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Brandt MJV, van Steenwinckel J, van Emst BL, Lohr J, Mank M, Schipper L, Harvey L, Benders MJNL, de Theije CGM. Human milk oligosaccharides improve white matter and interneuron development in a double-hit rat model for preterm brain injury. Neuropharmacology 2025; 276:110507. [PMID: 40350143 DOI: 10.1016/j.neuropharm.2025.110507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/27/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025]
Abstract
Mother's own milk is the preferred source of nutrition for preterm infants due to its beneficial compounds, including human milk oligosaccharides (HMOs). HMOs support microbiota and immune development, but their effect on the preterm brain remains unstudied. Here, we examined the therapeutic potential of HMOs and short-chain galacto- and long-chain fructo-oligosaccharides (scGOS/lcFOS) in a preclinical model for encephalopathy of prematurity. Pregnant Wistar rats were injected with 10 μg/kg lipopolysaccharides at embryonic day 20, and pups were exposed to hypoxia (8% O2, 140 min) at postnatal day (P)4 (fetal inflammation and postnatal hypoxia; FIPH). From P1, FIPH-pups of both sexes were treated intragastrically with HMOs, scGOS/lcFOS (9:1), or water. Transcriptomic analysis of CD11b/c + microglia was performed at P6, while immunohistochemical, microbial and short-chain fatty acid (SCFA) analyses were performed at P20. Decreased cortical myelin in FIPH animals was rescued exclusively by HMOs. Furthermore, both HMOs and scGOS/lcFOS treatments normalized reduced parvalbumin+ interneuron numbers in the hippocampus, potentially through promoting beneficial bacteria, including Lactobacillus and Bifidobacterium, and cecal acetic acid content. Interestingly, treatment with HMOs more effectively restored FIPH-induced upregulation of microglial genes associated with immune activation and normalized persistent activated microglial morphology in FIPH-males. HMOs supplementation holds promise to improve neurodevelopmental outcomes following preterm birth.
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Affiliation(s)
- Myrna J V Brandt
- Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands.
| | - Juliette van Steenwinckel
- Université Paris Cité, Inserm, NeuroDiderot, FHU Prem'impact, 48 Bd Sérurier, F-75019, Paris, France.
| | - Bobbie-Louise van Emst
- Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands.
| | - Julia Lohr
- Danone Research and Innovation, Uppsalalaan 12, 3584 HD, Utrecht, the Netherlands.
| | - Marko Mank
- Danone Research and Innovation, Uppsalalaan 12, 3584 HD, Utrecht, the Netherlands.
| | - Lidewij Schipper
- Danone Research and Innovation, Uppsalalaan 12, 3584 HD, Utrecht, the Netherlands.
| | - Louise Harvey
- Danone Research and Innovation, Uppsalalaan 12, 3584 HD, Utrecht, the Netherlands.
| | - Manon J N L Benders
- Department of Neonatology, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands
| | - Caroline G M de Theije
- Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands.
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Blesa-Baviera L, Albors A, Samblas P, Maraguat Ú, Coronel-Rodríguez C, Abad B, Viciano E, Pérez-Sádaba FJ, Martínez-Costa C. Growth and gastrointestinal tolerance of healthy formula-fed infants: a multicentre, prospective observational study. BMC Pediatr 2025; 25:229. [PMID: 40128711 PMCID: PMC11934750 DOI: 10.1186/s12887-025-05446-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 01/19/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Infant formula with human milk oligosaccharides (HMOs) and increased β-palmitate mimics breast milk nutritional composition and clinical benefits. We aimed to assess formula-fed infant growth, gastrointestinal tolerance, infections, and parental satisfaction with a partly fermented infant formula with an improved lipid profile (enriched with β-palmitate and docosahexaenoic/arachidonic acid) and short and long-chain oligosaccharides (scGOS/lcFOS [9:1]) and HMOs. METHODS A prospective descriptive observational study in healthy infants with formula feeding or breastfeeding (reference population) was conducted in six Spanish primary care centres following routine clinical practice. In the first, second and fourth month of life visits sociodemographic, clinical, and anthropometric variables (weight, length, head circumference), stool consistency (Brussels Infant and Toddler Stool Scale [BITSS]), gastrointestinal symptoms, infections incidence and associated healthcare resource utilisation, and caregivers' satisfaction with formula were collected. A descriptive statistical analysis was performed (STATA-v.14). Growth was estimated as the mean (standard deviation) increase in the anthropometric variables and z-scores. RESULTS A total of 61 formula-fed and 65 breastfed infants were included in the study (50.8% male). The average increase in weight, length and head circumference in the formula feeding and in the breastfeeding groups from the first to the fourth month of life was 2,566 (496) g, 9.7 (1.7) cm and 4.4 (1.0) cm, and 2,571 (702) g, 9.8 (1.8) cm and 4.4 (1.1) cm, respectively. The weight z-score was -0.1 (0.7) for formula-fed and 0.1 (1.1) for breastfed infants. In all visits, more than 88% of infants had loose/watery stools and most infants suffered gastrointestinal symptoms with low/medium frequency. In the fourth month of life visit, 16 (26.2%) formula-fed and 16 (24.6%) breastfed infants had infections, mainly respiratory, with 16% of formula-fed and 12% of breastfed infants requiring treatment. Most formula-feeding caregivers had a good/very good opinion of formula (85.2%). 75.4% infants drank the whole feeding bottle. CONCLUSIONS The growth, gastrointestinal tolerance, and incidence of infections of healthy formula-fed infants during the first four months of life were appropriate and in line with WHO standards. Formula feeding caregivers were satisfied with this partly fermented infant formula with an improved lipid profile and oligosaccharides.
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Affiliation(s)
| | - Ana Albors
- Paediatrician. Primary Health Care Centre Trafalgar, Valencia, Spain
| | - Pedro Samblas
- Paediatrician. Primary Health Care Centre El Restón, Madrid, Spain
| | - Úrsula Maraguat
- Paediatrician. Primary Health Care Centre Serrería I, Valencia, Spain
| | | | - Beatriz Abad
- Paediatrician. Primary Health Care Centre Malvarrosa, Valencia, Spain
| | - Elena Viciano
- Outcomes'10 (a ProductLife Group Company), Castellón, Spain
| | | | - Cecilia Martínez-Costa
- Department of Paediatrics, University of Valencia, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, Valencia, Spain.
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Gonsalves J, Bauzá-Martinez J, Stahl B, Dingess KA, Mank M. Robust and High-Resolution All-Ion Fragmentation LC-ESI-IM-MS Analysis for In-Depth Characterization or Profiling of Up to 200 Human Milk Oligosaccharides. Anal Chem 2025; 97:5563-5574. [PMID: 40047520 PMCID: PMC11923967 DOI: 10.1021/acs.analchem.4c06081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/28/2025] [Accepted: 02/25/2025] [Indexed: 03/19/2025]
Abstract
Human milk oligosaccharides (HMOs) represent the third most abundant fraction of biomolecules in human milk (HM) and play a crucial role in infant health and development. The unique contributions of HMOs to healthy development of breast-fed infants are assumed to rely on the extraordinary complexity and diversity of HMO isomeric structures, which in turn still cause a huge analytical challenge. Many contemporary analytical methods aiming for more detailed HMO characterization combine ion mobility (IM) with LC-MS for enhanced structural resolution but are typically lacking the robustness necessary for application to HM cohorts with hundreds of samples. To overcome these challenges, we introduce a novel, robust all-ion fragmentation (AIF) LC-ESI-IM-MS method integrating four analytical dimensions: high-resolution LC separation, IM drift time, accurate mass precursor, and fragment ion measurements. This four-dimensional (4D) analytical characterization is sufficient for resolving various HMO structural isomers in an efficient way. Thereby, up to 200 HMO compounds with a maximum degree of polymerization of 13 could be simultaneously identified and relatively quantified. We devised two methods using this 4D analytical approach. One intended for in-depth characterization of multiple known but also novel HMO structures and the second is designed for robust, increased-throughput analyses. With the first approach, five trifucosyl-lacto-N-tetraose isomers (TF-LNTs), four of which were never detected before in HM, as well as additional difucosyl-lacto-N-heaose isomers (DF-LNHs), were revealed and structures fully elucidated by AIF and IM. This exemplifies the potential of our method for in-depth characterization of novel complex HMO structures. Furthermore, the increased-throughput method featuring a shorter LC gradient was applied to real-world HM samples. Here, we could differentiate the HM types I-IV based on a broader range of partly new marker HMOs. We could also derive valuable new insights into variations of multiple and rare HMOs up to DP 11 across lactational stages. Overall, our AIF LC-ESI-IM-MS approach facilitates in-depth monitoring and confident identification of a broad array of distinct and simple to very complex HMOs. We envision this robust AIF LC-ESI-IM-MS approach to advance HMO research by facilitating the characterization of a broad range of HMOs in high numbers of HM samples. This may help to further extend our understanding about HMOs structure-function relationships relevant for infants' healthy development.
