Abstract: The effects of oral RNA and intraperitoneal nucleoside-nucleotide mixture administration on methicillin-resistant Staphylococcus aureus (MRSA) strain 8985N infection were studied in mice. BALB/c mice were fed a nucleic acid-free diet or nucleic acid-free diet or nucleic acid-free diet supplemented with 0.5% or 2.5% ribonucleic acid (RNA) for 30 days. Nucleoside-nucleotide mixture or saline (control) was intraperitoneally administered daily to these rats except for the 2.5% RNA group, which received saline only. On the 10th day of this treatment, the mice were inoculated intravenously with the viable MRSA organisms. Susceptibility to the MRSA was determined by animal survival and recovery of the MRSA from the organs. The survival rates in the three groups that were administered saline were 29% for nucleic acid-free diet, 0.5% RNA, and 2.5% RNA groups, respectively, whereas in the two groups that received the nucleoside-nucleotide mixture the rates were 69% for the nucleic acid-free diet group and 55% for 0.5% RNA group. The susceptibility of the mice to the MRSA challenge was not affected by dietary RNA. The combined survival rate in the two nucleoside-nucleotide groups (64%) was statistically different (p<.01)from that in the three saline groups (34%). There was a greater reduction in viable organism recovery in the kidney and spleen of the surviving mice that had been administered the nucleoside-nucleotide mixture than in those administered saline. The study showed that intraperitoneal administration of the nucleoside-nucleotide mixture was effective in increasing the host resistance, whereas oral RNA was not adequate in offering protection to the mice against MRSA infection.

Abstract:
Objective: To perform a meta-analysis addressing whether enteral nutrition with immune-enhancing feeds benefits critically ill patients after trauma, sepsis, or major surgery.
Data sources: Studies were identified by MEDLINE search (1967 to January 1998) for original articles in English using the search terms "human," "enteral nutrition," "arginine," "nucleotides," "omega-3 fatty acids," "immunonutrition," "IMPACT," and "Immun-Aid." Additionally, the authors of the studies and the manufacturers of the feeds were contacted for additional information. Access to original databases was obtained for the three largest studies.
Study selection: Fifteen randomized controlled trials comparing patients receiving standard enteral nutrition with patients receiving a commercially available immune-enhancing feed with arginine with or without glutamine, nucleotides, and omega-3 fatty acids were identified by two independent reviewers (Dr. Beale and Dr. Bryg).
Data extraction: Descriptive and outcome data were extracted independently from the papers by the same two reviewers, one of whom (Dr. Bryg) analyzed the original databases. Three studies were excluded from analysis, leaving 12 studies containing 1,557 subjects, 1,482 of whom were analyzed. Main outcome measures were mortality, infection, ventilator days, intensive care unit stay, hospital stay, diarrhea days, calorie intake, and nitrogen intake. The meta-analysis was performed on an intent-to-treat basis.
Data synthesis: There was no effect of immunonutrition on mortality (relative risk = 1.05, confidence interval [CI] = 0.78, 1.41; p = .76). There were significant reductions in infection rate (relative risk = 0.67, CI = 0.50, 0.89; p = .006), ventilator days (2.6 days, CI = 0.1, 5.1; p = .04), and hospital length of stay (2.9 days, CI = 1.4, 4.4; p = .0002) in the immunonutrition group.
Conclusions: The benefits of enteral immunonutrition were most pronounced in surgical patients, although they were present in all groups. The reduction in hospital length of stay and infections has resource implications.

Abstract:
Objective: To determine if early enteral feeding, in an intensive care unit (ICU) patient population, using a formula supplemented with arginine, dietary nucleotides, and fish oil (Impact©), results in a shorter hospital stay and a reduced frequency of infectious complications, when compared with feeding a common use enteral formula (Osmolite HN©).
Design: A prospective, randomized, double-blind, multicenter trail.
Setting: ICUs in eight different hospitals.
Patients: Of 326 patients enrolled in the study, 296 patients  were eligible for analysis. They were admitted to the ICU after an event such as trauma, surgery, or sepsis, and met a risk assessment screen (Acute Physiology and Chronic Health Evaluation II [APACHE II] score > 10, or a Therapeutic Intervention Scoring System score of >20) and study eligibility requirements. Patients were stratified by age (<60 or > 60 yrs of age) and disease (septic or systemic inflammatory response syndrome).
Interventions: Patients were enrolled and full-strength tube feedings were initiated within 48 hrs of the study entry event. Enteral feedings were advanced to a target volume of 60 mL/hr by 96 hrs of the event. One hundred sixty-eight patients were randomized to receive the experimental formula, and 158 patients were randomized to receive the common use control formula.
Measurements and Main Results: Both groups tolerated early enteral feeding well, and the frequency of tube feeding -related complications was low. There were no significant differences in nitrogen balance between groups on study days 4 and 7. Patients receiving the experimental formula had a significant ( p = .0001 ) increase in plasma arginine and ornithine concentrations by study day 7. Plasma fatty acid profiles demonstrated higher concentrations of linoleic acid (p < .01) in the patients receiving the common use formula and higher concentrations of eicosapentaenoic and docosahexaenoic acid (p<.01) in the patients the experimental formula. The mortality rate was not different between the groups and was significantly (p < .001) lower than predicted by the admission severity scores in both feeding groups. In patients who received at least 821 mL/day of the experimental formula, the hospital median length of stay was reduced by 8 days (p<.05). In patients stratified as septic, the median length of hospital stay was reduced by 10 days (p<.05), along with a major reduction in the frequency of acquired infections (p<.01) in the patients who received the experimental formula. In the septic subgroup fed at lest 821 mL/day, the median length of stay was reduced by 11.5 days, along with a major reduction in acquired infections (both p<.05) in the patients who received the experimental formula.
Conclusions: Early enteral feeding of the experimental formula was safe and well tolerated in ICU patients. In patients who received the experimental formula, particularly if they were septic on admission to the study, a substantial reduction in hospital length of stay was observed, along with a significant reduction in the frequency of acquired infections. 

Abstract: The effects of a nucleotide-supplemented formula on diarrhoeal disease was studied in 141 infants (group 1) who belonged to the low socioeconomic stratum; 148 controls (group 2) received the same formula but unsupplemented. Group 1 experienced less episodes of diarrhoea (109 versus 140), including less first episodes (74 versus 102; chi-square = 8.19, p < 0.004; odds ratio 2.01) and for a lesser number of days (807 versus 996 days); 45.0% and 31.1% of infants in groups 1 and 2, respectively, never developed episodes of diarrhoea. There were no differences in the clinical characteristics of the episodes or in the enteropathogens isolated from symptomatic or asymptomatic infants. The mechanisms through which nucleotides decrease the incidence of diarrhoeal disease in infants remain unclear.

