How gut health ingredients can support immunity via the microbiota

Galacto-oligosaccharides (GOS) and the human milk oligosaccharides (HMOs*) 2’-Fucosyllactose (2’-FL), Lacto-N-tetraose (LNT) and 3-Fucosyllactose (3-FL) have been shown to stimulate the growth of Bifidobacteria in the infant gut by serving as a substrate ¹⁵⁶Watson D, O’Connell Motherway M, Schoterman MHC, van Neerven RJJ, Nauta A, Van Sinderen D. Selective carbohydrate utilization by lactobacilli and bifidobacteria. J Appl Microbiol. Published online 2013. doi:10.1111/jam.12105  ¹⁶⁸Yu ZT, Chen C, Kling DE, et al. The principal fucosylated oligosaccharides of human milk exhibit prebiotic properties on cultured infant microbiota. Glycobiology. Published online 2013. doi:10.1093/glycob/cws138  ¹³⁰Salli K, Hirvonen J, Siitonen J, Ahonen I, Anglenius H, Maukonen J. Selective Utilization of the Human Milk Oligosaccharides 2′-Fucosyllactose, 3-Fucosyllactose, and Difucosyllactose by Various Probiotic and Pathogenic Bacteria. J Agric Food Chem. Published online 2021. doi:10.1021/acs.jafc.0c06041  ⁷Asakuma S, Hatakeyama E, Urashima T, et al. Physiology of consumption of human milk oligosaccharides by infant gut-associated ifidobacterial. J Biol Chem. Published online 2011. Doi:10.1074/jbc.M111.248138 . Upon fermentation of oligosaccharides, Bifidobacteria produce metabolites such as short-chain fatty acids (SCFAs), which lower the gut pH, thereby promoting the further growth of beneficial bacteria ¹⁰Ben, X.-M. et al. Low level of galacto-oligosaccharide in infant formula stimulates growth of intestinal Bifidobacteria and Lactobacilli. World J. Gastroenterol. 14, 6564 (2008) . Such environmental conditions in the gut also help to crowd out potentially pathogenic bacteria through competitive advantage ¹³⁰Salli K, Hirvonen J, Siitonen J, Ahonen I, Anglenius H, Maukonen J. Selective Utilization of the Human Milk Oligosaccharides 2′-Fucosyllactose, 3-Fucosyllactose, and Difucosyllactose by Various Probiotic and Pathogenic Bacteria. J Agric Food Chem. Published online 2021. doi:10.1021/acs.jafc.0c06041  ⁷Asakuma S, Hatakeyama E, Urashima T, et al. Physiology of consumption of human milk oligosaccharides by infant gut-associated ifidobacterial. J Biol Chem. Published online 2011. Doi:10.1074/jbc.M111.248138  ¹¹Berger B, Porta N, Foata F, et al. Linking human milk oligosaccharides, infant fecal community types, and later risk to require antibiotics. Mbio. Published online 2020. Doi:10.1128/mBio.03196-19 .

These underlying mechanisms of action have been connected with specific infant health outcomes: studies of babies nourished with formula containing GOS found a reduced incidence of infections ⁶Arslanoglu S, Moro GE, Boehm G. Early supplementation of prebiotic oligosaccharides protects formula-fed infants against infections during the first 6 months of life. J Nutr. Published online 2007. doi:10.1093/jn/137.11.2420  ¹²⁵Ranucci G, Buccigrossi V, Borgia E, et al. Galacto-oligosaccharide/polidextrose enriched formula protects against respiratory infections in infants at high risk of atopy: A randomized clinical trial. Nutrients. Published online 2018. doi:10.3390/nu10030286 . And in a study on formula containing 2’-FL and LNnT (Lacto-N-neotetraose), an association was found between gut microbiota communities high in Bifidobacteriaceae and a decreased risk of requiring antibiotics ¹³⁰Salli K, Hirvonen J, Siitonen J, Ahonen I, Anglenius H, Maukonen J. Selective Utilization of the Human Milk Oligosaccharides 2′-Fucosyllactose, 3-Fucosyllactose, and Difucosyllactose by Various Probiotic and Pathogenic Bacteria. J Agric Food Chem. Published online 2021. doi:10.1021/acs.jafc.0c06041 .

