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      The impact of human breast milk components on the infant metabolism

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          Abstract

          Background & aims

          Breastfeeding is beneficial for mothers and infants. Underlying mechanisms and biochemical mediators thus need to be investigated to develop and support improved infant nutrition practices promoting the child health. We analysed the relation between maternal breast milk composition and infant metabolism.

          Methods

          196 pairs of mothers and infants from a European research project (PreventCD) were studied. Maternal milk samples collected at month 1 and month 4 after birth were analysed for macronutrient classes, hormone, and fatty acid (FA) content. Phospholipids, acylcarnitines, and amino acids were measured in serum samples of 4-month old infants. Associations between milk components and infant metabolites were analysed with spearman correlation and linear mixed effect models (LME). P-values were corrected for multiple testing ( P LME).

          Results

          Month 1 milk protein content was strongly associated with infant serum lyso-phosphatidylcholine (LPC) 14:0 ( P LME = 0.009). Month 1 milk insulin was associated to infant acetylcarnitine ( P LME = 0.01). There were no associations between milk protein content and serum amino acids and milk total fat content and serum polar lipids. Middle- and odd-chain FA% in breast milk at both ages were significantly related to serum LPC and sphingomyelins (SM) species in infant serum (all P LME<0.05), while FA% 20:5n-3 and 22:6n-3 percentages were significantly associated to serum LPC 22:6 ( P LME = 1.91×10 −4/7.93×10 −5) in milk only at month 4. Other polyunsaturated fatty acids and hormones in milk showed only weak associations with infant serum metabolites.

          Conclusions

          Infant serum LPC are influenced by breast milk FA composition and, intriguingly, milk protein content in early but not late lactation. LPC 14:0, previously found positively associated with obesity risk, was the serum metabolite which was the most strongly associated to milk protein content. Thus, LPC 14:0 might be a key metabolite not only reflecting milk protein intake in infants, but also relating high protein content in milk or infant formula to childhood obesity risk.

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          Most cited references55

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          Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity.

          Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin-stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4-h insulin-stimulated euglycemic clamp. In obesity and T2DM, long-chain AcylCNs were similarly significantly increased in the fasted state; free-CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short- and medium-chain AcylCNs, both saturated and hydroxy, as well as increased C(4)-dicarboxylcarnitine (C(4)DC-CN) that correlated with an index of poor glycemic control (HbA(1c); r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long-chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.
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            The Long-Term Public Health Benefits of Breastfeeding.

            Breastfeeding has many health benefits, both in the short term and the longer term, to infants and their mothers. There is an increasing number of studies that report on associations between breastfeeding and long-term protection against chronic disease. Recent research evidence is reviewed in this study, building on previous authoritative reviews. The recent World Health Organization reviews of the short- and long-term benefits of breastfeeding concluded that there was strong evidence for many public health benefits of breastfeeding. Cognitive development is improved by breastfeeding, and infants who are breastfed and mothers who breastfeed have lower rates of obesity. Other chronic diseases that are reduced by breastfeeding include diabetes (both type 1 and type 2), obesity, hypertension, cardiovascular disease, hyperlipidemia, and some types of cancer.
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              Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus.

              This article reviews maternal metabolic strategies for accommodating fetal nutrient requirements in normal pregnancy and in gestational diabetes mellitus (GDM). Pregnancy is characterized by a progressive increase in nutrient-stimulated insulin responses despite an only minor deterioration in glucose tolerance, consistent with progressive insulin resistance. The hyperinsulinemic-euglycemic glucose clamp technique and intravenous-glucose-tolerance test have indicated that insulin action in late normal pregnancy is 50-70% lower than in nonpregnant women. Metabolic adaptations do not fully compensate in GDM and glucose intolerance ensues. GDM may reflect a predisposition to type 2 diabetes or may be an extreme manifestation of metabolic alterations that normally occur in pregnancy. In normal pregnant women, basal endogenous hepatic glucose production (R(a)) was shown to increase by 16-30% to meet the increasing needs of the placenta and fetus. Total gluconeogenesis is increased in late gestation, although the fractional contribution of total gluconeogenesis to R(a), quantified from (2)H enrichment on carbon 5 of glucose (65-85%), does not differ in pregnant women after a 16-h fast. Endogenous hepatic glucose production was shown to remain sensitive to increased insulin concentration in normal pregnancy (96% suppression), but is less sensitive in GDM (80%). Commensurate with the increased rate of glucose appearance, an increased contribution of carbohydrate to oxidative metabolism has been observed in late pregnancy compared with pregravid states. The 24-h respiratory quotient is significantly higher in late pregnancy than postpartum. Recent advances in carbohydrate metabolism during pregnancy suggest that preventive measures should be aimed at improving insulin sensitivity in women predisposed to GDM. Further research is needed to elucidate the mechanisms and consequences of alterations in lipid metabolism during pregnancy.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – review & editing
                Role: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 June 2018
                2018
                : 13
                : 6
                : e0197713
                Affiliations
                [1 ] Ludwig-Maximilians-Universität München, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, Munich, Germany
                [2 ] Department of Medical Translational Sciences and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy
                [3 ] Department of Pediatric Gastroenterology Unit, Hospital Universitari Sant Joan de Reus, URV, IIPV, Reus, Spain
                [4 ] Celiac Disease Center, Heim Pál National Pediatric Institute, Budapest, Hungary and Department of Pediatrics, University of Debrecen, Debrecen, Hungary
                [5 ] Department of Pediatric Gastroenterology and Nutrition, La Paz University Hospital, Madrid, Spain
                [6 ] U. Enfermedad Celiaca e Inmunopatología Digestiva, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
                [7 ] Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
                TNO, NETHERLANDS
                Author notes