Abstract: Nucleotides (NT) and their related metabolic products play key roles in many biological processes. NT can be synthesized endogenously and thus are not considered essential nutrients. Studies have demonstrated, however, that dietary NT can have beneficial effects; the term ‘conditionally essential’ has been used to describe their role in human nutrition. These nutrients may become essential when the endogenous supply is insufficient for normal function, even though their absence from the diet does not lead to a classic clinical deficiency syndrome. Most dietary NT are rapidly metabolized and excreted. However, some are incorporated into tissues, particularly at younger ages and with fasting. Under conditions of limited NT intake, rapid growth or certain disease states, dietary NT may spare the cost of de novo NT synthesis and optimize the function of rapidly dividing tissues such as those of the gastrointestinal and immune systems. Animals fed NT-supplemented versus non-NT supplemented diets have enhanced gastrointestinal growth and maturation, and improved recovery following small and large bowel injury. Indices of humoral and cellular immunity are enhanced, and survival rates are higher following infection with pathogens. Infants receive NT in human milk, where they are present as nucleic acids, nucleosides, nucleotides and related metabolic products. The NT content of human milk is significantly higher than most cow’s milk-based infant formulae. Dietary NT are reported to enhance the gastrointestinal and immune systems of formula-fed infants. Infants fed NT-supplemented versus non-supplemented formula have a lower incidence of diarrhea, higher antibody titers following Haemophilus influenza type b vaccination and higher natural killer cell activity. These data suggest that human milk NT may contribute to superior clinical performance of the breastfed infant.

Abstract: No abstract available.

Abstract: Analysis of the mid-Victorian period in the U.K. reveals that life expectancy at age 5 was as good or better than exists today, and the incidence of degenerative disease was 10% of ours. Their levels of physical activity and hence calorific intakes were approximately twice ours. They had relatively little access to alcohol and tobacco; and due to their correspondingly high intake of fruits, whole grains, oily fish and vegetables, they consumed levels of micro- and phytonutrients at approximately ten times the levels considered normal today. This paper relates the nutritional status of the mid-Victorians to their freedom from degenerative disease; and extrapolates recommendations for the cost-effective improvement of public health today.

Abstract: A double blind randomised controlled trial in small for gestational age (SGA) infants, whose intestinal mucosa was shown to be functionally impaired as a result of intrauterine undernutrition, was carried out to investigate the hypothesis that nucleotide supplementation of a milk formula could improve catchup growth. Anthropometric data were collected on 74 infants, 39 randomly allocated to the nucleotide supplemented group (group N) and 35 to a standard formula group (group S). From study entry to 2 months of age, infants in group N had significantly higher mean rates of weight gain (106.3 compared with 94.7 g/kg baseline weight/week) and length gain (21.8 v 19.7 mm/m baseline length/week). Over the whole six months for which the trial formula was provided group N had significantly higher mean rates of gain of weight (80.1 compared with 71.8 g/kg baseline weight/week), length (16.2 compared with 15.0 mm/m baseline length/week), and head circumference (11.8 compared with 10.8 mm/m baseline head circumference/week). Catchup growth in SGA infants is therefore improved by nucleotide supplementation of infant formula.

Abstract: Nucleotides (NT) are ubiquitous intracellular compounds of crucial importance to cellular function and metabolism. Much recent interest has focused on NT as components of the non-protein nitrogen fraction of human milk. MT supplementation of infant formula has now been introduced in several countries. Biological effects of NT have been reported in several fields. Dietary NT have been shown to have important effects on several components of the immune system; they may enhance intestinal absorption of iron; they affect lipoprotein and long-chain polyunsaturated fatty acid metabolism; they may alter intestinal flora; and they have been demonstrated to have trophic effects on the intestinal mucosa and liver in several experimental situations. Clinical studies have shown NT supplementation of infant formula reduces the incidence of diarrheal episodes among socioeconomically deprived infants, and enhances catch-up growth in infants born small for gestational age. Further work will continue to try to identify other clinical situations in which NT may have a beneficial role.

Abstract:
Background: Dietary nucleotide supplementation has been shown to have important effects on the growth and development of cells which have a rapid turnover such as those in the immune system and the gastrointestinal tract. Work with infants has shown that the incidence and duration of diarrhoea is lower when nucleotide supplementation is given, and animal work show that villi height and crypt depth in the intestine is increased as a result of dietary nucleotides. Dietary nucleotides may be semi-essential under conditions of ill-health, poor diet or stress. Since people with Irritable Bowel Syndrome tend to fulfil these conditions, we tested the hypothesis that symptoms would be improved with dietary nucleotide supplementation.
Methods: Thirty-seven people with a diagnosis of Irritable Bowel gave daily symptom severity ratings for abdominal pain, diarrhoea, urgency to have a bowel movement, complete feeling of evacuation after a bowel movement, bloating, flatulence and constipation for 28 days (baseline). They were then assigned to either placebo (56 days) followed by experimental (56 days) or the reverse. There was a four week washout period before crossover. During the placebo and experimental conditions participants took one 500 mg capsule three times a day; in the experimental condition the capsule contained the nutroceutical substances. Symptom severity ratings and psychological measures (anxiety, depression, illness intrusiveness and general health) were obtained and analysed by repeated measures ANOVAs.
Results: Symptom severity for all symptoms (except constipation) were in the expected direction of baseline>placebo>experimental condition. Symptom improvement was in the range 4-6%. A feeling of incomplete evacuation and abdominal pain showed the most improvement. The differences between conditions for diarrhoea, bloating and flatulence were not significant at the p < .05 level. There were no significant differences between the conditions for any of the psychological measures.
Conclusion: Dietary nucleotide supplementation improves some of the symptoms of irritable bowel above baseline and placebo level. As expected, placebo effects were high. Apart from abdominal pain and urgency to have a bowel movement, the improvements, while consistent, are modest, and were not accompanied by improvements in any of the psychological measures. We suggest that the percentage improvement over and above the placebo effect is a physiological effect of the nucleotide supplement on the gut. The mechanisms by which these effects might improve symptoms are discussed.

Abstract: Foods, which, in addition to their nutritional attributes, contain also elements that are considered to be health-promoting, have been termed “functional foods”. In this regard, human milk has gained recognition as being the ultimate functional food for infants - by its biological compatibility, nutritional value and the undisputed added value of its health promoting qualities. Intensive research activity has recently evolved in a quest to identify and define the components of human milk that might confer disease-preventing and health-enhancing properties and to determine the instances and clinical conditions in which these factors become particularly important. The outcome of such research would also provide a rationale for advocating the supplementation of commercial infant formulas with such substances. In effect, the body of data accumulated from scientific and clinical studies on nucleotides, probiotics, prebiotics and long-chain polyunsaturated fatty acids in human milk and as additives to infant formula, has become regarded as convincing enough by the infant formula industry so as to launch into the market formulas supplemented with one or more of these factors - in an effort to emulate human milk and its beneficial effects. The following review is intended for the reader to obtain a general idea of the new supplements that have been introduced to infant formulas. We summarize the pertinent experimental and clinical observations concerning each of the supplements, pointing out their potential specific benefits, their possible disadvantages and the issues that still remain unresolved.

