Nucleotide-fortified Formulas Can Boost Neonate Immunity, Gastrointestinal Tract Maturation

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.


January 2011

Human breast milk is the gold standard by which all other sources of infant nutrition are compared. Amongst its many advantages, it offers considerable immune bene?ts to the newborn baby’s immature immune system. To meet the environmental challenges that occur after birth, an infant’s immune system must develop rapidly during the ?rst 2 years of life.

Human milk contains a variety of natural compounds that help the development of the infant’s immune system. Nucleotides are one of the immunomodulating factors found in human milk. They serve as building blocks of DNA and RNA for cells in the body, including important immune system cells. According to Schlimme et al. (Br J Nutr 2000;84 (suppl 1):S59-S68), nucleotides are involved in essential metabolic reactions in cells. This is particularly important for the gut, where cell turnover is high and nucleotides are constantly required in the formation of these new cells. Furthermore, it is important to note that the gut plays a key role in the immune system. Approximately 70%-85% of the body’s immune system is located there.

Rapidly growing infants need nucleotides for protein synthesis and cell growth. Nucleotide requirements are met by a combination of de novo synthesis, salvage (from endogenous sources) and from the diet. During periods of additional demand—rapid growth or illness, for example—infants may not be able to synthesize or salvage enough nucleotides and dietary nucleotide sources may be necessary to supplement nucleotide synthesis (Carver JD. Acta Paediatr 1999;88(suppl 430):83-8).

In a meta-analysis of nucleotide-supplemented infant formula, Gutiérrez-Castrellón et al. (Br J Nutr 2007;98 (suppl 1):S64-S67) reviewed available evidence to establish the ef?cacy, safety and dose-response effect of nucleotide- supplemented infant formula. Nine studies were included in the analysis which showed that nucleotide-forti?ed formulas were associated with better antibody responses to immunization with Haemophilus in?uenzae type b (Hib) vaccine, diphtheria toxin and oral polio vaccine (OPV) compared to formula without nucleotides (control formula). Nucleotide-forti?ed formulas were also associated with fewer episodes of diarrhea than control formula. Moreover, they report considerably greater effects for the selected end points as well as signi?cantly larger clinical and statistical differences in the infants who received formulas with a higher level of supplementation. Consequently, they concluded that while the evidence supports the supplementation of formula at levels of at least 33 mg/L, “It is important to note that 50% of the evidence from studies with formula supplemented with 72 mg/L show greater effects on end point variables.”

Although nucleotides have been added to infant formula since 1997, most Canadian infant formula companies supplement only up to 28 mg/L. The only brand of infant formula with a higher level of nucleotide supplementation is Similac, providing 72 mg/L.

Immune Status

Schaller et al. (Pediatr Res 2004;56:883-90) speci?cally analyzed the effect of supplemental nucleotides on infant immune status as measured by antibody responses to routine infant immunizations. A cohort of human milk-fed infants was also included. Infants received Hib vaccine, diphtheria tetanus acellular pertussis (DTaP) vaccine and OPV at 2, 4 and 6 months of age and antibody responses were assessed at 2, 6, 7 and 12 months.

Results indicated that infants who received the formula supplemented with nucleotides had signi?cantly higher OPV type 1 neutralizing antibody (PV-VN1) responses than infants who received the same formula minus the nucleotides. Indeed, PV-VN1 responses in infants fed human milk were not different from infants who were fed the nucleotide-forti?ed formula.

In contrast, PV-VN1 responses were signi?cantly higher at 6 months among infants who were fed human milk than among those who received the unforti?ed formula. However, responses to Hib, diphtheria, tetanus toxoid, OPV-speci?c IgA and PV-VN3 were not signi?cantly different among infants fed the nucleotide-forti?ed formula than responses seen in either the human milk-fed infants or those fed the unforti?ed formulation, even though there was a trend towards increased Hib and diphtheria antibody response among the nucleotide group.

In summary, the group fed formula forti?ed with nucleotides at 72 mg/L had higher antibody responses following 3 doses of oral poliovirus vaccine compared to the control group and, statistically, the levels were not different from that of the breast-fed infants.

Additionally, growth measures were similar between the 2 formula-fed groups and both showed comparable growth to infants fed human milk.

Immune Function, Diarrhea, Birth Weight

The same infant cohorts were also investigated by Buck et al. (Pediatr Res 2004;56:891-900), who sought to determine whether dietary nucleotides altered immune cell phenotypes or function in the ?rst year of life. They concluded that nucleotide-associated increases in memory/effector T-cell populations as well as changes in natural kill (NK) cell subtypes observed in the nucleotide group provide evidence that infant formula supplemented with levels of nucleotides similar to levels in human milk may facilitate maturation and immunoregulatory shifts in some lymphocyte populations consistent with those seen in human milk-fed infants. “These shifts might support increased antibody responses and immune cell protection,” they added, “while the nucleotide-associated changes in immunoregulatory NK cell subsets may also enhance innate immune responses against tumours and/or intracellular pathogens.” Their research showed that infants fed formula supplemented with nucleotides at 72 mg/L had immune cell pro?les that more closely resembled those of babies fed human milk compared to infants fed formula without nucleotides.

Yau et al. (J Pediatr Gastroenterol Nutr 2003;36:37-43) similarly randomized infants between 1 and 7 days old to receive a formula forti?ed with 72 mg/L nucleotides or a control formula without nucleotides. At 48 weeks of age, investigators found that serum IgA concentrations—a component of humoral immunity—had increased in both groups; however, at every subsequent measurement, serum IgA concentrations were higher in infants fed the nucleotide-forti?ed formula than in controls. The risk of diarrhea was also about 25% lower among infants fed the nucleotide-forti?ed formula and stools were more frequent and softer than those of control infants. Softer stools are characteristic of breast-fed infants and are therefore desirable.

As observed in a different analysis (Yu V. J Paediatr Child Health 2002;38:543-9), the number of ?rst episodes of diarrhea was found to be signi?cantly lower in another group of infants fed a nucleotide-supplemented formula compared to those who were fed a non-supplemented formula, although no signi?cant differences were found in the presence or type of enteropathogens between the 2 groups.

Carver (Acta Paediatr 1999) noted that an infant recovering from diarrhea requires nucleotides to replace intestinal mucosal cells and to maintain normal growth; as such, they may bene?t from supplemental nucleotides in a period of high demand.


Nucleotides are increasingly considered by nutrition experts to be “conditionally essential,” in that they may become essential when the endogenous supply is insuf?cient to meet elevated demands. Under conditions of rapid growth, for example, dietary nucleotides may optimize the function of rapidly dividing cells, including cells in the GI tract and the immune system. Given that no adverse effects have been reported in healthy infants fed nucleotide-supplemented formulas, these have the potential to offer tangible health bene?ts for young infants.

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