Human Milk Oligosaccharides

Discuss about the case for and against the supplementation of infant formula.

Infant formulas are used to refer to manufactured goods that are designed and subsequently marketed for feeding infants under 12 months age. The basic advantage of such infant formula is providing all infants with essential nutrients that are imperative for growth and development. This in turn enhances their health and overall wellbeing. Whey and casein are the two primary proteins that are present in cow milk, and are thought to get easily digested than other formula types (11). The human milk is primarily composed of carbohydrates, of which oligosaccharides form the third most abundant element. The enzymes glycosyltransferases are thought to be responsible for assembling the carbohydrate structures (20).

The basic function ofoligosaccharides and glycoconjugates are associated with protecting the babies and infants, by preventing the binding of entero-pathogen to the host receptors (12). Thus, in an attempt to deliver similar health benefits to infants who feed on formula milk, several companies have begun supplementing the infant formulas with these oligosaccharides, for their potential immunomodulatory and prebiotic effects. This report will focus on the role of oligosaccharides on infant wellness and health and will illustrate the associated side effects as well.

Role of oligosachharides in infant health and wellness

Human milk oligosaccharides (HMOs) are considered as a family of unconjugated glycans that are structurally diverse and commonly found in human breast milk. However, they are actually not easily digested by human infants. These oligosaccharides act as prebiotic agents and help in establishing commensal microflora that safeguard against pathogens (6). The oligosaccharides had originally been identified in the human milk as ‘bifidus factor’, owing to their bifidogenic effects (17). These HMOs also play the role of anti-adhesives and help in preventing adhesion of these microbial pathogens to the surface of mucosal membranes. Most research evidences focus on the prebiotic effects of oligosaccharides. Most of the prebiotics identified till date are carbohydrates, primarily oligosaccharides. These oligosaccharides resist digestion inside the small intestine and reach the colon. The gut microflora plays an essential role in fermenting the HMOs in the colon (19).  Research evidences indicate that the most oligosaccharides get absorbed in the human bloodstream, which in turn support development of the immune system, beyond the gut in infants (7). This contributes to the fact that infants and babies primarily fed on breast milk develop stronger immune systems.

Prebiotic Effects of Oligosaccharides

Thus, it can be stated that the selection of the feed type plays an essential role in establishing the intestinal flora (2). Although, Streptococcus and Lactobacillus are found in moderate quantities, Bifidobacterium acts as the most abundant microorganism in the intestinal tract of infants who feed on breast milk, rich in oligosaccharides. Oligosaccharides present in breast milk also exert an inhibitiory function on urinogenital tract infection in the infants as well as among mothers. Fermentable oligosaccharides act in the form of dietary fibres (18). These increase the concentration and number of bidfidobacteria present in faecal matter, which in turn has been found to significantly prevent onset of epithelial mucosa atrophy in the colon of infants. Evidence from other studies suggest that HMOs are responsible for reducing cell growth and inducing apoptosis and differentiation in intestinal epithelial cells by making alterations in the cell cycle genes that are involved in growth (1).

Thus, it can be stated that action on oligosaccharides present in human breast milk can directly interact with the intestinal epithelial cells, thereby affecting genetic expression and reprogramming the cell cycle (8). Further research findings also provide evidence for the role of HMOs in influencing maturation of lymphocytes and promoting shifts in T-cell responses towards low level immunity and a balanced production Th1/Th2-cytokine. Other effects of oligosachharides have also been observed on brain development among infants (9). Preterm infants who feed on breast milk have shown superior brain development scores at an age of 18 months (3). They have further demonstrated greater intelligence quotient at the age of 7 years, as seen from research findings. Several researchers have emphasized on the role of Sia-containing gangliosides in modulating cognition and brain development among infants. The HMOs act as a rich source of Sia, the concentrations of which are found to be significantly greater in the brains of infants who depend on breast feeding (4). Thus, it can be stated that oligosaccharides are imperative for the holistic growth and wellness of infants.

Consideration of safety issues and dosage

Although oligosaccharides are considered safe for continuous development, several studies that focused on their short term interventions demonstrated that the total cholesterol level gets lowered by 4% on intake of fermented yoghurt (14). A decrease in cholesterol levels are often accompanied by a decrease in weight as well. Most infant formula is rich in fructo- and galacto-oligosaccharides. Evidences from research suggest that when administered at a dosage of more than 15 grams each day, these oligosaccharides are responsible for causing flatulence and intestinal noises (12). In addition to formation of intestinal gas, administration of these oligosaccharides at higher rates is also responsible for causing cramps in the stomach, bloating and diarrhea. Mild doses of oligosaccharides are generally considered at around 10 grams per day. While stronger evidences exist that support the use of oligosaccharides in fostering colony growth Bifidobactoerium, there are some studies that hint at possible correlation between these carbohydrates and their role as food source for less desirable bacterial strains (16).

Importance of Oligosaccharides for Infant Wellness

Other concerns are associated with fermentation of these oligosaccharides. The process of fermentation yields several byproducts such as, carbon dioxide and hydrogen, which cause uncomfortable symptoms among individuals. There are other issues related to intake of formula milk that violates the safety of infants (9). These side effects are associated with increased likelihood of developing pneumonia and ear infections. Formula feeding that contains oligosaccharides has also been linked to higher susceptibility to type 1 diabetes and inflammatory bowel disorders. Higher risk is also observed with respect to the incidence of hypersensitive reactions, asthma, childhood obesity and cancer (10). Therefore, a total amount of 8-10 grams of oligosaccharides is best suitable for formula milk. Thus, there is a need to adjust the dosage of these compounds in order to reduce the severity of adverse symptoms.