Abstract:
Background: Massive small-bowel resection (SBR) increases adaptive growth of residual intestine in animal models of short-bowel syndrome (SBS). Pyrimidine nucleotides are critical for DNA and RNA synthesis, but no previous study has evaluated whether supplementation of pyrimidines or their precursors in the diet enhances adaptive gut growth after SBR. This study determined growth responses in jejunal mucosa after 7 days of dietary supplementation with uracil, or its precursor, orotate, after massive SBR in rats.
Methods: Sprague-Dawley rats (200 g) underwent 80% jejunoileal resection (RX) or ileal transection (TX; control). Rats were pair-fed a purified (AIN-93G) powdered diet supplemented with or without 1% (wt/wt) orotate or uracil until killing at 7 days postsurgery. Defined jejunal segments were obtained for analysis of mucosal villus height (VH), crypt depth (CD), total mucosal height, bromodeoxyuridine (BrdU) incorporation, an index of cell proliferation, and full-thickness DNA and protein content as measures of intestinal adaptive growth.
Results: Jejunal VH increased significantly with SBR, as expected, and orotate further stimulated this response. Jejunal CD and total mucosal height increased significantly with both orotate and uracil supplementation compared with resected animals receiving standard diet. Orotate administration also increased jejunal DNA content compared with the increase observed with SBR alone. Finally, orotate, but not uracil, supplementation increased BrdU incorporation compared with resected rats fed standard or uracil-supplemented diet after SBR.
Conclusions: Supplementation of oral diet with the pyrimidine precursor orotate and uracil stimulated adaptive jejunal growth after massive SBR in rats. Dietary orotate had more potent growth-stimulatory effects than uracil in this animal model. Dietary supplementation with orotate and uracil represents a novel nutrition approach to enhance small-bowel mucosal adaptive growth and absorptive capacity in SBS.

Abstract: The influence of dietary nucleotides on susceptibility to candidiasis in mice was studied using two criteria: animal survival and recovery of viable Candida ablicans organisms from the kidney and spleen. One-month-old mice were placed on one of five diets with varying nucleotide content. The results show that mice maintained on a nucleotide-free diet (NF) exhibit a significantly decreased meaned survival time and a significantly increased viable organism recovery in the spleen following intravenous injection of graded inocula of C.albicans compared to mice fed diets containing RNA or uracil as a nucleotide source.

Abstract: Dietary nucleotides have been reportedly beneficial, especially for infants, since they positively influence lipid metabolism, immunity, and tissue growth, development and repair. Rapidly proliferating tissues, such as the immune system or the intestine are not able to fulfil the needs of cell nucleotides exclusively by de novo synthesis and they preferentially utilize the salvage pathway recovering nucleosides and nucleobases from blood and diet. In the present review we describe the modulatory effect of dietary nucleotides on the immune system together with some of their effects on gut-associated lymphoid tissue. Dietary nucleotides influence lymphocyte maturation, activation and proliferation. Likewise, they affect the lymphocyte subset populations in both the small intestine and blood. Moreover, they are involved in enhancing macrophage phagocytosis and delayed hypersensitivity as well as allograft and tumour responses. In addition, they contribute to the immunoglobulin response in early life, having a positive effect on infection. In fact the incidence and duration of acute diarrhoea is lower in infants fed supplemented-nucleotide formulas. The molecular mechanisms by which dietary nucleotides modulate the immune system are practically unknown. Dietary nucleotides have been shown to enhance the production and the genetic expression of IL-6 and IL-8 by foetal small intestinal explants. Dietary nucleotides may influence protein biosynthesis as well as signal membrane transduction mediated by the interaction of exogenous nucleosides and their receptors may also contribute to modulate the expression of a number of genes, some of which can directly affect the levels of intestinal cytokines.

Abstract: Strenuous bouts of prolonged exercise and heavy training are associated with depressed immune cell function. Furthermore, inadequate or inappropriate nutrition can compound the negative influence of heavy exertion on immunocompetence. Dietary deficiencies of protein and specific micronutrients have long been associated with immune dysfunction. An adequate intake of iron, zinc and vitamins A, E, B6 and B12 is particularly important for the maintenance of immune function, but excess intakes of some micronutrients can also impair immune function and have other adverse effects on health. Immune system depression has also been associated with an excess intake of fat. To maintain immune function, athletes should eat a well-balanced diet sufficient to meet their energy requirements. An athlete exercising in a carbohydrate-depleted state experiences larger increases in circulating stress hormones and a greater perturbation of several immune function indices. Conversely, consuming 30-60 g carbohydrate x h(-1) during sustained intensive exercise attenuates rises in stress hormones such as cortisol and appears to limit the degree of exercise-induced immune depression. Convincing evidence that so-called 'immune-boosting' supplements, including high doses of antioxidant vitamins, glutamine, zinc, probiotics and Echinacea, prevent exercise-induced immune impairment is currently lacking.

Abstract: 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.

Abstract:
Objective: To examine the effect of nucleotide (NT)-supplemented cow’s milk-based formula on growth and biochemical indices of immune function in healthy infants.
Design: Randomized controlled trial (RCT) of formula-fed term infants allocated to control formula with an innate level of NT at 10 mg/l (n=102), or formula fortified with NT at 33.5 mg/l (n=98). A parallel group 125 breastfed infants followed the same protocol as a reference.
Outcome measures: Growth was assessed at enrolment, 7 weeks, 4 months and 7 months of age. Natural killer cell activity, cytokine production and lymphocyte subpopulations were assessed at 7 weeks of age. Antibody responses to diphtheria toxoid, tetanus toxoid and Haemophilus influenza type b (Hib) immunizations were measured at 7 months of age.
Results: NT supplementation did not influence the growth of formula fed infants or any markers of immunity measured at 7 weeks of age. Antibody responses to tetanus toxoid were higher in the NT-supplemented group (n=70) at 7 months of age (median(5th, 95% percentile): 1.57(0.42, 3.43) vs 1.01(0.41, 4.66)IU/ml, P<0.03). A difference between treatments was seen in response to diphtheria toxoid but this effect disappeared when adjusted for hepatitis B Immunization at birth. There was no effect of treatment on antibody responses to Hib immunization.
Conclusions: Supplementation of formulas with NT at 33.5 mg/l resulted in a modest improvement in antibody response consistent with RCTs that used higher levels of NT supplementation. Whether this translates to clinical benefits with well-nourished infants requires further study.
Sponsorship: Supported by a grant from Wyeth Nutrition. Dr Makrides was supported by an RD Wright Fellowship from the National Health and Medical Research Council of Australia and Dr Gibson was partially supported by the MS McLeod Research Trust and a Senior Research Fellowship from the National Health and Medical Research Council of Australia.