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Affiliation(s)
- John Gonsalves
- Danone Research
& Innovation, Uppsalalaan
12, 3584 CT Utrecht, The Netherlands
| | | | - Bernd Stahl
- Danone Research
& Innovation, Uppsalalaan
12, 3584 CT Utrecht, The Netherlands
- Utrecht Institute
for Pharmaceutical Sciences, Department of Chemical Biology &
Drug Discovery, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Kelly A. Dingess
- Danone Research
& Innovation, Uppsalalaan
12, 3584 CT Utrecht, The Netherlands
| | - Marko Mank
- Danone Research
& Innovation, Uppsalalaan
12, 3584 CT Utrecht, The Netherlands
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Kadim M, Darma A, Kartjito MS, Dilantika C, Basrowi RW, Sungono V, Jo J. Gastrointestinal Health and Immunity of Milk Formula Supplemented with a Prebiotic Mixture of Short-Chain Galacto-oligosaccharides and Long-Chain Fructo-Oligosaccharides (9:1) in Healthy Infants and Toddlers: A Systematic Review with Meta-Analysis. Pediatr Gastroenterol Hepatol Nutr 2025; 28:1-18. [PMID: 39839466 PMCID: PMC11745571 DOI: 10.5223/pghn.2025.28.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 10/03/2024] [Indexed: 01/23/2025] Open
Abstract
Prebiotics are substrates selectively utilized by microorganisms to confer health benefits to their hosts. Various prebiotics have been supplemented in standard milk formulas for infants who cannot be exclusively breastfed, aiming to provide benefits similar to those of breast milk. One of the most commonly used prebiotics is a mixture of 90% short-chain galacto-oligosaccharides and 10% long-chain fructo-oligosaccharides (scGOS/lcFOS [9:1]). Systematic review and meta-analysis were conducted to determine the effectiveness of scGOS:lcFOS (9:1) supplementation in standard milk formula for improving gastrointestinal health and immunity among healthy infants and toddlers, using parameters such as stool pH and intestinal colonization with beneficial bacteria. This systematic review was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Randomized clinical trials comparing scGOS/lcFOS (9:1)-supplemented formula versus placebo- or non-supplemented formula milk were eligible for inclusion. Related studies on gastrointestinal health and immunity among healthy infants up to five years old were searched from the earliest available date until February 29, 2024. Eighteen publications (number of participants=1,675) were selected for the systematic review, of which 11 were subsequently subjected to a meta-analysis. Results showed that the standard formula supplemented with scGOS/lcFOS (9:1) was well tolerated and conferred various gastrointestinal health and immunity to healthy infants and toddlers. These findings support the supplementation of standard milk formula with scGOS/lcFOS (9:1) for healthy infants and toddlers.
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Affiliation(s)
- Muzal Kadim
- Cipto Mangunkusumo Hospital, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Andy Darma
- Department of Child Health, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
- Department of Child Health, Faculty of Medicine, University of Airlangga, Surabaya, Indonesia
| | | | | | | | - Veli Sungono
- Faculty of Medicine, University of Pelita Harapan, Tangerang, Indonesia
| | - Juandy Jo
- Department of Biology, Faculty of Health Sciences, University of Pelita Harapan, Tangerang, Indonesia
- Mochtar Riady Institute for Nanotechnology, Tangerang, Indonesia
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Garádi Z, Dancsó A, Piskarev V, Béni S. From mother's milk to structural insights: 1H- 15N NMR analysis of Lewis X antigen-bearing oligosaccharides isolated from human milk. Carbohydr Polym 2025; 347:122534. [PMID: 39486911 DOI: 10.1016/j.carbpol.2024.122534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/08/2024] [Accepted: 07/21/2024] [Indexed: 11/04/2024]
Abstract
Human milk oligosaccharides (HMOs) are complex unconjugated glycans abundant in breast milk, with vital roles in infant nutrition and health. The structural elucidation of HMOs remains challenging due to their diverse compositions and isomeric complexities. This study presents a novel approach employing 1H-15N NMR correlations to pinpoint and characterize HMOs, LNH, LNnH, and their fucosylated derivatives including those of bearing the Lewis X motif. Isolated from human milk, these hexa-, hepta-, and octasaccharides were extensively analysed by NMR. This enabled their first complete 1H, 13C and 15N resonance assignments. Using 1H-15N HSQC experiments, the distinctive 1H-15N correlations of GlcNAc units within the HMOs provided structural fingerprints, allowing for unequivocal differentiation of isomeric structures and fucosylation patterns. Results demonstrate the potential of 1H-15N NMR spectroscopy in decoding complex HMO structures, offering new perspectives on their detailed structural characterization and contributing to a deeper understanding of their potential benefits.
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Affiliation(s)
- Zsófia Garádi
- Department of Pharmacognosy, Semmelweis University, Budapest, Hungary; Directorate of Drug Substance Development, Egis Pharmaceuticals PLC, Budapest, Hungary
| | - András Dancsó
- Directorate of Drug Substance Development, Egis Pharmaceuticals PLC, Budapest, Hungary
| | - Vladimir Piskarev
- A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, Russian Federation
| | - Szabolcs Béni
- Department of Analytical Chemistry, Institute of Chemistry, ELTE, Eötvös Loránd University, Budapest, Hungary.
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6
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Duman H, Bechelany M, Karav S. Human Milk Oligosaccharides: Decoding Their Structural Variability, Health Benefits, and the Evolution of Infant Nutrition. Nutrients 2024; 17:118. [PMID: 39796552 PMCID: PMC11723173 DOI: 10.3390/nu17010118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 12/24/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Human milk oligosaccharides (HMOs), the third most abundant solid component in human milk, vary significantly among women due to factors such as secretor status, race, geography, season, maternal nutrition and weight, gestational age, and delivery method. In recent studies, HMOs have been shown to have a variety of functional roles in the development of infants. Because HMOs are not digested by infants, they act as metabolic substrates for certain bacteria, helping to establish the infant's gut microbiota. By encouraging the growth of advantageous intestinal bacteria, these sugars function as prebiotics and produce short-chain fatty acids (SCFAs), which are essential for gut health. HMOs can also specifically reduce harmful microbes and viruses binding to the gut epithelium, preventing illness. HMO addition to infant formula is safe and promotes healthy development, infection prevention, and microbiota. Current infant formulas frequently contain oligosaccharides (OSs) that differ structurally from those found in human milk, making it unlikely that they would reproduce the unique effects of HMOs. However, there is a growing trend in producing OSs resembling HMOs, but limited data make it unclear whether HMOs offer additional therapeutic benefits compared to non-human OSs. Better knowledge of how the human mammary gland synthesizes HMOs could direct the development of technologies that yield a broad variety of complex HMOs with OS compositions that closely mimic human milk. This review explores HMOs' complex nature and vital role in infant health, examining maternal variation in HMO composition and its contributing factors. It highlights recent technological advances enabling large-scale studies on HMO composition and its effects on infant health. Furthermore, HMOs' multifunctional roles in biological processes such as infection prevention, brain development, and gut microbiota and immune response regulation are investigated. The structural distinctions between HMOs and other mammalian OSs in infant formulas are discussed, with a focus on the trend toward producing more precise replicas of HMOs found in human milk.