Support for infant formula supplementation

A multicenter, randomized, double-blind trial was conducted among 2 parallel groups that comprised of infants who were fed with formula milk. The trial recruited infants aged ≤ 14 days. A permuted block algorithm was used in conjunction with the Medidata Balance for carrying out randomization. The parents, investigators and study staff were blinded to the study. The control formula contained intact cow’s milk– based whey protein with long-chain polyunsaturated fatty acids (1.8 g protein/100 kcal with a whey:casein ratio of 70%:30%; 67 kcal/100 mL reconstituted formula). On the other hand, the test formula additionally contained 2 HMOs that provided 0.5 g LNnT and 1.0 g 2’ FL per liter of the reconstituted formula. The methodology included safe distribution of the control and test formulas during the study visits till the infants reached the age of 6 months, following which their feeding habit was changed to intact cow’s milk based protein that did not contain HMOs. Analysis of the primary outcomes showed a mean weight gain of 29.84 (0.60) g/day for the sample and 30.15 (0.58) g/day for the control. No differences were observed in terms of adverse effects that include, vomiting, flatulence and stool proportion. Furthermore, the test group reported lesser number of colic (4%) than the control group (26%). The sample group also manifested less frequency of night-time awakenings and lower rates of allergy when compared to the control group. Thus, the RCT was able to provide evidence for the fact that formula milk supplemented with 2’ FL and LNnT are well tolerated and safe for infants (15).

Similar findings were supported by another double-blind, randomized, parallel and placebo-controlled trialthat demonstrated the efficacy of oligofructose and inulin supplemented infant formula. 252 formula fed infants aged below 4 weeks were randomized into 2 groups, where they received SYN1-supplemented formula milk (128) and controlled formula (124). A statistical analysis of the primary and secondary outcomes showed higher proportion of Bifidobacterium in the sample group (p < 0.05). The SYN1 gripu demonstrated a greater stool frequency, which was further established by linear regression analysis and models. Although, the trial failed to provide significant differences for anthropometric parameters and infection rates, K⁺ and urea concentration was found lower in the sample group. In addition, there were no differences in terms of digestive discomfort or regurgitation. Thus, the study showed congruency with the previous findings and suggested that oligofructose supplemented infant formula is safe and effective in promoting healthy gut microbial, similar to breastfeeding (5).

Safety and Side Effects of Oligosaccharides in Formula Milk

Arguments against infant formula supplementation

Growth is an major challenge faced by low birth weight and premature infants (born < 37 weeks gestation period). The Cochran methodology was followed for conduction of a systematic review that evaluated the effects of probiotic and prebiotic infant formula in the target population. The review included all randomized controlled trial, regardless of their language of publication and analysed the effects of formula milk on weight gain, linear growth, head growth, sepsis, infections and other health complications. A total of 13 articles were selected for the purpose. No statistically significant weight gains were demonstrated between probiotic and control groups from the studies. Furthermore, only 1 study reported linear growth as a primary outcome, but failed to find any significant difference in gain of length (p=0.124). Similar findings were observed during analysis of head growth between the probiotic and control groups (p=0.124). An evaluation of the secondary outcomes showed that probiotic administration failed to reduce NEC risks (RR 0.42, 95% CI: 0.15 to 1.16) and sepsis (RR 0.40, 95% CI: 0.11 to 1.45) when compared to the control. Furthermore, no significant reduction in mortality risk was observed due to probiotic supplementation (RR 0.33, 95% CI: 0.04 to 2.85). Similar to the aforementioned findings, infant formula also did not demonstrate any clinically relevant results with respect to count of Bifidobacteria, Lactobacillus and other pathogens. In addition, comparison of primary and secondary outcomes from prebiotic groups and control also showed similar results and were unable to demonstrate any beneficial effects of the infant formula (except count of Bifidobacteria and other pathogens). Thus, the review did not support the routine supplementation of formula milk with pre- and probiotics (11).

Another randomized controlled trial evaluated the effects of acidic and non-human neutral oligosaccharides on infectious and allergic diseases. The trial recruited 113 preterm infants (gestational age <32 weeks) and randomized them to receive placebo or oligosaccharide supplementation during 3-30 days of their lives. An analysis of the responses to the provided questionnaires suggested no significant effect of the supplementation on incidence of infectious or allergic diseases among the infants. While the rate of atropic dermatitis was 7/48 infants belonging to the sample group (15%), it was found among 8/43 individuals in the control group (19%). Furthermore, no significant improvements were observed in the rates of serious infection (38%), endogenous infection (13%), antibiotic use (73%), and mechanical ventilation (52%) during the neonatal period. Thus, the trial suggested that oligosaccharide supplementation did not decrease incidence of infectious and allergic diseases during the first year of their life (13).

Thus, it can be stated that infant nutrition is an essential aspect that holds relevance in overall health and development of children. Harmful food components and unbalanced diets are often responsible for inducing high risks that create adverse impacts on their health. Infant formula can therefore be used as food due to their suitability as a substitute for human milk. Probiotics and prebiotics are considered as the primary ingredients of formula milk. Prebiotics contain oligosaccharides that play an important role in governing the colonization of microflora in the gut of infants. Although, recent studies show that oligosachharide supplementation do not exert any beneficial effects on infant growth and prevention of infectious diseases, and infants are at an increased risk of developing dehydration, supplementation at measured dosage (8gm) is still recommended for production of an infant formulae. This recommendation can be attributed to the fact that oligosaccharides have shown several beneficial effects on the target population

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