News article

Role of Nutrition in Immune-Modulation of Healthy and Compromised Infants

Posted:  Friday, November 22, 2013

Gabriel M Anabwani, MBCH, MMed, FRCPE

Botswana-Baylor Children’s Clinical Centre of Excellence

Nutrition may modulate the immune system of both health and compromised infants. A number of factors may play a role, including, milk, breasfeeding, enteral feeding, prebiotics, and probiotics. A summary of indicative studies and some key conclusions follows.

Human Milk
We now understand from a number of studies on human infants, other species and in vitro models that milk and especially human milk is more than just a basic source of nutrition for infants. In his review Goldman1 (1)reports that there are various bioactive components in milk which influence the immune status of infants by providing protection while at the same time they facilitate development, tolerance, and appropriate inflammatory responses. Looking at the evidence from an evolutionary perspective, Goldman hypothesises that milk plays a critical link between the maternal immune system and the infant such that it actively directs and educates the immune, metabolic, and micro flora systems within the infant and provides multiple means of protection from pathogens.

In their study on how human milk modulates the immune system Pickering et al2 carried out a twelve month controlled, randomized, blinded, multisite feeding trial on infants fed using three strategies: an iron-fortified, milk-based control formula (Control); the same formula fortified with nucleotides or human milk exclusively for 2 months and then human milk or Similac with iron until 12 months of age. The level (72 mg/L) and ratio of inpidual nucleotides selected were patterned after those available in human milk. Of the 370 full-term, healthy infants enrolled, 311 completed the study – 107 Control, 101 nucleotide, 103 human milk/Similac with iron. Intake, tolerance and growth were similar in all three groups. However, compared to the control group 1 month after the third immunization (7 months of age), the nucleotide group had significantly higher Hib antibody concentration (geometric mean concentration of 7.24 vs 4.05 µg/mL, respectively, and significantly higher diphtheria antibody concentration (geometric mean of 1.77 vs 1.38 U/mL). The significantly higher Hib antibody response persisted at 12 months. The antibody response to tetanus and oral polio virus (OPV) was not enhanced by nucleotide fortification. There was also an effect of breastfeeding on immune response: infants who breastfed had significantly higher neutraliziang antibody titers to polio virus than either formula-fed group (1:346 vs 1:169 in the control and nucleotide groups, respectively) at 6 months of age.   The authors concluded that infant formula fortified with nucleotides enhanced H influenza type b and diphtheria humoral antibody responses; and that feeding human milk enhanced antibody response to OPV. Thus dietary factors play a role in the antibody response of infants to immunization. 

Annelli Ivarsson et al3 investigated the impact of breast-feeding on the development of celiac disease. Celiac disease or permanent gluten-sensitive enteropathy is an immunologic disease dependent on exposure to wheat gluten or related proteins in rye and barley. The study used a population-based incident case-referent approach among Swedish children in which 627 cases with celiac disease were matched with 1254 controls. 78% of the matched sets were used in the final analysis. A questionnaire was used to assess patterns of food introduction to infants and models were built to explore whether breast-feeding and the mode of introducing dietary gluten influence the risk of celiac disease.  The risk of celiac disease was reduced in children aged <2 years if they were still being breast-fed when dietary gluten was introduced [adjusted odds ratio (OR): 0.59; 95% CI: 0.42, 0.83]. This effect was even more pronounced in infants who continued to be breast-fed after dietary gluten was introduced (OR: 0.36; 95% CI: 0.26, 0.51). The risk was greater when gluten was introuduced in the diet in large amounts (OR: 1.5; 95% CI: 1.1, 2.1) than when introduced in small or medium amounts. In older children, these risk factors were of no or only minor importance.

While our understanding has increased, the jury is still out on the exact role of milk with regard to the immune stem. As Catherine Field4 has concluded after an exhaustive review, human milk is a complex mixture of interacting compounds and the composition differs between women and within the lactation period. Our understanding of the importance of this complex nutritional supplement on immune development, tolerance, and regulation of inflammation is still in its infancy; and this will be a fruitful area of research for nutritionists for many years.

