The two-year project, conducted by the Mucosal Immunology and Biology Research Center at MassGeneral Hospital for Children – the pediatric department of Massachusetts General Hospital, a major teaching hospital of Harvard Medical School – is investigating the protective mechanisms of breastmilk during the newborn period. The project, led by Professor W. Allan Walker and his team and supported by the Family Larsson-Rosenquist Foundation (FLRF), aims to reduce the number of children affected by inflammatory allergic and chronic diseases caused by unbalanced colonisation of infants’ intestines.
The study follows the hypothesis that breastmilk provides a protective link from mother to newborn in the extrauterine environment by stimulating a symbiotic, initial intestine colonisation; and in so doing, leads to intestinal immune homeostasis and a reduction of the intestinal inflammation that causes immune-mediated diseases.
“Initial gut bacteria colonisation is an important factor in the development of a newborn infant’s healthy immune system. This colonisation is favourably influenced by the presence of breastmilk, yet the specific mechanisms and metabolomics remain under-researched, and require further investigation.”
– W. Allan Walker, MD, Professor of Pediatrics and Conrad Taff Professor of Nutrition, Harvard Medical School; Director, Division of Nutrition, Harvard Medical School; and Professor of Nutrition, Harvard School of Public Health
Over the first year of the project, Dr. Walker and his team established the importance of nutrients in breastmilk (complex carbohydrates and tryptophan) interacting with either breastmilk microbiota or microbiota in the infant gut, stimulated by exclusive breastfeeding. In two submitted manuscripts, they showed that breastmilk-induced microbiota, e.g., “pioneer” bacteria, can metabolise breastmilk nutrients for protective functionality. For instance, short chained fatty acids produced by intestinal bacterial metabolism of complex carbohydrates of breastmilk have a unique protective effect on the immature intestine. They also identified indole-lactic acid (ILA), a metabolic product of breastmilk tryptophan interacting with Bifidobateria infantis (a “pioneer” bacterium); ILA inhibits the excessive inflammation seen with colonisation in the newborn intestine and may be an important protective factor when mother’s expressed breastmilk is fed to her premature infant to protect against necrotising enterocolitis.
The research team has a broad range of objectives:
• identify the differences in intestinal colonisation of bacteria between infants fed mother’s milk versus formula,
• elucidate the influence of specific health-promoting intestinal bacterial species on fundamental neonatal metabolic and immune functions, and
• determine anti-inflammatory effects and their cellular pathways using fetal intestinal cells.
Realising these objectives could have a direct, long-lasting impact on current feeding practices, especially in the neonatal intensive care unit, and could lead to better acceptance and understanding of the importance of breastmilk in general. FLRF made a USD 400,000 contribution to the project.
Huang W, Cho KY, Meng D, Walker WA. The impact of indole-3-lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis. Sci Rep. 2021;11(1):8088. DOI: 10.1038/s41598-021-87353-1
Gao Y, Davis B, Zhu W, Zheng N, Meng D, Walker WA. Short-chain fatty acid butyrate, a breast milk metabolite, enhances immature intestinal barrier function genes in response to inflammation in vitro and in vivo. Am J Physiol Gastrointest Liver Physiol. 2021;320(4):G521–30. DOI: 10.1152/ajpgi.00279.2020
Zheng N, Gao Y, Zhu W, Meng D, Walker WA. Short chain fatty acids produced by colonizing intestinal commensal bacterial interaction with expressed breast milk are anti-inflammatory in human immature enterocytes. PLoS One. 2020;15(2):e0229283. DOI: 10.1371/journal.pone.0229283
Meng D, Sommella E, Salviati E, Campiglia P, Ganguli K, Djebali K et al. Indole-3-lactic acid, a metabolite of tryptophan, secreted by Bifidobacterium longum subspecies infantis is anti-inflammatory in the immature intestine. Pediatr Res. 2020 Jan 16. DOI: 10.1038/s41390-019-0740-x. [Epub ahead of print]
Senger S, Ingano L, Freire R, Anselmo A, Zhu W, R Sadreyev et al. Human fetal-derived enterospheres provide insights on intestinal development and a novel model to study Necrotizing Enterocolitis (NEC). Cell Mol Gastroenterol Hepatol. 2018 Jan 31;5(4):549-568. DOI: 10.1016/j.jcmgh.2018.01.014. eCollection 2018.
Jiang F*, Meng D*, Zhu W, Weng M, Kasper DL, Walker WA. The symbiotic bacterial surface factor polysaccharide A on bacteroides fragilis Inhibits IL-1 β-induced inflammation in human fetal enterocytes via toll receptors 2 and 4. Plos One. 2017;12(3):e0172738. DOI: 10.1371/journal.pone.0172738. eCollection 2017. (*shared authorship)
Gregory KE*, Samuel BS*, Houghteling P, Shan G, Ausubel FM, Sadreyev RI et al. Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants. Microbiome. 2016;4(1):68. DOI: 10.1186/s40168-016-0214-x. (*shared authorship)
Walker WA, Iyengar RS. Breast milk, microbiota and intestinal immune homeostasis. Pediatr Res. 2014;77(1-2):220-228. DOI: 10.1038/pr.2014.160. Epub 2014 Oct 13.
Jeurink PV, van Bergenhenegouwen J, Jiménez E, Knippels LM, Fernández L, Garssen J et al. Human milk: a source of more life than we imagine. Benef Microbes. 2013;4(1):17-30. DOI: 10.3920/BM2012.0040.
Chichlowski M, De Lartigue G, German JB, Raybould HE, Mills DA. Bifidobacteria isolated from infants and cultured on human milk oligosaccharides affect intestinal epithelial function. J Pediatr Gastroenterol Nutr. 2012;55(3):321-327. DOI: 10.1097/MPG.0b013e31824fb899.
Schwartz S, Friedberg I, Ivanov IV, Davidson LA, Goldsby JS, Dahl DB et al. A metagenomic study of diet dependent interaction between gut microbiota and host in infants reveals differences in immune response. Genome Biol. 2012;13(4):R32. DOI: 10.1186/gb-2012-13-4-r32.
Rautava S, Walker WA. Academy of Breastfeeding Medicine founder’s lecture 2008: Breastfeeding – An extrauterine link between mother and child. Breastfeed Med. 2009;4(1):3-10. DOI: 10.1089/bfm.2009.0004.