Abstract: Nucleotide-supplemented infant formula has been shown to positively modify the composition of intestinal microflora, emulating the attribute of human milk. Quantification of nucleotides in infant formula is of interest because of its applicability in quality and safety assessments. There is no standard method for the analysis of nucleotides in infant formula. In the present study, ion-exchange liquid chromatography (IELC)- and centrifugal ultrafiltration (CUF)-based protocols were developed for routine determination of additive nucleotides in infant formula. Five target nucleotides, guanosine 5'-monophosphate (GMP), inosine 5'-monophosphate (IMP), uridine 5'-monophosphate (UMP), cytidine 5'-monophosphate (CMP), and adenosine 5'-monophosphate (AMP) were measured by IELC with a mobile phase of 50 mM diammonium hydrogen phosphate buffer, pH 4.0, with UV detection at 254 nm. The calibration was linear over the range 0.5-50 microg/mL; R(2) = 0.999. The calculated LOD and LOQ were 0.01-0.05 microg/mL and 0.05-0.5 microg/mL, respectively. Recovery values (spiked concentration levels: 0.5, 5, and 10 microg/mL) ranged from 85.0 +/- 1.4% to 92.3 +/- 2.1% using only CUF preparation. This was applied to measure the concentration of five nucleotides in common infant formulas.

Abstract: Nucleotides and nucleosides are essential components in all cells. However, nucleotides have not been supplied in parenteral nutrition regimens. We developed a well-balanced nucleoside-nucleotide mixture "OG-VI" and examined its effect in animals under some stressed conditions. OG-VI was composed of 30 mmol/l of inosine, 30 mmol/l of guanosine monophosphate, 30 mmol/l of cytidine, 22.5 mmol/l of uridine and 7.4 mmol/l of thymidine. The whole body protein turnover increased significantly in rats receiving total parenteral nutrition (TPN) with OG-VI solution after 70% hepatectomy, compared with rats receiving normal TPN without OG-VI (122.1 +/- 20.9 mgN.kg-1.h-1 vs. 97.4 +/- 10.1 mgN.kg-1.h-1, P < 0.01, n = 10). OG-VI significantly enhanced protein synthesis while it did not decrease protein breakdown. The effect of OG-VI on myocardium after hypoxic challenge was also examined in rats. The creatine phosphate (PCr)/inorganic phosphate (Pi) was decreased in normal rat myocardium after hypoxic challenge. However, in the rats administered OG-VI, PCr/Pi was maintained at baseline level and did not decrease after hypoxia. There was no significant change in the level of adenosine triphosphate (ATP) between before and after hypoxic challenge in myocardium of the rats administered OG-VI. In the rats receiving normal saline, instead of OG-VI, the ATP level decreased significantly after hypoxic challenge (4132 +/- 276 nmol/g tissue, n = 3, vs. 3439 +/- 465 nmol/g tissue, n = 5, P < 0.05). These data suggested that the well-balanced nucleoside-nucleotide mixture, OG-VI improved nitrogen metabolism and might stimulate synthesis of high-energy phosphate in recovery after severe surgical stress.

Abstract:
Purpose of review: This paper highlights recent studies of interest and provides rationale for why deficiencies with the current scientific paradigm of immunonutrition has produced studies with conflicting results, and why it should be replaced with a new paradigm termed 'pharmaconutrition'.
Recent findings: Considering the overall treatment effect of immune-modulating nutrients, parenteral glutamine is recommended in patients receiving parenteral nutrition, while enteral glutamine should be considered in burn and trauma patients. Antioxidants, particularly selenium, should be considered for critically ill patients, and enteral formulas enriched with fish oils are recommended in patients with acute respiratory distress syndrome. Arginine-supplemented diets are not recommended. There are currently insufficient data to enable useful recommendations on the optimal route, timing, duration and dosage of each nutrient. The pending results of a large, rigorously designed, randomized trial, however, in which nutrients are viewed and tested as pharmacological agents, promise to clarify some of the current ambiguities and inform future practice.
Summary: This review provides insights into why the current paradigm of immunonutrition has failed to consistently demonstrate a beneficial effect of key immunomodulating nutrients, and offers a timely solution through the new paradigm of pharmaconutrition.

Abstract: Dietary sources of preformed purines and pyrimidines seem to be important for optimal function of the cellular immune response. It was previously assumed that nucleotides were not needed for normal growth and development, but the results described in this review demonstrate a need for nucleotides in the response to immunological challenges. This effect is likely due to a requirement for preformed pyrimidines for proper development and activation of T cells. The need for sources of preformed nucleotides in defined formulas such as parenteral and enteral formulas and infant formulas is suggested by the studies reviewed below.

Abstract: Nucleotides are compounds that play a key role in numerous intracellular biochemical processes. Synthesized de novo by the body utilizing amino acid precursors or salvaged from degraded nucleic acids and nucleotides, they cannot be considered essential nutrients. However, the term semi or conditionally essential nutrients can be applied in certain conditions where the body’s needs are greater than the amounts of nucleotides synthesized or salvaged. Rapid growth, certain disease states, limited nutrient intake or disturbed endogenous synthesis of nucleotides represent such conditions.
Nucleotides participate in several biochemical processes that are essential to the function of the living body [1].

As nucleic acids: being the monomeric units they carry the genetic code as DNA and RNA.
In biosynthesis: for example, UDP-galactose in the synthesis of lactose or UDP-glucose in the process of glycogenesis
As components of co-enzymes: NAD, FAD and co-enzyme A
As biological regulators: cyclic AMP initiates second-messenger cascades and is ubiquitous in all forms of life, playing a key role in regulating biological processes
As an energy source: ATP is a universal currency of energy in biological systems.

Recently, several infant formula manufacturers announced the addition of nucleotides to their product. This step was taken following the results of studies suggesting potential benefits to intestinal flora, immunity, iron absorption, lipid metabolism and gut development. The question of whether infants require nucleotide supplementation for optimal nutrition cannot be answered categorically until other related questions are resolved. For example: Is there sufficient clinical evidence as to their beneficial effects? Which nucleotides should be added and in what concentration and relative proportions? Are they safe? Are they stable in the formula? Should they be given on a free basis or as a more complex molecule? In an attempt to answer these questions the present review summarizes the biological effects of nucleotides as nutrients and provides an update on their known side effects.

Abstract: This study examines the contribution of dietary nucleotides to liver nucleotide pools in rats. Liver acid-soluble nucleotides, DNA and RNA concentrations were monitored in two groups of rats fed either a diet supplemented with nucleotides or a diet free of nucleotides for 3 wk. Significantly lower concentrations of ATP, ADP, GTP and CDP as well as of RNA were found after 1 wk in the rats fed a nucleotide-free diet compared with those fed the nucleotide-supplemented diet; concentrations remained lower after 2 wk except for ATP and ADP. No changes over time were observed in the rats fed the nucleotide-supplemented diet. Between wk 2 and 3 an increase in both acid-soluble nucleotides and RNA was observed in the rats fed the nucleotide-free diet, reaching the values found in the rats fed the nucleotide-supplemented diet. These findings, which indicate that dietary nucleotides are utilized at least in part by the liver to maintain the cell nucleotide pools and that diets devoid of nucleotides affect hepatic nucleotide metabolism and RNA, support the hypothesis that liver nucleotide metabolism is modulated by the availability of dietary nucleotides.