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Affiliation(s)
- Hatice Duman
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale 17100, Türkiye;
| | - Mikhael Bechelany
- Institut Européen des Membranes (IEM), UMR 5635, University Montpellier, ENSCM, CNRS, F-34095 Montpellier, France
- Functional Materials Group, Gulf University for Science and Technology (GUST), Masjid Al Aqsa Street, Mubarak Al-Abdullah 32093, Kuwait
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart University, Çanakkale 17100, Türkiye;
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Welp A, Laser E, Seeger K, Haiß A, Hanke K, Faust K, Stichtenoth G, Fortmann-Grote C, Pagel J, Rupp J, Göpel W, Gembicki M, Scharf JL, Rody A, Herting E, Härtel C, Fortmann I. Effects of multistrain Bifidobacteria and Lactobacillus probiotics on HMO compositions after supplementation to pregnant women at threatening preterm delivery: design of the randomized clinical PROMO trial. Mol Cell Pediatr 2024; 11:6. [PMID: 39085734 PMCID: PMC11291828 DOI: 10.1186/s40348-024-00179-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND As an indigestible component of human breast milk, Human Milk Oligosaccharides (HMOs) play an important role as a substrate for the establishing microbiome of the newborn. They have further been shown to have beneficial effects on the immune system, lung and brain development. For preterm infants HMO composition of human breast milk may be of particular relevance since the establishment of a healthy microbiome is challenged by multiple disruptive factors associated with preterm birth, such as cesarean section, hospital environment and perinatal antibiotic exposure. In a previous study it has been proposed that maternal probiotic supplementation during late stages of pregnancy may change the HMO composition in human milk. However, there is currently no study on pregnancies which are threatened to preterm birth. Furthermore, HMO composition has not been investigated in association with clinically relevant outcomes of vulnerable infants including inflammation-mediated diseases such as sepsis, necrotizing enterocolitis (NEC) or chronic lung disease. MAIN BODY A randomized controlled intervention study (PROMO = probiotics for human milk oligosaccharides) has been designed to analyze changes in HMO composition of human breast milk after supplementation of probiotics (Lactobacillus acidophilus, Bifidobacterium lactis and Bifidobacterium infantis) in pregnancies at risk for preterm birth. The primary endpoint is HMO composition of 3-fucosyllactose and 3'-sialyllactose in expressed breast milk. We estimate that probiotic intervention will increase these two HMO levels by 50% according to the standardized mean difference between treatment and control groups. As secondary outcomes we will measure preterm infants' clinical outcomes (preterm birth, sepsis, weight gain growth, gastrointestinal complications) and effects on microbiome composition in the rectovaginal tract of mothers at delivery and in the gut of term and preterm infants by sequencing at high genomic resolution. Therefore, we will longitudinally collect bio samples in the first 4 weeks after birth as well as in follow-up investigations at 3 months, one year, and five years of age. CONCLUSIONS We estimate that probiotic intervention will increase these two HMO levels by 50% according to the standardized mean difference between treatment and control groups. The PROMO study will gain insight into the microbiome-HMO interaction at the fetomaternal interface and its consequences for duration of pregnancy and outcome of infants.
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Affiliation(s)
- A Welp
- Department of Gynecology and Obstetrics, University Hospital of Lübeck, Lübeck, Germany.
| | - E Laser
- Department of Pediatrics, University Hospital of Lübeck, Lübeck, Germany
| | - K Seeger
- Institute of Chemistry and Metabolomics, University of Lübeck, Lübeck, Germany
| | - A Haiß
- Department of Pediatrics, University Hospital of Lübeck, Lübeck, Germany
| | - K Hanke
- Department of Pediatrics, University Hospital of Lübeck, Lübeck, Germany
| | - K Faust
- Department of Pediatrics, University Hospital of Lübeck, Lübeck, Germany
| | - G Stichtenoth
- Department of Pediatrics, University Hospital of Lübeck, Lübeck, Germany
| | - C Fortmann-Grote
- Department of Microbial Population Biology, Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - J Pagel
- Department of Pediatrics, University Hospital of Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research, Lübeck, Germany
| | - J Rupp
- German Center for Infection Research, Lübeck, Germany
- Institute for Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany
| | - W Göpel
- Department of Pediatrics, University Hospital of Lübeck, Lübeck, Germany
| | - M Gembicki
- Department of Gynecology and Obstetrics, University Hospital of Lübeck, Lübeck, Germany
| | - J L Scharf
- Department of Gynecology and Obstetrics, University Hospital of Lübeck, Lübeck, Germany
| | - A Rody
- Department of Gynecology and Obstetrics, University Hospital of Lübeck, Lübeck, Germany
| | - E Herting
- Department of Pediatrics, University Hospital of Lübeck, Lübeck, Germany
| | - C Härtel
- Department of Pediatrics, University of Würzburg, Würzburg, Germany
| | - I Fortmann
- Department of Pediatrics, University Hospital of Lübeck, Lübeck, Germany
- German Center for Infection Research, Lübeck, Germany
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Peng W, Reyes CDG, Gautam S, Yu A, Cho BG, Goli M, Donohoo K, Mondello S, Kobeissy F, Mechref Y. MS-based glycomics and glycoproteomics methods enabling isomeric characterization. MASS SPECTROMETRY REVIEWS 2023; 42:577-616. [PMID: 34159615 PMCID: PMC8692493 DOI: 10.1002/mas.21713] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 05/03/2023]
Abstract
Glycosylation is one of the most significant and abundant posttranslational modifications in mammalian cells. It mediates a wide range of biofunctions, including cell adhesion, cell communication, immune cell trafficking, and protein stability. Also, aberrant glycosylation has been associated with various diseases such as diabetes, Alzheimer's disease, inflammation, immune deficiencies, congenital disorders, and cancers. The alterations in the distributions of glycan and glycopeptide isomers are involved in the development and progression of several human diseases. However, the microheterogeneity of glycosylation brings a great challenge to glycomic and glycoproteomic analysis, including the characterization of isomers. Over several decades, different methods and approaches have been developed to facilitate the characterization of glycan and glycopeptide isomers. Mass spectrometry (MS) has been a powerful tool utilized for glycomic and glycoproteomic isomeric analysis due to its high sensitivity and rich structural information using different fragmentation techniques. However, a comprehensive characterization of glycan and glycopeptide isomers remains a challenge when utilizing MS alone. Therefore, various separation methods, including liquid chromatography, capillary electrophoresis, and ion mobility, were developed to resolve glycan and glycopeptide isomers before MS. These separation techniques were coupled to MS for a better identification and quantitation of glycan and glycopeptide isomers. Additionally, bioinformatic tools are essential for the automated processing of glycan and glycopeptide isomeric data to facilitate isomeric studies in biological cohorts. Here in this review, we discuss commonly employed MS-based techniques, separation hyphenated MS methods, and software, facilitating the separation, identification, and quantitation of glycan and glycopeptide isomers.