Enteral Feeding
Okada et al5 investigated the effects of the addition of enteral feedings to parenteral nutrition (PN) on the immune status of human newborn infants. Ten surgical infants (age less than 6 months) requiring PN were studied in two consecutive phases: after PN with no enteral feeding and after addition of small volumes of enteral feeding to PN. The outcome of interest was host whole blood bactericidal activity against coagulase-negative staphylococci (CNS). Introduction of small volumes of enteral feed improved the impaired killing of CNS and the abnormal cytokine response observed during total PN – implying that stimulation of the gastrointestinal tract may modulate immune function in neonates and prevent bacterial infection.

Prebiotics are non-digestible food ingredients that stimulate the growth and/or activity of bacteria in the digestive system in ways that may be beneficial.  Arslanoglu et al6 recently carried out a prospective, randomized, placebo controlled trial in which they administered prebiotics (mixture of neutral short chain galacto-oligosaccharides and long chain fructo-oligosaccharides ) to young infants. The primary outcome measure was infectious episodes, number of infections requiring antibiotics and incidence of infections. They demonstrated a significant reduction in the number of infectious episodes and the incidence of recurring infections during the first 6 mo of life. Though the exact mechanism of action is under investigation, it is very likely that the immune modulating effect of this prebiotic mixture through intestinal flora modification is the principal mechanism for the observed infection prevention early in life.

Probiotics are live bacteria that may confer a health benefit on the host. Lactic acid bacteria in food can transiently colonize the intestine and exert beneficial effects (probiotic). In their study Schiffrin et al7 pided 28 healthy volunteers in two groups and gave them a fermented product containing one of the two strains (Lactobacillus acidophilus strain La1 or Bifidobacterium bifidum strain Bb12. Lymphocyte subsets and leukocyte phagocytic activity were studied in blood. No modifications were detected in lymphocytes subsets. In contrast, phagocytosis of Escherichia coli ssp was enhanced in both groups (p<0.001 for both). They concluded that antiinfective mechanisms of defense can be enhanced after ingestion of specific lactic acid bacteria strains. ; and hypothesize that contact with immune cells - survival during intestinal transit or adhesion to epithelium or both - seem to be important for modifying the host's immune reactivity.

On May 1, 2010 — during the Pediatric Academic Societies (PAS) annual meeting in Vancouver, British Columbia, Canada, Al-Hosni8 provided further evidence of the benefits of probiotics among extremely low birthweight infants (ELBW) who received feedings supplemented with probiotics.  In their randomized, controlled, double-blind study 50 infants received 500 million colony-forming units (CFU) of Lactobacillus rhamnosus GG and 500 million CFU of Bifidobacterium infantis in enteral feedings once a day until discharge or 34 weeks postmenstrual age; and 51 infants received feedings with no probiotics. There were no significant differences in complications of prematurity such as sepsis or necrotizing enterocolitis. ELBW who received feedings supplemented with probiotics had better weight gain than infants who were not given the supplements. The findings strongly suggest that probiotic supplementation to enteral feedings plays a major role in feeding tolerance and nutrient absorption.

Malnutrition and HIV
Irrespective of cause, malnutrition can have adverse, even devastating effects on the antigen-specific arms of the immune system and on generalized host defensive mechanisms.9Thus, protein energy malnutrition and or deficiencies of single nutrients that assist in nucleic acid metabolism generally lead to atrophy of lymphoid tissues and dysfunctions of cell-mediated immunity. Deficiencies of single nutrients can impair production of key proteins. Essential fatty acid deficiencies can reduce or perturb the synthesis of cytokine-induced eicosanoids. Arginine deficiency can diminish the production of nitric oxide, and deficiencies of antioxidant nutrients can allow increases in the damaging effects of free oxygen radicals.  Immunological dysfunctions associated with malnutrition have been termed Nutritionally Acquired Immune Deficiency Syndromes (NAIDS). Infants and small children are at great risk because they possess immature, inexperienced immune systems and very small protein reserves; and also because they are still growing and developing.