Abstract:
Aim: The aim of this work was to determine the ergogenic effects of a nucleotide supplement on the metabolic and immune responses to short term high intensity exercise in volunteer, trained, male subjects.
Methods: Thirty moderately trained male subjects were randomly divided into 3 equal sized groups, control (C), placebo (P) or experimental (E). Each subject undertook a 2 min maximal exercise test prior to, and after, 60 days, on either a nucleotide (E) or placebo supplement. Prior to exercise testing unstimulated saliva samples and blood samples were taken.  Saliva analysed for lactate, lactate dehydrogenase and creatine kinase.
Results: The post exercise C value was significantly higher than the pre-exercise concentration (P<0.0001; for C, P and E).  In the post supplement C analysis, the E postexercise group was significantly lower than either the C (P<0.005) or the P group (P<0.05). In the pre- and postsupplementation periods, the pre-exercise SIgA values were significantly higher than the post exercise values (P<0.0001). However, in the postsupplementation period, the SIgA value in the E group was significantly higher than either the P (P<0.05) or C(P<0.05) groups. There were no significant changes in blood lactate, lactate dehydrogenase, or creatine kinase concentrations post supplementation.
Conclusion: We concluded that a chronically ingested nucleotide supplement blunts the response of the hormones associated with physiological stress.

Abstract:
Aim: The aim of this work was to determine the ergogenic effects of a nucleotide supplement on the salivary immunoglobulin A (SIgA) and cortisol (C) responses after prolonged endurance cycle exercise.
Methods: Fourteen moderately trained male subjects (mean body mass and VO2max) completed two 90 min cycle ergometer trials (60% VO2max) prior to and after 60 days of either a nucleotide (E group, n=7) or placebo (P group, n=7) supplement. Each of the subjects provided an unstimulated saliva sample prior to and following exercise for determination of SIgA and C. 
Results: SIgA was significantly lower after exercise trials in both E and P groups (P<0.0001) prior to as well as after the supplementation period. However, SIgA was significantly higher (P<0.01) in the E group than the P group after supplementation. There were no significant (P>0.11) differences in pre-exercise C level.  Post-exercise C concentrations were significantly (P<0.001) higher than pre-exercise levels in both groups of subjects. However, after the supplementation period, C concentration was significantly (P<0.0001) lower after exercise in E compared to P.
Conclusion: This work suggests that a nucleotide supplement, given chronically may offset the hormonal response associated with demanding endurance exercise.

Abstract: No abstract available.

Abstract: The World Health Organization recommends exclusive breast-feeding for the first six months of life. Breast milk remains the best source of nutrition for infants and mothers need to be motivated to continue as long as possible. However, when breast milk is not an option, health care professionals should be able to advise parents on the best alternative. Many different formulae are available for infants between 0-6 months. Although the main ingredients are strictly regulated by the European Union, formulae may differ in their protein and fat source, and in the addition of novel ingredients offering different benefits. Whey protein dominant infant formulae empty from the stomach in a similar way to breast milk, which is also high in this protein. Long chain polyunsaturated fatty acids impact on visual attention, cognitive behaviour and the immune system, whereas nucleotides decrease the risk of developing diarrhoea. The addition of specific prebiotics to infant formulae is relatively new, but the impact of these on the development of immunity in early childhood has been well researched. Health care professionals need to take these factors into account when advising parents on a suitable alternative to breast milk.

Abstract: In recent years, intense scientific interest has been focused on the identification of factors within bovine milk that may be relevant to improving human health. This paper provides an overview of current areas of research with regard to a number of minor bioactive milk components (growth factors, vitamins and nucleotides), and focuses on aspects that are directly relevant to nutritional and technological matters.

Abstract: Nucleotides have been identified as conditionally essential nutrients. As prevention studies, conducted with nucleotide-supplemented formula, have shown statistically significant decrease in the risk of diarrhea, we tested the hypothesis that the consumption of nucleotide-supplemented formula during an acute diarrhea episode is associated with therapeutic effects in the treatment of infants with acute diarrhea and dehydration. A randomized, double-blind, controlled clinical trial was conducted in which patients were randomly assigned to 1 of 2 treatment groups. The “test” group consumed a nucleotide-supplemented infant formula and the “control” group consumed a nonsupplemented formula. Infants were accommodated in a metabolic unit where body weight, and all intakes and outputs were recorded at 24-hour intervals during hospitalization. Laboratory parameters including blood gases and electrolytes were monitored during hospitalization. Eighty-one male infants ranging in age from older than 1 month and younger than 1 year, with acute non-cholera diarrhea and dehydration were studied. Primary outcomes were stool output and duration of diarrhea and did not differ significantly between the groups, with a stool output of 304.2 (SD 254.0) vs 350.3 (SD 269.1) g/kg and a duration of diarrhea of 83.3 (SD 44.5) vs 88.8 (SD 46.6) for the test and control groups, respectively. Anemia was highly prevalent and breast-feeding practice was not frequent in both groups. The average energy intake and weight gain were similar in the 2 groups. This study demonstrated that nucleotide supplementation of infant formula during episodes of acute diarrhea has no therapeutic advantage compared to conventional infant formula.

Abstract: Many components of the immune system exhibit adverse change after marathon-type exertion. These immune changes occur in several compartments of the immune system and body (e.g. the skin, upper respiratory tract mucosal tissue, lung, peritoneal cavity, blood and muscle). Of all immune cells, natural killer (NK) cells, neutrophils and macrophages (of the innate immune system) exhibit the greatest changes in response to marathon competition, both in terms of numbers and function. Many mechanisms appear to be involved, including exercise-induced changes in stress hormone and cytokine concentrations, body temperature changes, increases in blood flow and dehydration. During this 'open window' of immune dysfunction (which may last between 3 and 72 hours, depending on the immune measure), viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. Of the various nutritional and pharmacological countermeasures to marathon-induced immune perturbations that have been evaluated thus far, ingestion of carbohydrate beverages during intense and prolonged exercise has emerged as the most effective. However, carbohydrate ingestion during a marathon attenuates increases in plasma cytokines and stress hormones, but is largely ineffective against changes in other immune components including suppression of NK and T-cell function, and salivary IgA output. Other countermeasures, such as glutamine, antioxidant supplements and ibuprofen, have had disappointing results and thus the search for companion agents to carbohydrate continues.

Abstract: Newborn babies possess a functional but immature immune system as a defense against a world teeming with microorganisms. Breast milk contains a number of biological, active compounds that support the infant's immune system. These include secretory immunoglobulin A (IgA), which confers specific protection against enteric pathogens, as well as numerous other immunological, active ingredients. A number of these ingredients can be used as supplements for infant formulas based on cow's milk. Here, the strength of evidence regarding the immune-stimulating effects of selected minerals, vitamins, fatty acids, pre- and probiotics, and nucleotides is reviewed. An assessment of how these ingredients are used in infant-formula products currently available on the market is also presented.