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Affiliation(s)
- Wenjing Peng
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | | | - Sakshi Gautam
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | - Aiying Yu
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | - Byeong Gwan Cho
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | - Mona Goli
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | - Kaitlyn Donohoo
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | | | - Firas Kobeissy
- Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, University of Florida, Gainesville, Florida, USA
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
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Peng W, Kobeissy F, Mondello S, Barsa C, Mechref Y. MS-based glycomics: An analytical tool to assess nervous system diseases. Front Neurosci 2022; 16:1000179. [PMID: 36408389 PMCID: PMC9671362 DOI: 10.3389/fnins.2022.1000179] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/05/2022] [Indexed: 08/27/2023] Open
Abstract
Neurological diseases affect millions of peopleochemistryorldwide and are continuously increasing due to the globe's aging population. Such diseases affect the nervous system and are characterized by a progressive decline in brain function and progressive cognitive impairment, decreasing the quality of life for those with the disease as well as for their families and loved ones. The increased burden of nervous system diseases demands a deeper insight into the biomolecular mechanisms at work during disease development in order to improve clinical diagnosis and drug design. Recently, evidence has related glycosylation to nervous system diseases. Glycosylation is a vital post-translational modification that mediates many biological functions, and aberrant glycosylation has been associated with a variety of diseases. Thus, the investigation of glycosylation in neurological diseases could provide novel biomarkers and information for disease pathology. During the last decades, many techniques have been developed for facilitation of reliable and efficient glycomic analysis. Among these, mass spectrometry (MS) is considered the most powerful tool for glycan analysis due to its high resolution, high sensitivity, and the ability to acquire adequate structural information for glycan identification. Along with MS, a variety of approaches and strategies are employed to enhance the MS-based identification and quantitation of glycans in neurological samples. Here, we review the advanced glycomic tools used in nervous system disease studies, including separation techniques prior to MS, fragmentation techniques in MS, and corresponding strategies. The glycan markers in common clinical nervous system diseases discovered by utilizing such MS-based glycomic tools are also summarized and discussed.
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Affiliation(s)
- Wenjing Peng
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Firas Kobeissy
- Program for Neurotrauma, Neuroproteomics and Biomarkers Research, Department of Emergency Medicine, University of Florida, Gainesville, FL, United States
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Chloe Barsa
- Program for Neurotrauma, Neuroproteomics and Biomarkers Research, Department of Emergency Medicine, University of Florida, Gainesville, FL, United States
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
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10
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Association of human milk oligosaccharides and nutritional status of young infants among Bangladeshi mother-infant dyads. Sci Rep 2022; 12:9456. [PMID: 35676397 PMCID: PMC9177541 DOI: 10.1038/s41598-022-13296-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 05/17/2022] [Indexed: 11/13/2022] Open
Abstract
Human milk oligosaccharides (HMOs) support the development of a healthy gut microbiome and the growth of infants. We aimed to determine the association of different HMOs with severe acute malnutrition (SAM) among Bangladeshi young infants. This study was nested within a single-blind, randomized, pilot clinical trial (NCT0366657). A total of 45 breastmilk samples from mothers of < 6 months old infants who had SAM (n = 26) or were non-malnourished (n = 19) and were analyzed for constituent HMOs. Of the infants with SAM, 14 (53.85%) had secretor mothers, and 11 (57.89%) of the non-malnourished infants had secretor mothers. A one-unit increase in the relative abundance of sialylated HMOs was associated with higher odds of SAM in age and sex adjusted model (aOR = 2.00, 90% CI 1.30, 3.06), in age, sex, and secretor status adjusted model (aOR = 1.96, 90% CI 1.29, 2.98), and also in age and sex adjusted model among non-secretor mothers (aOR = 2.86, 90% CI 1.07, 7.62). In adjusted models, there was no evidence of a statistically significant association between SAM and fucosylated or undecorated HMOs. Our study demonstrates that a higher relative abundance of sialylated HMOs in mothers’ breastmilk may have a negative impact on young infants’ nutritional status.
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11
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Effect of sialyllactose administration on growth performance and intestinal epithelium development in suckling piglets. Anim Feed Sci Technol 2022. [DOI: 10.1016/j.anifeedsci.2022.115205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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12
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Human Milk Oligosaccharides: A Comprehensive Review towards Metabolomics. CHILDREN-BASEL 2021; 8:children8090804. [PMID: 34572236 PMCID: PMC8465502 DOI: 10.3390/children8090804] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/06/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022]
Abstract
Human milk oligosaccharides (HMOs) are the third most represented component in breast milk. They serve not only as prebiotics but they exert a protective role against some significant neonatal pathologies such as necrotizing enterocolitis. Furthermore, they can program the immune system and consequently reduce allergies and autoimmune diseases’ incidence. HMOs also play a crucial role in brain development and in the gut barrier’s maturation. Moreover, the maternal genetic factors influencing different HMO patterns and their modulation by the interaction and the competition between active enzymes have been widely investigated in the literature, but there are few studies concerning the role of other factors such as maternal health, nutrition, and environmental influence. In this context, metabolomics, one of the newest “omics” sciences that provides a snapshot of the metabolites present in bio-fluids, such as breast milk, could be useful to investigate the HMO content in human milk. The authors performed a review, from 2012 to the beginning of 2021, concerning the application of metabolomics to investigate the HMOs, by using Pubmed, Researchgate and Scopus as source databases. Through this technology, it is possible to know in real-time whether a mother produces a specific oligosaccharide, keeping into consideration that there are other modifiable and unmodifiable factors that influence HMO production from a qualitative and a quantitative point of view. Although further studies are needed to provide clinical substantiation, in the future, thanks to metabolomics, this could be possible by using a dipstick and adding the eventual missing oligosaccharide to the breast milk or formula in order to give the best and the most personalized nutritional regimen for each newborn, adjusting to different necessities.
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13
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Presence and Levels of Galactosyllactoses and Other Oligosaccharides in Human Milk and Their Variation during Lactation and According to Maternal Phenotype. Nutrients 2021; 13:nu13072324. [PMID: 34371833 PMCID: PMC8308909 DOI: 10.3390/nu13072324] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 12/14/2022] Open
Abstract
Among the human milk oligosaccharides (HMOS), the galactosyllactoses (GLs) are only limitedly studied. This study aims to describe the presence and relative levels of HMOS, including GLs, in human milk (HM) according to maternal Secretor and Lewis (SeLe) phenotype and lactation stage. Relative levels of 19 HMOS were measured in 715 HM samples collected in the first 4 months postpartum from 371 donors participating in the PreventCD study. From a subset of 24 Dutch women (171 HM samples), samples were collected monthly up to 12 months postpartum and were additionally analyzed for relative and absolute levels of β6′-GL, β3′-GL and α3′-GL. Maternal SeLe phenotype or HM group was assigned based on the presence of specific fucosylated HMOS. Most HMOS, including β6′- and β3′-GL, were present in the vast majority (≥75%) of HM samples, whereas others (e.g., LNDFH II, 2′-F-LNH and α3′-GL) only occurred in a low number (<25%) of samples. Clear differences were observed between the presence and relative levels of the HMOS according to the maternal phenotype and lactation stage. Absolute concentrations of β6′-GL and β3′-GL were higher in HM group IV samples compared to samples of the other three HM groups. β3′-GL was also higher in HM group II samples compared to HM group I samples. β3′-GL and β6′-GL were stable over lactation stages. In conclusion, presence and levels of HMOS vary according to HM group and lactation stage. Not all HMOS behave similarly: some HMOS depend strongly on maternal phenotype and/or lactation stage, whereas others do not. β3′-GL and β6′-GL were present in low concentrations in over 75% of the analyzed HM samples and showed differences between HM groups, but not between the lactation stages.