Supporting immunity beyond the microbiota

Microbiota-independent immune-supporting effects have also been reported for ingredients like lactoferrin, milk fat globule membrane (MFGM), 2’-FL and polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and arachidonic acid (ARA).

• Lactoferrin, a natural iron-binding milk glycoprotein, has been found to help the development and maturation of the gut during early life ⁹⁴Manzoni, P., Dall’Agnola, A., Tomé, D., Kaufman, D. A., Tavella, E., Pieretto, M., Messina, A., De Luca, D., Bellaiche, M., Mosca, A., Piloquet, H., Simeoni, U., Picaud, J. C., & Del Vecchio, A. (2018). Role of Lactoferrin in Neonates and Infants: An Update. American Journal of Perinatology, 35(6), 561–565. https://doi.org/10.1055/s-0038-1639359. It has been shown to reduce the risk of gut- and respiratory tract infections ¹⁷²Zavaleta, N., Kvistgaard, A. S., Graverholt, G., Respicio, G., Guija, H., Valencia, N., & Lönnerdal, B. (2011). Efficacy of a Complementary Food Enriched with a Milk Fat Globule Membrane Protein Fraction on Diarrhea, Anemia and Micronutrient Status in Infants. Journal of Pediatric Gastroenterology and Nutrition. https://doi.org/10.1097/MPG.0b013e318225cdaf  ¹⁴³Timby, N., Hernell, O., Vaarala, O., Melin, M., Lönnerdal, B., & Domellöf, M. (2015). Infections in infants fed formula supplemented with bovine milk fat globule membranes. Journal of Pediatric Gastroenterology and Nutrition. https://doi.org/10.1097/MPG.0000000000000624  ³⁵Li, F., Wu, S. S., Berseth, C. L., Harris, C. L., Richards, J. D., Wampler, J. L., Zhuang, W., Cleghorn, G., Rudolph, C. D., Liu, B., Shaddy, D. J., & Colombo, J. (2019). Improved Neurodevelopmental Outcomes Associated with Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula: A Randomized, Controlled Trial. Journal of Pediatrics. https://doi.org/10.1016/j.jpeds.2019.08.030 , presumably via multiple mechanisms of action: by binding iron, which is essential for viability of several pathogens; by directly inactivating pathogens; by blocking receptors for pathogens on epithelial cells; and by immuno-modulatory effects via direct interactions with gut epithelial cells and immune cells ⁷⁸Kell, D. B., Heyden, E. L., & Pretorius, E. (2020). The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria. Frontiers in Immunology, 11, 1221. https://doi.org/10.3390/molecules20069703 .
• Consisting of phospholipids, cholesterol and glycoproteins, the tri-layered membrane surrounding milk fat droplets in human and bovine milk is known as the MFGM. Whey-based MFGM ingredients have been shown to support immune function: a reduced prevalence of diarrhoea ¹⁷²Zavaleta, N., Kvistgaard, A. S., Graverholt, G., Respicio, G., Guija, H., Valencia, N., & Lönnerdal, B. (2011). Efficacy of a Complementary Food Enriched with a Milk Fat Globule Membrane Protein Fraction on Diarrhea, Anemia and Micronutrient Status in Infants. Journal of Pediatric Gastroenterology and Nutrition. https://doi.org/10.1097/MPG.0b013e318225cdaf  and reduced episodes of middle ear infection ¹⁴³Timby, N., Hernell, O., Vaarala, O., Melin, M., Lönnerdal, B., & Domellöf, M. (2015). Infections in infants fed formula supplemented with bovine milk fat globule membranes. Journal of Pediatric Gastroenterology and Nutrition. https://doi.org/10.1097/MPG.0000000000000624  were observed in clinical trials studying infants. As a combination, lactoferrin and MFGM supplementation resulted in a lower incidence of upper respiratory tract infections and diarrhoea ³⁵Li, F., Wu, S. S., Berseth, C. L., Harris, C. L., Richards, J. D., Wampler, J. L., Zhuang, W., Cleghorn, G., Rudolph, C. D., Liu, B., Shaddy, D. J., & Colombo, J. (2019). Improved Neurodevelopmental Outcomes Associated with Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula: A Randomized, Controlled Trial. Journal of Pediatrics. https://doi.org/10.1016/j.jpeds.2019.08.030 .