Abstract:
Objective: To review the effects of immunonutrients in the perioperative patient.
Data sources: Articles and published peer-review abstracts of studies reported on immune enhancing diets in patients during the perioperative period.
Summary of review: Enteral nutrition is the method of choice for substrate supplementation in patients with a normal gastrointestinal tract but who are otherWise unable to eat normally. It is also a safer, more practical and less expensive alternative to the parenteral route and is now being used successfully in previously contraindicated conditions including pancreatitis and major abdominal trauma. Advances in enteral nutrition include the development of immunonutrients which have been used to attenuate the adverse effects of starvation, illness and surgery on the architecture and function of the gastrointestinal tract, implicated in the development of multiple organ dysfunction syndrome. These agents stimulate immune function and are potentially an effective strategy in improving the outcome in the peri-operative period by reducing post-operative infections and length of hospital stay.
Conclusions: Immunonutrition confers an additive benefit when compared with standard enteral and parenteral nutrient preparations in the management of perioperative malnourished patients. What is less clear is at what severity of illness this benefit begins, whether there is a significant reduction in mortality and at what point the cost benefit in the reduction in complications no longer occurs.

Abstract: The effect of a nucleoside-based mixture (OG-VI) on protein synthesis in partially hepatectomized rats was evaluated. Twenty male Wistar rats weighing about 200 g underwent 70% hepatectomy by Higgins and Anderson's method, and then were subjected to total parenteral nutrition (TPN) for 3 days: the control group received only standard TPN (S-TPN group) and the experiment group received standard TPN supplemented with a nucleoside-nucleotide mixture (13% W/V, OG-VI) (OG-TPN group). The rates of whole body protein turnover and protein synthesis and breakdown were determined for 3 days after hepatectomy by the method of Picou and Taylor-Roberts with [15N] glycine. The nitrogen balances on days 1 and 3 and the cumulative nitrogen balance were significantly higher in the OG-TPN group than in the control group. Moreover, the rates of protein turnover and protein synthesis were significantly higher in the OG-TPN group than in the control group. Thus, increase in protein synthesis, rather than change in protein breakdown, was concluded to be responsible for the better nitrogen balance of the OG-TPN group. These findings suggest that the nucleoside-nucleotide mixture was used for the syntheses of RNA and DNA through the salvage pathway in regenerating liver and that this resulted in enhanced protein turnover with simultaneous increase in protein synthesis.

Abstract: No abstract available.

Abstract: Cirrhosis is characterized by altered lipid and protein metabolism and an excessive accumulation of extracellular matrix components. The aim of this work was to determine the effect of dietary nucleotide intake on the intracellular pools of nucleic acids and nucleotides, hepatic redox state, and protein synthesis during cirrhosis. Rats were given 300 mg/L thioacetamide (TAA) in drinking water and were fed diets without (TAA-Nt) or with nucleotides (Nt) (TAA+Nt, 3 g each of AMP, inosine 5'-monophosphate, CMP, GMP, and UMP per kg diet) for 4 mo. The degree of liver histological injury was less in group TAA+Nt than in TAA-Nt. The intake of nucleotides significantly increased the hepatic concentration of total nucleotides, adenine nucleotides, and ATP+ADP+AMP. Interestingly, the concentration of CDP-choline, a nucleotide necessary for phospholipid synthesis, was significantly higher in TAA+Nt than in TAA-Nt. The hepatic pyruvate:lactate (P = 0.075) and acetoacetate:beta-hydrodybutyrate (P < 0.05) ratios, indicators of cytosolic and mitochondrial redox states, were lower in TAA-Nt than in TAA+Nt. The total protein concentration was higher in the livers of TAA+Nt than in TAA-Nt. Although there were no differences in the expression of the albumin gene, the hepatic albumin concentration was significantly higher in TAA+Nt than in TAA-Nt. These data indicate that the reduction of liver injury in nucleotide-supplemented rats may be due to the increased intracellular availability of key metabolic nucleotides, the restoration of mitochondrial function, and the augmentation of protein synthesis.

Abstract: Nucleotides (NT) and nucleosides (NS) play a key role in gastrointestinal development and in enterocyte healing after tissue damage. Exogenous NT and NS may therefore represent a novel therapy for maintaining gastrointestinal tract integrity. An exogenous NS mixture of thymidine, cytidine, guanosine and inosine (T-CGI) increases the proliferation rate of rat intestinal epithelial cell line 6 (IEC-6) cells, while a mixture of uridine, cytidine, guanosine and inosine (U-CGI) reduces IEC-6 proliferation independently of necrosis or apoptosis. This study aimed to analyze the effects of exogenous NS on IEC-6 differentiation under proliferation and differentiation conditions. To this end, IEC-6 cells were treated with NS T-CGI and NS U-CGI mixtures under low- and high-density conditions. Enterocyte differentiation was also assessed by flow cytometry, Western blotting, and light, fluorescence and transmission electron microscopy. Under proliferative conditions, villin expression was reduced in all cases, but NS-treated cells showed twofold the expression observed in NS-free cultures (controls) and more frequently showed characteristics of mature enterocytes. When cells were grown after confluence, villin expression, total protein production and morphology of NS-treated cultures were more differentiated compared with the control group. Our results demonstrate that T-CGI and U-CGI mixtures promote IEC-6 cell differentiation, with no significant differences between them. Unlike previous authors, we obtained this effect in cultures without an exogenous extracellular matrix such as Matrigel, reducing the variability among independent assays.

Abstract: Nucleotides are phosphate esters of nucleosides that contain a sugar linked through a glycosidic linkage with purine and pyrimidine bases. Purine and pyrimidine nucleotides are major components of the cells that make up the monomeric units of DNA and RNA, and they function in all cellular processes. Biosynthesis, interconversion, catabolism and other aspects of nucleotide metabolism, along with various cellular roles of nucleotides, will be discussed, and the possible use of dietary sources of preformed purines and pyrimidines will be considered.

Abstract: Dietary nucleotides are required nutrients for some tissues under certain circumstances. A lack of dietary nucleotides negatively influences protein synthesis in both the liver and the small intestine of rats. Ribosome degradation has been observed as being among the mechanisms responsible for this effect. Dietary nucleotides can also modulate gene expression by interaction with specific transcription factors, in both the liver and the small intestine.

Abstract: The objective of this study was to further explore previously identified defects of supplemental ribonucleotides on infant immune status as measured by antibody responses to routine infant immunizations. Infants were randomized to a milk-based formula with (FN, n=138) or without (F, n=147) 72 mg ribonucleotides/L. A cohort of human milk-fed (HMF, n = 192) infants was also followed. Subjects were given Haemophilus influenza type b (Hib), diphtheria tetanus acellular pertussis, and oral poliovirus vaccinations at 2, 4, and 6 mo of age, and specific antibody responses were assessed at 2, 6,7, and 12 mo. Growth and safety data were also monitored. Using a two-group repeated measures analysis (RMA), FN-fed infants had significantly higher poliovirus type 1 neutralizing antibody (PV-VN1) responses than F-fed infants (p = 0.045). Using three-group RMA, PV-VN1 responses in HMF infants were not different from FN-fed infants, while HMF-fed infant PV-VN1 responses were significantly higher than F-fed infants at 6 (p = 0.0004) and 12 mo (p = 0.0001). FN-fed infants had responses to Hib Farr, diphtheria, tetanus toxoid, oral poliovirus-specific IgA, and PV-VN3 not significantly different from those of F and HMF infants. Growth, gastrointestinal tolerance, and adverse events were equivalent among the three groups. The FN-associated increase in PV-VN1 response and nonstatistically significant trends toward increased Hib and diphtheria antibody responses were consistent with observations from earlier studies, indicating immune benefits of nucleotide supplementation of infant formula.