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14
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Moore RE, Xu LL, Townsend SD. Prospecting Human Milk Oligosaccharides as a Defense Against Viral Infections. ACS Infect Dis 2021; 7:254-263. [PMID: 33470804 DOI: 10.1021/acsinfecdis.0c00807] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In addition to providing maximal nutritional value for neonatal growth and development, human milk functions as an early defense mechanism against invading pathogens. Human milk oligosaccharides (HMOs), which are abundant in human milk, are a diverse group of heterogeneous carbohydrates with wide ranging protective effects. In addition to promoting the colonization of beneficial intestinal flora, HMOs serve as decoy receptors, effectively blocking the attachment of pathogenic bacteria. HMOs also function as bacteriostatic agents, inhibiting the growth of gram-positive bacteria. Based on this precedence, an emerging area in the field has focused on characterizing the antiviral properties of HMOs. Indeed, HMOs have been evaluated as antiviral agents, with many possessing activity against life-threatening infections. This targeted review provides insight into the known glycan-binding interactions between select HMOs and influenza, rotavirus, respiratory syncytial virus, human immunodeficiency virus, and norovirus. Additionally, we review the role of HMOs in preventing necrotizing enterocolitis, an intestinal disease linked to viral infections. We close with a discussion of what is known broadly regarding human milk oligosaccharides and their interactions with coronaviruses.
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Affiliation(s)
- Rebecca E. Moore
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37212, United States
| | - Lianyan L. Xu
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37212, United States
| | - Steven D. Townsend
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37212, United States
- Vanderbilt Microbiome Initiative, Vanderbilt University, Nashville, Tennessee 37212, United States
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15
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Sergius-Ronot M, Suwal S, Shama S, Chamberland J, Unger S, O'Connor DL, Pouliot Y, Doyen A. The ultrafiltration molecular weight cut-off has a limited effect on the concentration and protein profile during preparation of human milk protein concentrates. J Dairy Sci 2021; 104:3820-3831. [PMID: 33485685 DOI: 10.3168/jds.2020-18762] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 11/04/2020] [Indexed: 11/19/2022]
Abstract
Optimizing protein intake for very low birth weight (<1,500 g) infants is fundamental to prevent faltering postnatal growth with the potential association of impaired neurodevelopment. The protein content of human milk is not sufficient to support the growth of very low birth weight infants. To meet their elevated protein requirements, human milk is currently fortified using typically bovine milk-based protein isolates (>85% on a dry basis). However, these products have several limitations for use in this vulnerable population. To overcome the shortcomings of bovine milk-based protein supplement, a human milk protein concentrate (HMPC) was developed. In preliminary attempts using 10 kDa ultrafiltration (UF) membranes, it was not possible to reach the protein content of commercial protein isolates, presumably due to the retention of human milk oligosaccharides (HMO). Consequently, it was hypothesized that the use of a UF membrane with a higher molecular weight cut-off (50 kDa rather than 10 kDa) could improve the transmission of carbohydrates, including HMO, in the permeate, thus increasing the protein purity of the subsequent HMPC. The results showed that permeate fluxes during the concentration step were similar to either UF molecular weight cut-off, but the 50-kDa membrane had a higher permeate flux during the diafiltration sequence. However, it was not sufficient to increase the protein purity of the human milk retentate, as both membranes generated HMPC with similar protein contents of 48.8% (10 kDa) and 50% (50 kDa) on a dry basis. This result was related to the high retention of HMO, mainly during the concentration step, although the diafiltration step was efficient to decrease their content in the HMPC. As the major bioactive proteins (lactoferrin, lysozyme, bile salt stimulated lipase, and α1-antitrypsin) in human milk were detected in both HMPC, the 50-kDa membrane seems the most appropriate to the preparation of HMPC in terms of permeation flux values. However, improving the separation of HMO from proteins is essential to increase the protein purity of HMPC.
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Affiliation(s)
- Mélanie Sergius-Ronot
- Departement of Food Science, Institute for Nutrition and Functional Foods (INAF) and Dairy Research Centre (STELA), Laval University, Quebec, G1V 0A6 Canada
| | - Shyam Suwal
- Department of Food Science, University of Copenhagen, Frederiksberg C, DK-1958 Denmark
| | - Sara Shama
- Department of Nutritional Sciences, University of Toronto, Toronto, M5S 1A8 Canada; Translational Medicine Program, The Hospital for Sick Children, Toronto, M5G 0A4 Canada
| | - Julien Chamberland
- Departement of Food Science, Institute for Nutrition and Functional Foods (INAF) and Dairy Research Centre (STELA), Laval University, Quebec, G1V 0A6 Canada
| | - Sharon Unger
- Department of Nutritional Sciences, University of Toronto, Toronto, M5S 1A8 Canada; Department of Pediatrics, University of Toronto, Toronto, M5G 1X8 Canada; Department of Neonatology, The Hospital for Sick Children, Toronto, M5G 1X8 Canada; Department of Pediatrics, Mount Sinai Hospital, Toronto, M5G 1X5 Canada; Rogers Hixon Ontario Human Milk Bank, Mount Sinai Hospital, Toronto, M5G 1X5 Canada
| | - Deborah L O'Connor
- Department of Nutritional Sciences, University of Toronto, Toronto, M5S 1A8 Canada; Translational Medicine Program, The Hospital for Sick Children, Toronto, M5G 0A4 Canada; Rogers Hixon Ontario Human Milk Bank, Mount Sinai Hospital, Toronto, M5G 1X5 Canada
| | - Yves Pouliot
- Departement of Food Science, Institute for Nutrition and Functional Foods (INAF) and Dairy Research Centre (STELA), Laval University, Quebec, G1V 0A6 Canada
| | - Alain Doyen
- Departement of Food Science, Institute for Nutrition and Functional Foods (INAF) and Dairy Research Centre (STELA), Laval University, Quebec, G1V 0A6 Canada.
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16
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Hale OJ, Ryumin P, Brown JM, Morris M, Cramer R. Production and analysis of multiply charged negative ions by liquid atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2021; 35 Suppl 1:e8246. [PMID: 30067883 PMCID: PMC7757204 DOI: 10.1002/rcm.8246] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/13/2018] [Accepted: 07/17/2018] [Indexed: 05/08/2023]
Abstract
RATIONALE Liquid atmospheric pressure matrix-assisted laser desorption/ionisation (AP-MALDI) has been shown to enable the production of electrospray ionisation (ESI)-like multiply charged analyte ions with little sample consumption and long-lasting, robust ion yield for sensitive analysis by mass spectrometry (MS). Previous reports have focused on positive ion production. Here, we report an initial optimisation of liquid AP-MALDI for ESI-like negative ion production and its application to the analysis of peptides/proteins, DNA and lipids. METHODS The instrumentation employed for this study is identical to that of earlier liquid AP-MALDI MS studies for positive analyte ion production with a simple non-commercial AP ion source that is attached to a Waters Synapt G2-Si mass spectrometer and incorporates a heated ion transfer tube. The preparation of liquid MALDI matrices is similar to positive ion mode analysis but has been adjusted for negative ion mode by changing the chromophore to 3-aminoquinoline and 9-aminoacridine for further improvements. RESULTS For DNA, liquid AP-MALDI MS analysis benefited from switching to 9-aminoacridine-based MALDI samples and the negative ion mode, increasing the number of charges by up to a factor of 2 and the analyte ion signal intensities by more than 10-fold compared with the positive ion mode. The limit of detection was recorded at around 10 fmol for ATGCAT. For lipids, negative ion mode analysis provided a fully orthogonal set of detected lipids. CONCLUSIONS Negative ion mode is a sensitive alternative to positive ion mode in liquid AP-MALDI MS analysis. In particular, the analysis of lipids and DNA benefited from the complementarity of the detected lipid species and the vastly greater DNA ion signal intensities in negative ion mode.
