Clinical Interventions with HMOs in Infancy

Human milk oligosaccharides (HMO) are abundant in human milk (5-20 g/L) (1) and exert numerous beneficial effects (2-4). The two predominant HMO are lacto-N-tetraose (LNT) and 2´-fucosyllactose (2´-FL), although 2´-FL presence depends upon maternal secretor type (1). Bovine milk oligosaccharide content and composition are lower and less complex (5), thus infant formulae are nearly devoid of oligosaccharides (6). Most contain prebiotics, but large scale production has enabled the recent addition of 2´-FL and LNnT to formula (6). Note that LNT type 1 and LNnT type 2 cores differ, which affects their recognition (7) and utilization (8), thus their functionality is likely not identical.

Two randomized clinical trials have investigated adding HMO to formula (9, 10). In the first, infants were fed control formula (CF) or formula containing 0.2 or 1.0 g/L 2´-FL for the first 4 months of life and were compared to a breast-fed (BF) reference (9). All formulae also contained galactooligosaccharides, which was reduced in the 2´-FL formulae to maintain a total oligosaccharide content of 2.4 g/L. Growth, stool consistency or adverse events were similar across treatments (9). Immune outcomes were assessed in these infants using blood samples collected on day of life 42 (11).

Infants fed the 2´-FL formulae did not differ from BF, but had 29 to 83% lower plasma proinflammatory cytokine concentrations than CF-fed infants. In terms of immune cells, BF infants had higher total T-cell and cytotoxic (CD8+) T-cells than CF-fed infants. Total T-cells in infants fed 2´-FL were intermediate between BF and CF, and CD8+ T cells in infants fed 1.0 g/L 2´-FL were intermediate between BF and CF (11).

In the second study, infants received a CF or a formula with 1.0 g/L 2´-FL and 0.5 g/L LNnT for 6 months, after which all were fed the CF until 12 months of age (10). Weight gain and digestive symptoms were similar in both groups, except infants fed HMO had softer stool and fewer nighttime wake-ups at 2 months. Secondary outcomes showed that consuming HMO-supplemented formula reduced parent- reported morbidity (particularly bronchitis) and antipyretics and antibiotics use (10). In addition, the HMO formula shifted the microbiome composition to be more similar to that of BF and increased Bifidobacterium abundance (12). Taken together, supplementing formula with 2´-FL or 2´-FL+LNnT affected infant immunity, reduced infection and medication use, and increased bifidobacteria abundance, thus narrowing the gap between breast-and formula-fed infants.
 

References

1. Thurl S, Munzert M, Boehm G, Matthews C, Stahl B. Systematic review of the concentrations of oligosaccharides in human milk. Nutr Rev. 2017; 75:920-933.
2. Musilova S, Rada V, Vlkova E, Bunesova V. Beneficial effects of human milk oligosaccharides on gut microbiota. Benef Microbes. 2014; 5:273-283.
3. Donovan SM, Comstock SS. Human milk oligosaccharides influence neonatal mucosal and systemic immunity. Ann Nutr Metab. 2016;69  Suppl 2:42-51 
4. Mudd AT,  Fleming    SA, Labhart B, Chichlowski M, Berg BM, Donovan SM, Dilger RN. Dietary sialyllactose influences sialic acid concentrations in the prefrontal cortex and magnetic resonance imaging measures in corpus callosum of young pigs. Nutrients. 2017;9(12). pii: E1297. doi: 10.3390/nu9121297.
5. Zivkovic AM, Barile D. Bovine milk as a source of functional oligosaccharides for improving human health. Adv Nutr. 2011; 2:284-9.
6. Nijman RM, Liu Y, Bunyatratchata A, Smilowitz JT, Stahl B, Barile D. Characterization and quantification of oligosaccharides in human milk and infant formula. J Agric Food Chem. 2018; 66:6851-6859
7. Bohari MH, Yu X, Zick Y, Blanchard H. Structure-based rationale for differential recognition of lacto- and neolacto- series glycosphingolipids by the N-terminal domain of human galectin-8. Sci Rep. 6: 39556. doi: 10.1038/srep39556
8. Özcan E, Sela DA. Inefficient metabolism of the human milk oligosaccharides Lacto-N-tetraose and Lacto-N-neotetraose shifts Bifidobacterium longum subsp. infantis physiology. Front Nutr. 2018; 5:46. doi: 10.3389/fnut.2018.00046
9. Marriage BJ, Buck RH, Goehring KC, Oliver JS, Williams JA. Infants fed a lower calorie formula with 2’FL show growth and 2’FL uptake like breast-fed infants. J Pediatr Gastroenterol Nutr. 2015; 61:649-658.
10. Puccio G, Alliet P, Cajozzo C, Janssens E, Corsello G, Sprenger N, Wernimont S, Egli D, Gosoniu L, Steenhout P. Effects of infant formula with human milk oligosaccharides on growth and morbidity: A randomized multicenter trial. J Pediatr Gastroenterol Nutr. 2017; 64:624-631.
11.Goehring KC, Marriage BJ, Oliver JS, Wilder JA, Barrett EG, Buck RH. Similar to those who are breastfed, infants fed a formula containing 2’-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. J Nutr. 2016; 146:2559-2566.
12. Steenhout Ph, Sperisen P, Martin F-P, Sprenger N, Wernimont S, Pequet S, Berger B. Term infant formula supplemented with human milk oligosaccharides (2’Fucosyllactose and Lacto-N-neotetraose) shifts stool microbiota and metabolic signatures closer to that of breastfed infants. FASEB J. 2016; 30:275.7.