Abstract: Nucleotides, nucleosides and nucleobases belong to the non-protein-nitrogen (NPN) fraction of milk. The largest amounts of ribonucleosides and ribonucleotides - ribose forms only were considered in this review - were measured directly after parturition in bovine milk and other ruminants as well as in the milk of humans. Generally, concentrations of most of the nucleo(t)ides tend to decrease gradually with advancing lactation period or nursing time. The species-specific pattern of these minor constituents in milk from different mammals is a remarkable property and confirms, at least, the specific physiological impact of these minor compounds in early life. The physiological capacity of these compounds in milk is given by the total potentially available nucleosides. The main dietary sources of nucleos(t)ides are nucleoproteins and nucleic acids which are converted in the course of intestinal digestion into nucleosides and nucleobases the preferred forms for absorption in the intestine. Thus, nucleosides and nucleobases are suggested to be the acting components of dietary and/or supplemented nucleic acid-related compounds in the gut. They are used by the body as exogenous trophochemical sources and can be important for optimal metabolic functions. Up to 15% of the total daily need for a breast-fed infant was calculated to come from this dietary source. Concerning their biological role they not only act as metabolites but are also involved as bioactive substances in the regulation of body functions. Dietary nucleotides affect immune modulation, e.g. they enhance antibody responses of infants as shown by a study with more than 300 full-term healthy infants. Dietary nucleos(t)ides are found to contribute to iron absorption in the gut and to influence desaturation and elongation rates in fatty acid synthesis,  in particular long-chain polyunsaturated fatty acids in early stages of life. The in vitro modulation of cell proliferation and apoptosis has been described by ribonucleosides, in particular by modified components using human cell culture models. Due to the bio- and trophochemical properties of dietary nucleos(t)ides, the European Commission has allowed the use of supplementation with specific ribonucleotides in the manufacture of infant and follow-on formula. From the technochemical point of view, the ribonucleoside pattern is influenced by thermal treatment of milk. In addition ribonucleosides are useful indicators for quantifying adulterations of milk and milk products.

Abstract:
Background: Recently we demonstrated an increased 2,3-diphosphoglycerate (2,3-DPG) erythrocyte concentration in rat pups subjected to nucleotide-enriched artificial feeding.
Design: The present study was carried out to test the hypothesis that a possible increase in 2,3-DPG concentration can also be obtained in human neonates who are fed nucleotide-enriched formula. Preterm neonates born or referred to the neonatal intensive care unit of the G. Gaslini Hospital, Genoa University, with a gestational age >30 weeks and <37 weeks were enrolled in our randomized trial. Recruitment took place within 48-72 hours from birth. Only newborns of mothers deciding not to breast-feed were eligible to be randomized for the supplemented group (FN) or non-supplemented group (RF). Breast-fed newborns were considered the control group (C). The study window (for supplementation and blood samples) was restricted to the first two weeks following birth (from the 2nd (t1) to the 16th (t2) day of life). At the end of our study, only 21 neonates were eligible for statistical analysis.
Results: The stimulating action of dietary nucleotides on 2,3-DPG concentration failed to be demonstrated; increases in 2,3-DPG concentration that were observed in newborns fed with nucleotide supplemented formula (FN) were comparable to those observed in newborns fed with regular formula (RF) and breast-fed newborns.
Conclusions: The EC recommendation for the amount of nucleotides allowed in formula milk does not seem to be high enough to have positive effects on 2,3-DPG synthesis. Whether this possible 'pharmacological' effect can be achieved by a higher intake of ingested nucleotides and/or a change in the proportions of single nucleotides contained in milk formulas remain interesting end points to be elucidated.

Abstract: We previously showed that intravenous total parenteral nutrition supplemented with nucleosides and nucleotides (NS/NT) promoted ulcer healing in rats with indomethacin-induced ileitis. The present study evaluated whether dietary NT supplementation would similarly affect ulcer healing in this model. Female Lewis rats were randomized into either control or experimental groups receiving yeast RNA containing NT or arginine, glutamine, fish oil, guar gum, or a combination of yeast RNA+arginine diets. Ileitis was induced by two doses of indomethacin (7.5 mg/kg) administered subcutaneously 24 hr apart. Ulcer number and length were determined at 4, 8, and 14 days after induction of ileitis. Ileal villous and crypt length, crypt-villous ratio, and bromodeoxyuridine (BrdU) labeling were studied in the control and yeast RNA-supplemented diet groups. Ileal ulceration was present in all groups at 4 and 8 days and was almost healed by 14 days. Rats receiving yeast RNA, arginine, and yeast RNA + arginine diets showed a significant decrease in ulcer number (56%, 28%, and 34%, respectively) and length (67%, 41%, and 48%, respectively) compared to controls at 8 but not at 4 days. Glutamine, fish oil, and guar gum had no effect on ulcer healing at 4, 8, or 14 days. Among the histological parameters, a significant decrease in crypt length in the yeast RNA-supplemented group at 8 days suggested an acceleration of the healing process and restoration to a near-normal crypt-villous architecture. We conclude that the yeast RNA, arginine, and yeast RNA + arginine diets accelerated ulcer healing, as indicated by decreased ulcer number and length. We postulate that the underlying mechanism(s) contributing to ulcer healing may be related, in part, to increased cell proliferation.

Abstract: 
Purpose of review: Nutritional supplementation is paramount to the care of severely injured patients. Despite its widespread use in trauma, many areas of clinical nutrition remain controversial and not well defined. The benefit of early enteral nutrition in the care of injured patients has been well established, with further benefit derived by the administration of immune-enhancing formulas supplemented with glutamine, arginine, nucleotides, and omega-3-fatty acids. A new paradigm of pharmaconutrition has been developed that separates the administration of immunomodulatory nutrients from that of nutritional support. The optimal utilization and benefit of pharmaconutrients, however, remains unclear, as does the need for full caloric provision in the early postinjury phase.
Recent findings: Nutrition studies with the greatest reduction in morbidity and mortality are those utilizing specific nutrients. The use of pharmaconutrients to modulate the inflammatory and immune response associated with critical illness seems to provide benefit to critically ill and injured patients. Additionally, studies at least suggest that trauma patients derive comparable if not additional benefit from hypocaloric feeding during the acute phase of injury.
Summary: Building upon previous well performed studies in trauma patients, the current focus of nutritional investigations center on the use of pharmaconutrients to modulate the inflammatory response and the use of hypocaloric feeds. These practices will be reviewed and evidence presented for their use in critically ill and injured patients.

Abstract: Studies have demonstrated that a fecal flora with a predominance of bifidobacteria develops in infants fed a nucleotide-supplemented commercial formula, closer to that in breast-fed infants. In contrast, enterobacteria predominate in the fecal flora of infants fed an unsupplemented formula. When given parenterally, nucleotides promote recovery from injuries caused by hepatotoxic agents. These results suggest that dietary nucleotides may potentially play a significant role in nutrition.

