Ribonucleotides: Conditionally essential nutrients shown to enhance immune function and reduce diarrheal disease in infants

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Summary

It remains a goal of pediatric nutrition to provide optimal nourishment for infants who are not fed human milk. Investigators have attempted to emulate the composition and functionality of human milk, the gold standard for infant nutrition. These efforts began with the analysis of milk components and continued with assessments of biological effects that culminated in clinical studies in infants. This chapter summarizes the path that researchers followed to study ribonucleotides and their role in infant nutrition. Based on analytical methods for the quantification of ribonucleotides in human milk, investigators assessed their potential impact on the immune systems of infants and looked for concomitant mechanistic explanations. These inquiries evolved into clinical trials in which ribonucleotide-supplemented formula performance was compared with that of non-supplemented formulas and with human milk. This chapter intends to summarize an area of pediatric nutrition that has yielded both enlightening evidence and seemingly contradictory data.

Introduction

Development and maturation of the neonatal immune system occurs over time. Induction of significant priming of IgG responses begins at 2–3 months of age and reaches adult-like levels of immunoglobulins that show specificity for most protein and polysaccharide antigens by 18–24 months of age.1 This immune immaturity during the first year of life is demonstrated by the relatively weak IgA and IgG immune responses in early infancy to viral2 or bacterial3 pathogens, and by the age-dependent increase of immune response to measles vaccine.4 Delay in both innate and acquired immune function, however, is compensated for by: (1) in utero transfer of pathogen-specific IgG to the developing fetus; and (2) various protective factors found in human milk.5 Published studies report that during the first year of life, human-milk-fed infants are significantly more resistant to the development of various infectious diseases than formula-fed infants.6 Some of the various immune factors in human milk identified as responsible for this protection include pathogen-specific antibodies,7, 8 oligosaccharides,9 lipids,10 and mucin.11 In addition, various components in human milk, including ribonucleotides,12 are thought to facilitate immune maturation of the human-milk-fed infant and their addition might make infant formula perform more like human milk.

Ribonucleotides (NT) were described as important dietary components, suitable for addition to infant formula, by Gil,13 and are considered ‘conditionally essential’ for the neonate.14, 15 As ‘conditionally essential’ nutrients, the supply of NT through de novo synthesis and endogenous salvage pathway sources is thought to be insufficient for optimal functioning of rapidly growing intestinal and lymphoid tissues, even though their low levels might not result in an overt clinical deficiency syndrome.15 Instances where NT might function in this capacity include periods of limited nutrient intake or rapid growth demand and metabolic stress associated with various disease states.15 Over the past two decades, NT have been extensively studied as ingredients in these formulas and several reviews of the rationale for, and importance as, ingredients in infant formulas have been published.12, 16, 17, 18, 19, 20 Several lines of evidence led to their consideration as important human milk constituents, not the least of which was the observation that nucleotides are present in higher amounts in human milk than in cow milk and cow-milk-based infant formulas.17, 21 A decade earlier, it was found that the absence of NT in animal diets increased mortality to staphylococcus challenge and suppressed lymphocyte function.22 Additional evidence showed that fortification in animal diets with NT derivatives improved resistance to infection.23

Knowledge of the biological roles of NT in infant nutrition has been evolving as infant formulas have been fortified, aiming to provide health benefits attributed to human milk.12, 20 In the past decade, research on NT supplementation has progressed from basic studies on mechanism of action to clinical outcomes, attempting to measure potential or putative health benefits. Outcomes in these studies have included immune function, growth, and infectious morbidity, including diarrheal episodes.

Clinical studies evaluating NT as ingredients in infant formulas can be grouped into those evaluating lower levels ranging from 10 to 33 mg/L free NT,24, 25, 26, 27 and those adding higher levels of ∼72 mg/L.28, 29, 30, 31, 32 Results from these clinical investigations are reviewed here, preceded by a brief description of NT-associated metabolic function and research results on levels identified in human milk, and the strategies used to examine these levels.

Section snippets

Metabolic functions attributed to nucleotides

Nucleotides have been identified as important participants in numerous metabolic functions; as major components of RNA and DNA, the mediation of energy metabolism, signal transduction, and general regulation of cell growth.33 Other examples include participation in lipoprotein metabolism, enhanced high-density lipoprotein (HDL) plasma concentration, as well as enhanced synthesis of apolipoprotein (Apo) A1 and Apo A1V in preterm infants, and an upregulation of long-chain polyunsaturated fatty

Levels in human milk, unsupplemented and supplemented formulas

As stated above, nucleotides (NT) and nucleosides (NS) were characterized in human milk by high-performance liquid chromatography (HPLC) methods; however, no NS and only small amounts of NT were found in bovine milk and cow-milk-based formula.43 Studies examining all sources of NT in human milk revealed that traditional measurements of the free NT content underestimates the total amount available to the infant by approximately 50%.44, 45 These investigators examined human milk from American,

Evaluating clinical outcomes in nutritional studies

The assessment of immune outcome measures and of infectious disease incidence has been used in various studies evaluating nutritional intervention.50, 51 Some of the approaches outlined in these reviews have been employed repeatedly in studies to explore the biological activities of NT and are summarized below.

Decreased susceptibility to infection is generally accepted as being linked to improved immune function. Enhanced resistance to infection is therefore assumed to be associated with

Human clinical studies evaluating nucleotides in infant formulas

The effects of free NT supplementation at levels of 12–33 mg/L were evaluated in full-term (five studies) and premature (two studies) infants receiving cow-milk-based infant formula; the effects of TPAN levels were evaluated in full-term infants receiving cow-milk-based formula (four studies) and soy formula (one study) (Table 1, Table 2).

Summary of the evidence

This review presents an overview of most relevant studies describing the effects of NT supplementation to formulas for full-term and premature infants. In brief, studies to date show that the addition of NT to infant formula provides an immunologic benefit not provided in unsupplemented formulas and resulting in some outcome measures similar to those provided by human milk feeding. Analytical methods used by Leach et al.44 measured all forms and sources of ribonucleic acids in human milk that

Acknowledgments

The authors gratefully acknowledge the critical review and most helpful suggestions by Russell J. Merritt MD, PhD; Pedro A. Prieto, PhD; Jeffrey H. Baxter, PhD; James L. Leach; and Debra L. Thomas during the preparation of the manuscript.

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