Arguably, HIV has become the most important public health problem in Sub-Saharan Africa. HIV is a retrovirus that causes a cytokine driven hyper-metabolic disease that is associated with progressive immune depletion due to damage and depletion of CD4+ve T-lymphocytes. Immune depletion in turn leads to opportunistic infections which cause an increase in resting metabolic rate. The fever that accompanies these infections cause a 12 % increase in energy needs for every one degree increase of fever (centigrade). HIV infection causes a broad spectrum of disease and has a varied clinical course. AIDS represents the most severe end of spectrum. Gastrointestinal manifestations of HIV and AIDS include diarrhea, nausea, vomiting, loss of appetite, mal-absorption and oral and oesophageal ulcers. Younger children are prone to neurological manifestations that may lead to altered food taste and delayed feeding skills or swallowing difficulties. In turn, decreased intake of nutrients coupled with increased energy consumption and nutrient loss, lead to malnutrition. 

Thus AIDS and NAIDS are intensely synergistic. AIDS-induced malnutrition can lead to the secondary development of NAIDS, with its much broader array of additional immunological dysfunctions. The complex and far reaching insults to the immune system caused by NAIDS, and the synergistic combination of NAIDS and AIDS, thereby hasten disease progression to death.

This brief review attests to the view that while our understanding of the ramifications of nutrition and immune modulation in infants is itself “infantile,” the key players include: human milk; enteral feeding; malnutrition (both macro and micronutrient); prebiotics; probiotics; and HIV/AIDS.

Armond S Goldman. Modulation of the Gastrointestinal Tract of Infants by Human Milk. Interfaces and Interactions. An Evolutionary Perspective. Journal of Nutrition. 2000; 130:426S-431S.

Larry K Pickering, Dan M Granoff, Julie Reed Erickson, Marc L Masor, Christopher T Cordle, Joseph P Schaller, Timothy R Winship, Charles L Paule and Milo D Hitty. Modulation of the Immune System by Human Milk and Infant Forumula Containing Nucleotides. Pediatrics Vol. 101 No. 2 February 1998, pp. 242-249

Anneli Ivarsson, Olle Hernel, Hans Stenlund and Lars A Persson. Breastfeeding protects against celiac disease. American Journal of Clinical Nutrition, vol 75, No. 5, 914-921, May 2002.

Catherine J Field. Recent Advances in Nutritional Sciences. The Immunologic Components of Human Milk and Their Effect on Immune Development in Infants. J Nutr. 135:1-4, Jan 2005.

Yasuhiro Okada, Nigel Klein, HKF van Saene and Agostino Pierro. Small Volumes of enteral feedings normalise immune function in infants receiving parenteral nutrition. Journal of Pediatric Surgery, Vol 33 (1), p16-19; 1998.

Sertac Arslanoglu, Guido E Moro and Gunther Boehm.Early Supplementation of Prebiotic Oligosaccharides Protects Formula-Fed Infants against Infections during the First 6 Months of Life. J. Nutr. 137:2420-2424, November 2007.

EJ Schiffrin, D Brassart, AL Servin, F Rochat and A Donnet-Hughes. Immune modulation on blood leukocytes in humans by lactic acid bacteria: criteria for strain selection. American Journal of Clinical Nutrition, Vol 66, 515S-520S, 1997. Accessed 24 June 2013.

Susanna Cunningham-Rundles, David F McNeeley, and Aeri Moon. Mechanisms of nutrient modulation of the immune response. The Journal of Allergy and Clinical Immunology, Vol 115 (6) P1119-1128 (June 2005).