• A good immune response against pathogens that adhere to, and pass through the intestinal barrier and cause infections, is of key interest for infant immune health.2’-FL can serve as a decoy receptor ¹⁶Bode, L. (2012). Human milk oligosaccharides: Every baby needs a sugar mama. In Glycobiology. https://doi.org/10.1093/glycob/cws074  and inhibits in vitro binding of viral and bacterial pathogens associated with childhood diarrhoea, like norovirus, rotavirus and ETEC ⁸⁵Laucirica, D. R., Triantis, V., Schoemaker, R., Estes, M. K., & Ramani, S. (2017). Milk Oligosaccharides Inhibit Human Rotavirus Infectivity in MA104 Cells. Journal of Nutrition, 147(9), 1709–1714.  ¹⁵⁷Weichert, S., Jennewein, S., Hüfner, E., Weiss, C., Borkowski, J., Putze, J., & Schroten, H. (2013). Bioengineered 2’-fucosyllactose and 3-fucosyllactose inhibit the adhesion of Pseudomonas aeruginosa and enteric pathogens to human intestinal and respiratory cell lines. Nutrition Research (New York, N.Y.), 33(10), 831–838. https://doi.org/10.1016/j.nutres.2013.07.009  ¹⁵⁸Weichert, S., Koromyslova, A., Singh, B. K., Hansman, S., Jennewein, S., Schroten, H., & Hansman, G. S. (2016). Structural Basis for Norovirus Inhibition by Human Milk Oligosaccharides. Journal of Virology, 90(9), 4843–4848. https://doi.org/10.1128/JVI.03223-15 . In addition, GOS was shown to inhibit the adhesion of coli to human intestinal cells ⁴Ambrogi, V., Bottacini, F., Sharry, J. Mac, Breen, J. Van, Keeffe, E. O., Walsh, D., Schoemaker, B., Cao, L., Kuipers, B., Hernandez-hernandez, O., Moreno, F. J., & Schoterman, M. (2021). Bifidobacterial β -Galactosidase-Mediated Production of Galacto-Oligosaccharides : Structural and Preliminary Functional Assessments. Frontiers in Microbiology, 12(750635), 1–19. https://doi.org/10.3389/fmicb.2021.750635 . These data suggest that GOS and 2’-FL have a direct inhibitory effect on pathogen infection, shedding light on the role of oligosaccharides in supporting immunity in early life.
• The long-chain polyunsaturated fatty acids (LCPUFAs) DHA and ARA like those in our microencapsulated Vana® Sana range, can potentially help to modulate immune responses in infants ¹²⁸Richard, C., Lewis, E. D., & Field, C. J. (2016). Evidence for the essentiality of arachidonic and docosahexaenoic acid in the postnatal maternal and infant diet for the development of the infant’s immune system early in life. In Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. https://doi.org/10.1139/apnm-2015-0660 . Studies with infant milk formulas supplemented with a combination of DHA and ARA have shown a lower incidence of immunity-related issues or fewer doctor visits ¹²Birch, E. E., Khoury, J. C., Berseth, C. L., Castañeda, Y. S., Couch, J. M., Bean, J., Tamer, R., Harris, C. L., Mitmesser, S. H., & Scalabrin, D. M. (2010). The Impact of Early Nutrition on Incidence of Allergic Manifestations and Common Respiratory Illnesses in Children. Journal of Pediatrics. https://doi.org/10.1016/j.jpeds.2010.01.002  ⁸⁴Lapillonne, A., Pastor, N., Zhuang, W., & Scalabrin, D. M. F. (2014). Infants fed formula with added long chain polyunsaturated fatty acids have reduced incidence of respiratory illnesses and diarrhea during the first year of life. BMC Pediatrics. https://doi.org/10.1186/1471-2431-14-168 . Moreover, early supplementation with LCPUFAs has been demonstrated to influence the profile of immune cells and cytokines in formula-fed infants, more closely mirroring the profile of infants who were breastfed ³⁸Field, C. J., Van Aerde, J. E., Robinson, L. E., & Clandinin, M. T. (2008). Effect of providing a formula supplemented with long-chain polyunsaturated fatty acids on immunity in full-term neonates. British Journal of Nutrition. https://doi.org/10.1017/S0007114507791845 .