Lipid profiling reveals the presence of unique lipid mediators in human milk from healthy and mastitic subjects
Introduction
Breast milk is the major source of nutrition during infancy. Human milk provides essential nutrients and bioactive products that support development of the infant immune system [1]. Lipids constitute approximately 30% of human milk content (other than water) and are important as an energy source. In addition, some polyunsaturated fatty acids (PUFAs) are essential components among milk lipids for optimal visual and neurologic development. However, not much is known about the variety and quantity of bioactive lipids in human milk and their effects on infants.
The ratio of dietary saturated fatty acids (SFAs) and PUFAs is important for maternal and child health. Overconsumption of SFAs leads to development of lifestyle-related diseases, and replacement of SFAs with PUFAs reduces the incidence of coronary heart disease in adults [2,3]. In children, reduced intake of SFAs significantly decreases total and LDL-cholesterol levels in plasma as well as diastolic blood pressure without evidence of adverse effects on growth and development [4]. Exposure of infants to SFAs such as palmitic acid (C16:0) affects the balance of intestinal innate immunity and induces a highly inflammatory environment, thereby leading to induction or exacerbation of atopic dermatitis [5]. Therefore, the content of SFAs and the ratio of SFAs and PUFAs supplied by milk during the very early stage of life could crucially influence the proper development of the immune system in later life.
PUFAs including arachidonic acid (AA, C20:4, ω-6 PUFA), eicosapentaenoic acid (EPA, C20:5, ω-3 PUFA) and docosahexaenoic acid (DHA, C22:6, ω-3 PUFA) are critically important as major constituents of the cell membrane and precursors of signal transmitters. AA and DHA are abundant in the brain and are necessary for growth and maturation of both the brain and retina in infants [6]. The metabolites of AA, EPA and DHA act as bioactive molecules known as lipid mediators. Lipid mediators derived from AA, often referred to as eicosanoids, play important roles in various pathophysiological events, acting in an autocrine or a paracrine manner [7]. AA-derived prostaglandins (PGs), thromboxane (TX) A2, and leukotrienes (LTs) act in general as pro-inflammatory lipid mediators, and their overproduction leads to initiation or exacerbation of inflammation [8]. On the other hand, AA-derived lipoxins (LXs), EPA-derived resolvin (Rv) E series, and DHA-derived RvD series, protectins and maresins are often referred to as specialized pro-resolving mediators (SPMs), which exhibit anti-inflammatory and pro-resolving actions [[9], [10], [11]]. A proper balance of various lipid mediators and their PUFA precursors is important for maintenance of tissue homeostasis and health, and its disturbance often leads to induction or exacerbation of various diseases. However, only a few reported studies have comprehensively analyzed free fatty acids (FFAs) and their metabolites in human milk. Since milk is essential for health of infants, young children and even beyond, comprehensive characterization of the profile of milk lipids is of particular importance.
Infants are incapable of properly digesting long-chain-fatty-acid triglyceride (TG) because of their lower pancreatic lipase activity, and therefore intake of fatty acids in the form of FFAs is favored. In the present study, therefore, we investigated the profiles of long-chain FFAs and their metabolites (i.e., PUFA-derived lipid mediators) in human milk in comparison with cow milk, and analyzed the differences in lipid profiles between normal and mastitic human milk, identifying two particular lipid mediators as potential biomarkers of mastitis.
Section snippets
Milk samples
Human milk samples were obtained from fifty donors, both healthy and with mastitis, at Uchikado maternity center (Kurashiki, Japan) and Tanpopo maternity center (Kurashiki, Japan), and the donors were diagnosed by midwives who recorded lactation age and any symptoms of mastitis. On the basis of breast-related symptoms such as erythema, swelling, pain, heat, induration, axilla lymphadenopathy, accessory breast tissue, engorgement, pus, and systemic fever (37 °C or higher), milk provided by the
Proportion of total fat, protein, TG, and long-chain FFAs in normal human milk and cow milk
Both human milk and cow milk contained approximately 45 mg/mL total fat (Fig. 1A). The protein concentration in human milk (12.6 ± 0.524 mg/mL) was 55% lower than that in cow milk (28.1 ± 2.31 mg/mL) (Fig. 1B). The TG content of human milk (1.81 ± 0.175 g/dL) was 1.6-fold higher than that of cow milk (1.11 ± 0.114 g/dL) (Fig. 1C).
The concentrations of long-chain FFAs in human milk and cow milk were 997 ± 197 μM and 53.6 ± 3.04 μM, respectively. The ratio of TG long-chain FFAs in human milk was
Discussion
In this study, we performed a comprehensive analysis of lipid constituents in human milk in comparison with those in cow milk, a major source of infant formula, and revealed distinctive features of the lipid profile including major FFAs and their metabolites in human milk. In contrast to cow milk, human milk was characterized by a high content of long-chain FFAs (Fig. 1D), particularly PUFAs (Fig. 1E), and a high ratio of ω-3 PUFA (EPA + DHA)/ω-6 PUFA (AA) (Fig. 1F). Secretion of pancreatic TG
Authors' contributions
Conceptualization, Y.N. and T.S.-Y.; Investigation, Y.N., E.K., S.M., M.O., Y.K., I.T., Y.Takahashi, Y.M., Y.Taketomi and K.Y.; Resources, Y.O., Y.M., Y.Taketomi, K.Y, and M.M.; Methodology, K.Y., M.M. and T.S.-Y.; Writing-original draft preparation, Y.N.; writing-review and editing, M.M. and T.S.-Y.; Funding acquisition, T.S.-Y. Supervision, T.S.-Y. All authors contributed to interpretation of the data and writing of the manuscript and approved the published version of the manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have influenced the reported work.
Acknowledgement
This work was financially supported by Japan Society for the Promotion of Science KAKENHI [21K19664 to T.S.-Y. and 21J15268 to Y.N.]. We thank Douglas David Beck in Douglas Science English Proofreading Service for English language review.
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