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Affiliation(s)
- Oliver J Hale
- Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
| | - Pavel Ryumin
- Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
| | - Jeffery M Brown
- Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
- Waters Corporation, Stamford Avenue, Wilmslow, SK9 4AX, UK
| | - Michael Morris
- Waters Corporation, Stamford Avenue, Wilmslow, SK9 4AX, UK
| | - Rainer Cramer
- Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK
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17
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Kumar H, Collado MC, Wopereis H, Salminen S, Knol J, Roeselers G. The Bifidogenic Effect Revisited-Ecology and Health Perspectives of Bifidobacterial Colonization in Early Life. Microorganisms 2020; 8:E1855. [PMID: 33255636 PMCID: PMC7760687 DOI: 10.3390/microorganisms8121855] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022] Open
Abstract
Extensive microbial colonization of the infant gastrointestinal tract starts after parturition. There are several parallel mechanisms by which early life microbiome acquisition may proceed, including early exposure to maternal vaginal and fecal microbiota, transmission of skin associated microbes, and ingestion of microorganisms present in breast milk. The crucial role of vertical transmission from the maternal microbial reservoir during vaginal delivery is supported by the shared microbial strains observed among mothers and their babies and the distinctly different gut microbiome composition of caesarean-section born infants. The healthy infant colon is often dominated by members of the keystone genus Bifidobacterium that have evolved complex genetic pathways to metabolize different glycans present in human milk. In exchange for these host-derived nutrients, bifidobacteria's saccharolytic activity results in an anaerobic and acidic gut environment that is protective against enteropathogenic infection. Interference with early-life microbiota acquisition and development could result in adverse health outcomes. Compromised microbiota development, often characterized by decreased abundance of Bifidobacterium species has been reported in infants delivered prematurely, delivered by caesarean section, early life antibiotic exposure and in the case of early life allergies. Various microbiome modulation strategies such as probiotic, prebiotics, synbiotics and postbiotics have been developed that are able to generate a bifidogenic shift and help to restore the microbiota development. This review explores the evolutionary ecology of early-life type Bifidobacterium strains and their symbiotic relationship with humans and discusses examples of compromised microbiota development in which stimulating the abundance and activity of Bifidobacterium has demonstrated beneficial associations with health.
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Affiliation(s)
- Himanshu Kumar
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (H.K.); (H.W.); (J.K.)
| | - Maria Carmen Collado
- Department of Biotechnology, Institute of Agrochemistry and Food Technology-Spanish National Research Council (IATA-CSIC), Paterna, 46980 Valencia, Spain;
- Functional Foods Forum, Faculty of Medicine, University of Turku, 20500 Turku, Finland;
| | - Harm Wopereis
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (H.K.); (H.W.); (J.K.)
| | - Seppo Salminen
- Functional Foods Forum, Faculty of Medicine, University of Turku, 20500 Turku, Finland;
| | - Jan Knol
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (H.K.); (H.W.); (J.K.)
- Laboratory for Microbiology, Wageningen University, 6708 PB Wageningen, The Netherlands
| | - Guus Roeselers
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (H.K.); (H.W.); (J.K.)
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18
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Chia LW, Mank M, Blijenberg B, Bongers RS, van Limpt K, Wopereis H, Tims S, Stahl B, Belzer C, Knol J. Cross-feeding between Bifidobacterium infantis and Anaerostipes caccae on lactose and human milk oligosaccharides. Benef Microbes 2020; 12:69-83. [PMID: 33191780 DOI: 10.3920/bm2020.0005] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The establishment of the gut microbiota immediately after birth is a dynamic process that may impact lifelong health. At this important developmental stage in early life, human milk oligosaccharides (HMOs) serve as specific substrates to shape the gut microbiota of the nursling. The well-orchestrated transition is important as an aberrant microbial composition and bacterial-derived metabolites are associated with colicky symptoms and atopic diseases in infants. Here, we study the trophic interactions between an HMO-degrader, Bifidobacterium infantis and the butyrogenic Anaerostipes caccae using carbohydrate substrates that are relevant in the early life period including lactose and total human milk carbohydrates. Mono- and co-cultures of these bacterial species were grown at pH 6.5 in anaerobic bioreactors supplemented with lactose or total human milk carbohydrates. A. caccae was not able to grow on these substrates except when grown in co-culture with B. infantis, leading to growth and concomitant butyrate production. Two levels of cross-feeding were observed, in which A. caccae utilised the liberated monosaccharides as well as lactate and acetate produced by B. infantis. This microbial cross-feeding points towards the key ecological role of bifidobacteria in providing substrates for other important species that will colonise the infant gut. The progressive shift of the gut microbiota composition that contributes to the gradual production of butyrate could be important for host-microbial crosstalk and gut maturation.
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Affiliation(s)
- L W Chia
- Laboratory of Microbiology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands
| | - M Mank
- Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
| | - B Blijenberg
- Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
| | - R S Bongers
- Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
| | - K van Limpt
- Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
| | - H Wopereis
- Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
| | - S Tims
- Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
| | - B Stahl
- Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands.,Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands
| | - C Belzer
- Laboratory of Microbiology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands
| | - J Knol
- Laboratory of Microbiology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, the Netherlands.,Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
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19
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Chia LW, Mank M, Blijenberg B, Aalvink S, Bongers RS, Stahl B, Knol J, Belzer C. Bacteroides thetaiotaomicron Fosters the Growth of Butyrate-Producing Anaerostipes caccae in the Presence of Lactose and Total Human Milk Carbohydrates. Microorganisms 2020; 8:E1513. [PMID: 33019531 PMCID: PMC7601031 DOI: 10.3390/microorganisms8101513] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/20/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022] Open
Abstract
The development of infant gut microbiota is strongly influenced by nutrition. Human milk oligosaccharides (HMOSs) in breast milk selectively promote the growth of glycan-degrading microbes, which lays the basis of the microbial network. In this study, we investigated the trophic interaction between Bacteroides thetaiotaomicron and the butyrate-producing Anaerostipes caccae in the presence of early-life carbohydrates. Anaerobic bioreactors were set up to study the monocultures of B. thetaiotaomicron and the co-cultures of B. thetaiotaomicron with A. caccae in minimal media supplemented with lactose or a total human milk carbohydrate fraction. Bacterial growth (qPCR), metabolites (HPLC), and HMOS utilization (LC-ESI-MS2) were monitored. B. thetaiotaomicron displayed potent glycan catabolic capability with differential preference in degrading specific low molecular weight HMOSs, including the neutral trioses (2'-FL and 3-FL), neutral tetraoses (DFL, LNT, LNnT), neutral pentaoses (LNFP I, II, III, V), and acidic trioses (3'-SL and 6'-SL). In contrast, A. caccae was not able to utilize lactose and HMOSs. However, the signature metabolite of A. caccae, butyrate, was detected in co-culture with B. thetaiotaomicron. As such, A. caccae cross-fed on B. thetaiotaomicron-derived monosaccharides, acetate, and d-lactate for growth and concomitant butyrate production. This study provides a proof of concept that B. thetaiotaomicron could drive the butyrogenic metabolic network in the infant gut.
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Affiliation(s)
- Loo Wee Chia
- Laboratory of Microbiology, Wageningen University and Research, 6708 WE Wageningen, The Netherlands; (L.W.C.); (S.A.); (J.K.)
| | - Marko Mank
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (M.M.); (B.B.); (R.S.B.); (B.S.)
| | - Bernadet Blijenberg
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (M.M.); (B.B.); (R.S.B.); (B.S.)
| | - Steven Aalvink
- Laboratory of Microbiology, Wageningen University and Research, 6708 WE Wageningen, The Netherlands; (L.W.C.); (S.A.); (J.K.)
| | - Roger S. Bongers
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (M.M.); (B.B.); (R.S.B.); (B.S.)
| | - Bernd Stahl
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (M.M.); (B.B.); (R.S.B.); (B.S.)
- Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Jan Knol
- Laboratory of Microbiology, Wageningen University and Research, 6708 WE Wageningen, The Netherlands; (L.W.C.); (S.A.); (J.K.)
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands; (M.M.); (B.B.); (R.S.B.); (B.S.)
| | - Clara Belzer
- Laboratory of Microbiology, Wageningen University and Research, 6708 WE Wageningen, The Netherlands; (L.W.C.); (S.A.); (J.K.)
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20
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Sarkozy D, Borza B, Domokos A, Varadi E, Szigeti M, Meszaros-Matwiejuk A, Molnar-Gabor D, Guttman A. Ultrafast high-resolution analysis of human milk oligosaccharides by multicapillary gel electrophoresis. Food Chem 2020; 341:128200. [PMID: 33065525 DOI: 10.1016/j.foodchem.2020.128200] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 07/26/2020] [Accepted: 09/23/2020] [Indexed: 12/26/2022]
Abstract
There is recently growing interest towards synthesized human milk oligosaccharides (HMOs) as baby formula additives, and interestingly also as dietary supplements for adults. Currently quite a few manufacturers synthesize HMOs, however, their analysis is challenging, both in resolution and speed. In this paper an ultrafast high-resolution method is introduced for the separation of HMOs by multicapillary gel electrophoresis. Two gel compositions were evaluated with complementary resolving power. One was a conventionally used industrial standard carbohydrate separation matrix, resolving oligosaccharides according to their charge to hydrodynamic volume ratios. The other one was a borate-buffered dextran gel, which utilized the secondary equilibrium of the borate-vicinal diol complexation to enhance resolution. Considering the rapid analysis time and multiplexing (12-channel system), a 96 well sample plate can be analyzed in less than 80 min with the conventional type carbohydrate separation matrix and in less than one hour with the borate-buffered dextran gel. Exploiting the one fluorophore per molecule labeling stoichiometry, the limit of detection (S/N > 3) and limit of quantitation (S/N > 10) were determined as 0.025 and 0.100 mg/mL, respectively, with good linearity. Based on the calibration plot, the quantities of several low concentration HMOs were determined from a human milk sample.
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Affiliation(s)
- Daniel Sarkozy
- Horváth Csaba Memorial Laboratory of Bioseparation Sciences, Research Center for Molecular Medicine, Faculty of Medicine, Doctoral School of Molecular Medicine, University of Debrecen, Hungary
| | - Beata Borza
- Horváth Csaba Memorial Laboratory of Bioseparation Sciences, Research Center for Molecular Medicine, Faculty of Medicine, Doctoral School of Molecular Medicine, University of Debrecen, Hungary; Translation Glycomics Group, Research Institute of Biomolecular and Chemical Engineering, University of Pannonia, Veszprem, Hungary
| | - Apolka Domokos
- Horváth Csaba Memorial Laboratory of Bioseparation Sciences, Research Center for Molecular Medicine, Faculty of Medicine, Doctoral School of Molecular Medicine, University of Debrecen, Hungary
| | - Eszter Varadi
- Horváth Csaba Memorial Laboratory of Bioseparation Sciences, Research Center for Molecular Medicine, Faculty of Medicine, Doctoral School of Molecular Medicine, University of Debrecen, Hungary
| | - Marton Szigeti
- Horváth Csaba Memorial Laboratory of Bioseparation Sciences, Research Center for Molecular Medicine, Faculty of Medicine, Doctoral School of Molecular Medicine, University of Debrecen, Hungary; Translation Glycomics Group, Research Institute of Biomolecular and Chemical Engineering, University of Pannonia, Veszprem, Hungary
| | | | | | - Andras Guttman
- Horváth Csaba Memorial Laboratory of Bioseparation Sciences, Research Center for Molecular Medicine, Faculty of Medicine, Doctoral School of Molecular Medicine, University of Debrecen, Hungary; Translation Glycomics Group, Research Institute of Biomolecular and Chemical Engineering, University of Pannonia, Veszprem, Hungary.
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21
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Akkermansia muciniphila uses human milk oligosaccharides to thrive in the early life conditions in vitro. Sci Rep 2020; 10:14330. [PMID: 32868839 PMCID: PMC7459334 DOI: 10.1038/s41598-020-71113-8] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/10/2020] [Indexed: 02/07/2023] Open
Abstract
Akkermansia muciniphila is a well-studied anaerobic bacterium specialized in mucus degradation and associated with human health. Because of the structural resemblance of mucus glycans and free human milk oligosaccharides (HMOs), we studied the ability of A. muciniphila to utilize human milk oligosaccharides. We found that A. muciniphila was able to grow on human milk and degrade HMOs. Analyses of the proteome of A. muciniphila indicated that key-glycan degrading enzymes were expressed when the bacterium was grown on human milk. Our results display the functionality of the key-glycan degrading enzymes (α-l-fucosidases, β-galactosidases, exo-α-sialidases and β-acetylhexosaminidases) to degrade the HMO-structures 2′-FL, LNT, lactose, and LNT2. The hydrolysation of the host-derived glycan structures allows A. muciniphila to promote syntrophy with other beneficial bacteria, contributing in that way to a microbial ecological network in the gut. Thus, the capacity of A. muciniphila to utilize human milk will enable its survival in the early life intestine and colonization of the mucosal layer in early life, warranting later life mucosal and metabolic health.
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22
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Mank M, Hauner H, Heck AJR, Stahl B. Targeted LC-ESI-MS 2 characterization of human milk oligosaccharide diversity at 6 to 16 weeks post-partum reveals clear staging effects and distinctive milk groups. Anal Bioanal Chem 2020; 412:6887-6907. [PMID: 32794008 PMCID: PMC7496073 DOI: 10.1007/s00216-020-02819-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/03/2020] [Accepted: 07/14/2020] [Indexed: 12/17/2022]
Abstract
Many molecular components in human milk (HM), such as human milk oligosaccharides (HMOs), assist in the healthy development of infants. It has been hypothesized that the functional benefits of HM may be highly dependent on the abundance and individual fine structures of contained HMOs and that distinctive HM groups can be defined by their HMO profiles. However, the structural diversity and abundances of individual HMOs may also vary between milk donors and at different stages of lactations. Improvements in efficiency and selectivity of quantitative HMO analysis are essential to further expand our understanding about the impact of HMO variations on healthy early life development. Hence, we applied here a targeted, highly selective, and semi-quantitative LC-ESI-MS2 approach by analyzing 2 × 30 mature human milk samples collected at 6 and 16 weeks post-partum. The analytical approach covered the most abundant HMOs up to hexasaccharides and, for the first time, also assigned blood group A and B tetrasaccharides. Principal component analysis (PCA) was employed and allowed for automatic grouping and assignment of human milk samples to four human milk groups which are related to the maternal Secretor (Se) and Lewis (Le) genotypes. We found that HMO diversity varied significantly between these four HM groups. Variations were driven by HMOs being either dependent or independent of maternal genetic Se and Le status. We found preliminary evidence for an additional HM subgroup within the Se- and Le-positive HM group I. Furthermore, the abundances of 6 distinct HMO structures (including 6'-SL and 3-FL) changed significantly with progression of lactation. Graphical abstract.
