Nucleotides as immunomodulators in clinical nutrition George K. Grimble and Olwyn M. Westwood Dietary nucleotides, like glutamine, have attracted attention as a key ingredient missing from nutritional formulae for many years. They are the building blocks of tissue RNA and DNA and of ATP and their presence in breast milk has stimulated research in babies which has indicated that supplementation of infant formula milk leads to improved growth and reduced susceptibility to infection. Animal studies have confirmed some of these data. In particular, dietary nucleotides modulate immune function, promote faster intestinal healing and have trophic effects on the intestine of parenterally-fed rats which are similar to those resulting from glutamine supplementation, but at much lower intakes. Nucleotide supplementation has also been shown to improve some aspects of tissue recovery from ischaemia/reperfusion injury or radical resection. There is, however, a fundamental paradox. The intestine and liver possess powerful homeostatic mechanisms which degrade intake of purines and pyrimidines (i.e. salvage) and replace it with de novo synthesised output. It is possible that peripheral tissues receive only small amounts of nucleotides of dietary origin. Previously, nucleotides have been proposed as being conditionally-essential nutrients that provide an adequate supply of purines and pyrimidines for nucleic acid synthesis in neonates or in the stressed patient. This review explores this puzzle in the light of recent data from nutritional studies and from research into purinergic signalling in the intestine, heart and cells of the immune system. We propose that dietary nucleotides should be considered within a pharmacological and metabolic framework. Curr Opin Clin Nutr Metab Care 4:57±64. # 2001 Lippincott Williams & Wilkins. School of Life Sciences, University of Surrey Roehampton, London, United Kingdom Correspondence to George K. Grimble, School of Life Sciences, University of Surrey Roehampton, Whitelands College, West Hill, London SW15 3SN, UK Tel: +44 (0) 20 8392 3567; e-mail: g.grimble@roehampton.ac.uk Current Opinion in Clinical Nutrition and Metabolic Care 2001, 4:57±64 # 2001 Lippincott Williams & Wilkins 1363-1950 Introduction Nucleotides: ebb and ¯ow of the Irish Sea off Sella®eld [1] There is increasing evidence that nucleotides adminis- tered intravenously or in the diet are capable of modifying immune responsiveness and recovery of organs that have undergone a metabolic or in¯ammatory insult. Some of these studies are listed in Table 1 and the increasing importance of this topic can be judged from the number of recent reviews that have dealt with this topic singly or as part of an overview of immuno- nutrition [12±21]. Nucleotides are commonly found in human breast milk and cows milk, in which about 30% of nitrogen is nonprotein and comprises about 5% nucleotides. In contrast, formula feeds have very low nucleotide content because it may have been removed during processing of casein and whey concentrates which are added during manufacture of the diet. Breast-fed infants suffer from fewer gastrointestinal infections and have increased natural killer cell counts and higher antibody titres than formula fed infants. In addition, dietary nucleosides are thought to ful®ll a role in enhancing growth and maturation of the gut, as demonstrated in the rat model where villus height was signi®cantly higher, and enzyme activities modulated with supplements [17]. Moreover, neurological and physical development is also accelerated, and the catchup growth of infants who suffered intrauterine growth retardation is faster when nucleotide supple- ments are given [22]. This has been explained by the reduced energy demands made by reduced infections arising from a more robust and active immune system and less `leaky' gut following supplementation with nucleotides [18,19]. Fig. 1 summarises the major routes of mammalian nucleotide metabolism. The three features of this process are that nucleotides can be synthesised from other metabolites such as glutamine, aspartate, glycine or formate, or they can be salvaged from nucleotides released from RNA and DNA degradation or from dietary sources. The relative contribution of salvage and de novo pathways to maintenance of the intracellular nucleotide triphosphate (NTP) pools not only varies from tissue to tissue but may also alter at different phases of the cell cycle [13,23]. Thus, lymphocytes undergoing blastogenesis switch predominantly to de novo synthesis although salvage is also upregulated to a lesser extent [12,23,24]. Nucleotides comprise a purine or pyrimidine attached to a ribose sugar (as in ribonucleic 57