Abstract: Dietary nucleoside (DN) as a precursor for nucleic acid synthesis may be important for rapidly dividing cells, since gut epithelial cells have limited capacity for de novo purine and pyrimidine synthesis. We evaluated in a controlled blinded study the effect of added nucleosides, 0.8% by weight, given for 2 weeks, on gut growth and maturation in 20 weanling rats. Mucosal protein and DNA in the proximal intestinal segment were 50% and 77% higher, respectively, in the DN-supplemented group (n = 10; p less than 0.05). Villus height based on cell count was 25% greater in the DN group (p less than 0.05). Maltase activity was significantly greater in proximal, middle, and distal intestinal segments, and the largest increase, 87%, was seen in the proximal gut mucosa. The maltase/lactase ratio was also higher in this segment. Increases in sucrase were less prominent. Lactase was minimally affected. The pattern of change in disaccharidase activity suggests that DN may enhance gut growth and maturation of the intestine in the weanling rat, the effects being more pronounced in the proximal segment. Diets free of nucleosides and nitrogenous bases may have adverse effects on the gut.

Abstract: The objective of the present study is to demonstrate the effect of nucleotide intake and intensive nutritional support on the concentration of insulin-like growth factor I (IGF-I) and other hormonal biomarkers in severely malnourished children. Twenty-six severely malnourished children < 48 months of age received formula without lactose via enteral feeding for 2 weeks and ad libitum for an additional 2 weeks. Anthropometrical measurements were performed and serum concentrations of IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3), leptin, soluble leptin receptor (sOB-R), as well as the estimated molar excess of sOB-R over leptin were obtained. Two groups were formed. One group received formula with nucleotides (NT+; n 13) and the other without nucleotides (NT-; n 13). A control group was included (n 13). Parametric and non-parametric tests as well as ANOVA models were used. Nutritional recovery, nucleotides intake, type of malnutrition, age and the interaction between gender and malnutrition influenced the concentration of IGF-I (P < 0.001). Nutritional recovery, nucleotides intake, gender and type of malnutrition had an effect on IGFBP-3 (P < 0.001). Nutritional recovery had a significant effect on serum leptin (P = 0.001). Age and nutritional recovery had an effect on sOB-R (P < 0.001); all variables included affected the molar excess of sOB-R over leptin (P < 0.001). In conclusion, nucleotide intake and nutritional recovery had a notable effect on IGF-I, IGFBP-3 and other hormonal biomarkers. This outcome could stimulate the catch-up growth of severely malnourished infants and toddlers during the nutritional recovery period.

Abstract:
Purpose: Dietary nucleotides are thought to be conditionally essential nutrients in infancy. However, studies have reported inconsistent findings regarding the association between nucleotide supplementation and infant physical growth. We conducted this meta-analysis to examine the efficacy of nucleotide supplementation of infant formula in promoting early infant growth.
Methods: Randomized controlled trials that evaluated the association between nucleotide supplementation and infant growth through June 2017 were included. Study quality was assessed using the Cochrane Collaboration's Risk of Bias tool. Standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated. Heterogeneity was assessed using Q and I2 tests.
Results: Nucleotide supplementation significantly increased the rate of weight gain (SMD 0.26; 95% CI 0.06-0.47), but had no effect on weight (SMD - 0.16; 95% CI - 0.55-0.23), weight Z score (SMD, - 0.42; 95% CI - 1.64-0.81), length (SMD 0.01; 95% CI - 0.18-0.21) and length Z score (SMD 0.15; 95% CI - 0.10-0.40). Occipitofrontal head circumference (OFC) at 7-8 weeks (SMD 0.30; 95% CI 0.10-0.50) and the rate of OFC gain (SMD 0.34; 95% CI 0.09-0.58) were significantly improved with nucleotide supplementation, whereas, 16- and 20-week OFC values did not differ.
Conclusions: Our meta-analysis indicated that nucleotide supplementation can increase the rate of weight gain, OFC and rate of OFC gain; however, we cannot conclude that it affects weight, weight Z score, length or length Z score. Large-scale randomized controlled trials of long-term nucleotide supplementation are needed to reach definitive conclusions.

Abstract: Human milk has a higher concentration of nucleotides than bovine milk which is the source of most infant formulas. As the composition of human milk is considered the 'gold standard,' an increasing number of infant formulas are supplemented with nucleotides. This review summarises the biology of human milk nucleotides and evaluates the studies which investigated the clinical benefits of feeding infants with nucleotide-supplemented formulas. Although dietary nucleotides have been suggested to have beneficial gastrointestinal and immunological effects, nucleotide-supplemented formula feeding has not been shown to confer the same benefits as breast feeding, and randomised controlled trials have yet to prove that healthy term infants fed nucleotide-supplemented formulas compared to those fed nonsupplemented formulas, have accelerated physical growth and neurological development, better growth and development of their gastrointestinal tract resulting in improved digestive and absorptive functions, enhanced development of their immune system resulting in increased resistance to infection and lower bacterial and viral infection rates during infancy, and a more favourable intestinal microflora associated with a lower rate of infectious diarrhoea. However, a randomised controlled trial has reported that term infants with severe intrauterine growth retardation do have better catch-up growth with nucleotide supplementation. The hypothesis that nucleotides are semi-essential nutrients needs to be further studied, in particular in the presence of prematurity, fetal growth retardation, intestinal injury and limited nutrient intake. As no deleterious effects have been reported with the use of nucleotide-supplemented formulas, the first of which was introduced over 30 years ago, such products are considered safe when nucleotides are supplemented to an amount equivalent to the free nucleotide concentration of human milk. More basic and clinical research studies are awaited to further define the biology and role of human milk nucleotides, and to critically assess the potential benefits and appropriate level of nucleotide supplementation of infant formula.

Abstract: The present review examines the role of dietary nucleotides in infants, and the scientific rationale and benefits of nucleotide supplementation of infant formula. The immunoprotective benefits of human milk, the biology of human milk nucleotides, and the immunological and gastrointestinal effects of dietary nucleotides in animal studies and in vitro experiments are examined. Clinical studies are reviewed, especially those examining the efficacy of nucleotide-supplemented infant formula in enhancing immunity and reducing the risk of sepsis. The presence of human milk cells, and a variety of immunoactive and trophic components of human milk, can explain the reduced incidence of sepsis in breastfed term and preterm infants. Nucleotides, believed to play an immunomodulatory role, are found in lower concentrations in infant formula. Animal studies have shown that dietary nucleotides enhance a number of immune responses and the growth, differentiation and repair of the gut. Several clinical studies have reported beneficial effects of nucleotide supplementation on gut microflora, diarrhoea and immune function, and one study has reported better catch-up growth in term infants with severe intrauterine growth retardation. More basic research studying the metabolism of nucleotides in neonates is encouraged. Additional randomized controlled trials are necessary to demonstrate the clinical benefits of nucleotide supplementation of infant formula, as it cannot be presumed that nucleotides produce the same benefits for the infant as human milk. Studies are especially necessary in high-risk neonatal situations, such as extreme prematurity, significant suboptimal nutrient intake before and after birth, and recovery from gut injury.