⁶. 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.
 

Patients who receive enteral or parenteral feeds as their sole source of nutrition could potentially be a group whose intake of nucleotides is minimal and in whom deficiency symptoms might manifest. It is not clear whether this has been observed but studies in critically ill, ICU patients show that whilst enteral feeds improve nutritional deficiencies they do not ameliorate the impaired immune response⁷.

Several enteral feeds containing so-called immunomodulators (usually arginine, omega-3 fatty acids and nucleotides) are available for clinical use. Several have been subject to clinical review with encouraging results in terms of decreased infection rate⁷, improvements in markers of immune function⁸ and shorter hospital stay⁷.

A systematic review undertaken by Beale et al., (1999) has examined the benefits of enteral feeds, including those that contain nucleotides. They concluded that whilst there was no effect on mortality, there were significant reductions in infection rate, ventilator days and length of stay in hospital and the benefits were most pronounced in surgical⁹ and malnourished patients¹⁰.

Another review of enteral feeds has concluded that, on the whole, evidence pertaining to the benefits of enteral and parenteral feeds supplemented with arginine, glutamine or omega-3 fatty acids are inconclusive and inconsistent¹¹. Clearly there still is the potential for further investigation in nucleotide supplemented feeds.

A number of aspects of the immune systems in athletes exhibit transient dysfunction after prolonged, heavy exertion, effectively leaving an open window of impaired immunity for pathogens to gain a foothold, increasing infection risk¹². Indeed prolonged training increases the rates of infection, particularly upper respiratory tract infections (URTI) like colds and coughs¹³. Nutritional supplements (glutamine, omega-3 fatty acids and antioxidants) have been studied as countermeasures to exercise-induced immune changes with limited success¹⁴. This may be due to the limitation of a single nutrient in abolishing immune suppression. But human studies have demonstrated an improvement in markers of immune function with nucleotides³.

Endurance exercise has been shown to decrease salivary IgA¹⁵. Salivary IgA is the first line of defence against pathogens causing URTI.

Two small studies by McNaughton et al., (2006 & 2007) examined trained males before and after a 60 day supplementation period with a commercially available nucleotide supplement, Nucell (Pro Bio Healthcare, Daresbury Innovation Centre, UK) on salivary IgA following a 2 minute maximum exercise test¹⁶ and a 90 minute cycle ride¹⁷. No difference was observed in performance, lactate or other markers of physiological stress but salivary IgA was significantly increased following the period of supplementation after both exercise trials. These results are encouraging and warrant further investigation to show whether the incidence of URTI is affected.
 

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 repair¹⁸. The majority of standard infant formulas are now supplemented with nucleotides.

Nucleotide supplemented formulas have also decreased the prevalence and duration of diarrhoeal disease in infants but this was not associated with changes in faecal microflora¹⁹. 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.

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.

A small randomised cross-over trial (n=37) of IBS sufferers found that taking IntestaidIB (Pro Bio Healthcare, Daresbury Innovation Centre, UK), a nucleotide based supplement (1 x 500mg capsule three times daily) resulted in a 4-6% improvement in three of seven symptom scores of IBS compared to placebo²². The authors speculate that improved gut function could be via similar mechanisms found in animal studies, namely increased mucosal protein, DNA and villus height.

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Bower, R. H., Cerra, F. B., Bershadsky, B., Licari, J. J., Hoyt, D.B., Jensen, G.L., Van Buren, C. T., Rothkopf, M. M., Daly, J. M. and Adelsberg, B. R. (1995). Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized, clinical trial. Crit Care Med. 23:3, 436-49.
8. 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.
9. Beale, R. J., Bryg, D. J. and Bihari, D. J. (1999). Immunonutrition in the critically ill: a systematic review of clinical outcome. Critical Care Medicine 27:12, 2799-805.
10. O'Callaghan, G. and Beale, R. J. (2003). The role of immune-enhancing diets in the management of perioperative patients. Crit. Care. Resusc. 5:4, 277-83.
11. Jones, N. E. and Heyland, D. K. (2008). Pharmaconutrition: a new emerging paradigm. Curr. Opin. in Gastroenterol.  24:2, 215-22.
12. Gleeson, M., Nieman, D. C. and Pedersen, B. K. (2004). Exercise, nutrition and immune function. J. Sports Sci. 22:1, 115 - 125
13. Maughan, R. and Gleeson, M. (2004). The biochemical basis of sports performance. Oxford University Press. 
14. Pedersen, B. K., Ostrowski, K., Rohde, T. and Bruunsgaard, H. (1998). Nutrition, exercise and the immune system. Proceedings of the Nutrition Society 57: 43-47.
15. Nieman, D. (2007). Marathon training and immune function. Sports Med. 37:4-6, 412-415.
16. McNaughton, L.,  Bentley, D.  Koeppel, P. (2007). The effects of a nucleotide supplement on the immune and metabolic response to short term, high intensity exercise performance in trained male subjects. Journal of Sports Medicine and Physical Fitness. 47:1, 112-119.
17. McNaughton, L.,  Bentley, D.  Koeppel, P. (2006). The effect of a nucleotide supplement on salivary IgA and cortisol after moderate endurance exercise. Journal of Sports Medicine and Physical Fitness. 46, 84-89.
18. Carver, J. D. and Walker, W. A. (1995). The role of nucleotides in human nutrition. J. Nutr. Biochem. 6:2, 58-72.
19. 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.
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.
22. 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.

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