                Competing Interests: The authors report no conflict of interest with respect to the study reported.

                Author information
                http://orcid.org/0000-0001-6863-1202
                Article
                PONE-D-17-42554
                10.1371/journal.pone.0197713
                5983411
                29856767
                e236200d-6997-46a8-a862-8c6538b4b029
                © 2018 Hellmuth et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 January 2018
                : 27 April 2018
                Page count
                Figures: 3, Tables: 1, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100011103, Sixth Framework Programme;
                Award ID: 36383
                Funded by: funder-id http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;
                Award ID: 289346
                Funded by: funder-id http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: 322605
                Funded by: funder-id http://dx.doi.org/10.13039/501100005155, Azrieli Foundation;
                Funded by: Deutsche Zöliakie Gesellschaft
                Funded by: funder-id http://dx.doi.org/10.13039/501100004804, Eurospital;
                Funded by: Fondazione Celiachia
                Funded by: Fria Bröd
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Funded by: Spanish Society for Pediatric Gastroenterology, Hepatology and Nutrition
                Funded by: funder-id http://dx.doi.org/10.13039/501100006047, Komitet Badań Naukowych;
                Award ID: 1715/B/P01/2008/34
                Funded by: Fundacja Nutricia
                Award ID: 1W44/FNUT3/2013
                Funded by: funder-id http://dx.doi.org/10.13039/501100003549, Országos Tudományos Kutatási Alapprogramok;
                Award ID: OTKA101788, NKFI120392 and TAMOP 2.2.11/1/KONV-2012-0023
                Funded by: Stichting Coeliakie Onderzoek Nederland
                Funded by: funder-id http://dx.doi.org/10.13039/100011033, Thermo Fisher Scientific;
                Funded by: European Society for Pediatric Gastroenterology, Hepatology, and Nutrition
                This work was financially supported by the Commission of the European Communities, the 6th Framework Programme, contract FP6-2005-FOOD-4B-36383–PREVENTCD, the 7th Framework Programme, contract FP7-289346-EARLY NUTRITION, the European Research Council Advanced Grant ERC-2012-AdG – no.322605 META-GROWTH, the Azrieli Foundation, Deutsche Zöliakie Gesellschaft, Eurospital, Fondazione Celiachia, Fria Bröd, Instituto de Salud Carlos III, Spanish Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Komitet Badań Naukowych (1715/B/P01/2008/34), Fundacja Nutricia (1W44/FNUT3/2013), Hungarian Scientific Research Funds (OTKA101788, NKFI120392 and TAMOP 2.2.11/1/KONV-2012-0023), Stichting Coeliakie Onderzoek Nederland, Thermo Fisher Scientific, and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. This manuscript does not necessarily reflect the views of the Commission and in no way anticipates the future policy in this area. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare to have no conflict of interest.
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                Custom metadata
                Data cannot be made publicly available as the dataset contains sensitive and identifying information. The restriction of sharing data sets is made by the Medical Ethical Committee of the Leiden University Medical Center, PO box 9600, 2300 RC Leiden, the Netherlands. The authors confirm that the data will be kept safe for 15 year and will be made available upon request. Requests may be send to the coordinator of PreventCD: Dr. M.L. Mearin, Leiden University Medical Center, dept. of Pediatrics, PO box 9600, 2300 RC Leiden, the Netherlands. Phone number 0031.71.5262806, email address m.l.mearin_manrique@ 123456lumc.nl or the non-author institutional e-mail address preventcd@ 123456lumc.nl . Or to the coordinator of Early Nutrition: Prof. Dr. B. Koletzko, Dr. von Hauner Children's Hospital, Univ. of Munich Medical Center, Campus Innenstadt Lindwurmstr. 4, D-80337 Muenchen, Germany. Phone number 0049.8944005 2826, email address Berthold.Koletzko@ 123456med.uni-muenchen.de or the non-author institutional e-mail address metabolomics@ 123456med.lmu.de .

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