Multifaceted Effects of Human Milk Oligosaccharides

(See the major article by Lin et al on pages 389–98.) A report published in this issue of The Journal [1] from an interdisciplinary research team working at the University of California–San Diego nicely presents a series of experiments indicating that sialylated complex oligosaccharides present in human milk block invasion, but not the initial binding of uropathogenic Escherichia coli strain CFT073, to bladder epithelial cells (using the HTB-9 tissue culture cell line). The composition of human milk is complex, with oligosaccharides forming a large component of the nonwater constituents of breast milk [2]. The complex array of sugars present in human milk oligosaccharides (HMOs) have evolved to provide the newborn infant with a rich source of nutrient that promotes the growth of selected enteric bacteria. The HMOs serve as substrate for specific microbes [3], particularly bifidobacteria and selected lactic acid–producing bacteria, that are present in high abundance in the gut microbiota of the exclusively breastfed infant [4]. As a result, the amount and structural composition of HMOs as substrate for luminal bacteria serve to shape the development of the human gut microbiota [5], as well as directly affecting the developing neonatal mucosal immune system [6]. In addition, HMOs have antibacterial effects on pathogens, such as Campylobacter jejuni and rotavirus [7], in the intestinal tract. The findings of Lin et al [1] now raise for consideration the potential extraintestinal effects of HMOs. Prebiotic formulations that are now added into infant formula commercially are mixtures of galacto-oligosaccharides, short chained fructo-oligosaccharides, and polydextrose. These sugars are provided in roughly the same concentration as in human milk (4 g/L),but do not mimic the diversity and complexity of sugar side-chains present in breast milk [8]. It is not yet clear whether the simplified replacements added into formula have the capacity to mimic all of the diverse beneficial effects of HMOs [9]. Additional research is required to more fully address this issue, including reductionist and appropriate animal models and studies in humans, in settings of both health [10] and various disease conditions [11]. Lin et al [1] note that HMOs are present in the urine of infants fed breast milk, but not those fed formula. However, it remains to be determined whether the concentrations employed in the reported in vitro studies (5–15 g/L) are achieved at sites in the body beyond the intestinal tract. This is an important issue related to defining the biological relevance of the observations reported. An alternative explanation for the low frequency of urinary tract infection in breastfed infants is an indirect effect of breast milk on reducing gut colonization by potential uropathogens. Lin et al [1] were able to separate out the effects of initial adhesion of the urinary pathogen from subsequent invasion and cell cytotoxicity. This distinction affords the opportunity to develop strategies to intervene with complementary approaches that target various steps of the infectious process. For instance, distinct antiadhesive strategies [12] could be used to complement and further augment the antibacterial effects of HMOs. Such an approach is likely to prove fruitful, because it has been shown that there is a relationship between the precise fucose and sialic acid composition of HMOs and the observed antiadhesive effects against both specific bacterial and protozoan pathogens [13]. Although breastfeeding reduces the risk of infectious diseases, such as lower rates of respiratory infections and acute otitis media in infancy, the effect is quite variable. This variability could be explained, at least in part, by varying levels of bioactive components, including HMOs, in breast milk. The studies of Lin et al [1] also used pooled human milk. It will be of interest to test the variability among mothers of various ethnic backgrounds and varying levels of nutrient status. Genetic variations in secretor status and the resulting impact on the terminal sugars present in HMOs also influence the composition of the developing microbiota in offspring [14]. Recent evidence from studying milk metabolites of 52 healthy women 90 days after delivery indicates that the total level of HMOs is conserved among individuals but that there is marked variation between subjects relating to secretor or nonsecretor status in the fucosyltransferase 2 gene [15]. Perhaps therapies targeted at the mother could be used in the future to promote the optimal levels and composition of bioactive ingredients, including HMOs, that are present in human breast milk. Financial support. This work was supported by the Canadian Institutes of Health Research (operating grants MOP-89894 and IOP-92890). P. M. S. is the recipient of a Canada Research Chair in Gastrointestinal Disease. Potential conflicts of interest. Research advisory boards: 1. Antibe Therapeutics (stockholder). 2. ILSI North America (honorarium). 3. Alberta Inflammatory Bowel Disease Research Consortium (honorarium). Medical advisory boards: 1. Abbott Nutrition (honorarium). 2. Mead Johnson Nutrition (honorarium). 3. Nestlé Nutrition (honorarium). 4. Procter & Gamble (no financial support). Industry research grants: 1. Institut Rosell-Lallemand (research contract funding). All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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