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Affiliation(s)
- Marko Mank
- Danone Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, The Netherlands.
| | - Hans Hauner
- Else Kröner-Fresenius Center for Nutritional Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675, Munich, Germany.,Nutritional Medicine Unit, Research Center for Nutrition and Food Sciences (ZIEL), Technische Universität München, Weihenstephaner Berg 1, 85354, Freising, Germany
| | - Albert J R Heck
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, 3584 CH, Utrecht, The Netherlands.,Netherlands Proteomics Center, Padualaan 8, 3584 CH, Utrecht, The Netherlands
| | - Bernd Stahl
- Danone Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, The Netherlands.,Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
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23
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Salminen S, Stahl B, Vinderola G, Szajewska H. Infant Formula Supplemented with Biotics: Current Knowledge and Future Perspectives. Nutrients 2020; 12:E1952. [PMID: 32629970 PMCID: PMC7400136 DOI: 10.3390/nu12071952] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/27/2020] [Accepted: 06/28/2020] [Indexed: 02/06/2023] Open
Abstract
Breastfeeding is natural and the optimal basis of infant nutrition and development, with many benefits for maternal health. Human milk is a dynamic fluid fulfilling an infant's specific nutritional requirements and guiding the growth, developmental, and physiological processes of the infant. Human milk is considered unique in composition, and it is influenced by several factors, such as maternal diet and health, body composition, and geographic region. Human milk stands as a model for infant formula providing nutritional solutions for infants not able to receive enough mother's milk. Infant formulas aim to mimic the composition and functionality of human milk by providing ingredients reflecting those of the latest human milk insights, such as oligosaccharides, bacteria, and bacterial metabolites. The objective of this narrative review is to discuss the most recent developments in infant formula with a special focus on human milk oligosaccharides and postbiotics.
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Affiliation(s)
- Seppo Salminen
- Functional Foods Forum, Faculty of Medicine, University of Turku, 20520 Turku, Finland;
| | - Bernd Stahl
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands;
- Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Gabriel Vinderola
- Instituto de Lactología Industrial (INLAIN, UNL-CONICET), Facultad de Ingeniería Química, Universidad Nacional del Litoral, Santiago del Estero 2829, Santa Fe 3000, Argentina;
| | - Hania Szajewska
- Department of Paediatrics at the Medical University of Warsaw, 02091 Warsaw, Poland
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24
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van Leeuwen SS. Challenges and Pitfalls in Human Milk Oligosaccharide Analysis. Nutrients 2019; 11:E2684. [PMID: 31698698 PMCID: PMC6893418 DOI: 10.3390/nu11112684] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/29/2019] [Accepted: 11/02/2019] [Indexed: 01/08/2023] Open
Abstract
Human milk oligosaccharides have been recognized as an important, functional biomolecule in mothers' milk. Moreover, these oligosaccharides have been recognized as the third most abundant component of human milk, ranging from 10-15 g/L in mature milk and up to and over 20 g/L reported in colostrum. Initially, health benefits of human milk oligosaccharides were assigned via observational studies on the differences between breastfed and bottle fed infants. Later, pools of milk oligosaccharides were isolated and used in functional studies and in recent years more specific studies into structure-function relationships have identified some advanced roles for milk oligosaccharides in the healthy development of infants. In other research, the levels, diversity, and complexity of human milk oligosaccharides have been studied, showing a wide variation in results. This review gives a critical overview of challenges in the analysis of human milk oligosaccharides. In view of the myriad functions that can be assigned, often to specific structures or classes of structures, it is very relevant to assess the levels of these structures in the human milk correctly, as well as in other biological sample materials. Ultimately, the review makes a case for a comparative, inter-laboratory study on quantitative human milk oligosaccharide analysis in all relevant biological samples.
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Affiliation(s)
- Sander S van Leeuwen
- Department of Laboratory Medicine, Cluster Human Nutrition & Health, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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25
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Fischöder T, Cajic S, Grote V, Heinzler R, Reichl U, Franzreb M, Rapp E, Elling L. Enzymatic Cascades for Tailored 13C 6 and 15N Enriched Human Milk Oligosaccharides. Molecules 2019; 24:E3482. [PMID: 31557948 PMCID: PMC6803985 DOI: 10.3390/molecules24193482] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 09/06/2019] [Accepted: 09/22/2019] [Indexed: 12/21/2022] Open
Abstract
Several health benefits, associated with human milk oligosaccharides (HMOS), have been revealed in the last decades. Further progress, however, requires not only the establishment of a simple "routine" method for absolute quantification of complex HMOS mixtures but also the development of novel synthesis strategies to improve access to tailored HMOS. Here, we introduce a combination of salvage-like nucleotide sugar-producing enzyme cascades with Leloir-glycosyltransferases in a sequential pattern for the convenient tailoring of stable isotope-labeled HMOS. We demonstrate the assembly of [13C6]galactose into lacto-N- and lacto-N-neo-type HMOS structures up to octaoses. Further, we present the enzymatic production of UDP-[15N]GlcNAc and its application for the enzymatic synthesis of [13C6/15N]lacto-N-neo-tetraose for the first time. An exemplary application was selected-analysis of tetraose in complex biological mixtures-to show the potential of tailored stable isotope reference standards for the mass spectrometry-based quantification, using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) as a fast and straightforward method for absolute quantification of HMOS. Together with the newly available well-defined tailored isotopic HMOS, this can make a crucial contribution to prospective research aiming for a more profound understanding of HMOS structure-function relations.
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Affiliation(s)
- Thomas Fischöder
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany
| | - Samanta Cajic
- Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany
| | - Valerian Grote
- Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany
| | - Raphael Heinzler
- Institute of Functional Interfaces, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany
| | - Udo Reichl
- Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany
- Chair of Bioprocess Engineering, Otto-von-Guericke-University, Universitätsplatz 2, 39106 Magdeburg, Germany
| | - Matthias Franzreb
- Institute of Functional Interfaces, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany
| | - Erdmann Rapp
- Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany.
- glyXera GmbH, Leipziger Straße 44, 39120 Magdeburg, Germany.
| | - Lothar Elling
- Laboratory for Biomaterials, Institute for Biotechnology and Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Pauwelsstraße 20, 52074 Aachen, Germany.
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26
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Gao X, Lu Y, Wei M, Yang M, Zheng C, Wang C, Zhang Y, Huang L, Wang Z. Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Analysis of Human Milk Neutral and Sialylated Free Oligosaccharides Using Girard's Reagent P On-Target Derivatization. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:8958-8966. [PMID: 31334644 DOI: 10.1021/acs.jafc.9b02635] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The functional role of human milk oligosaccharides (HMOs) is closely associated with their type, composition, and structure. However, a detailed analysis of HMOs is difficult because neutral oligosaccharides (NHMOs) are mixed with sialylated oligosaccharides (SHMOs) in milk. Here, NHMOs were separated from SHMOs by DEAE-52 anion chromatography, and lactose was removed by graphite carbon solid-phase extraction. Lactose-free NHMOs were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) based on Girard's reagent P on-target derivatization (GPOD), and SHMOs were analyzed by MALDI-TOF-MS following selective sialic acid derivatization and GPOD. Sixty-four oligosaccharides were detected: 36 NHMOs, of which 28 were fucosylated, and 28 SHMOs, of which 8 with α-2,3-linked monosialic acid, 2 with α-2,3-linked disialic acid, 10 with α-2,6-linked monosialic acid, 2 with α-2,6-linked disialic acid, and 5 with both α-2,3- and α-2,6-linked disialic acid. These findings provide the groundwork for further characterization of the structure and activity of HMOs.
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Affiliation(s)
| | | | | | | | - CaiXia Zheng
- The Second Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710069 , China
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27
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Monteagudo-Mera A, Rastall RA, Gibson GR, Charalampopoulos D, Chatzifragkou A. Adhesion mechanisms mediated by probiotics and prebiotics and their potential impact on human health. Appl Microbiol Biotechnol 2019; 103:6463-6472. [PMID: 31267231 PMCID: PMC6667406 DOI: 10.1007/s00253-019-09978-7] [Citation(s) in RCA: 363] [Impact Index Per Article: 60.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/07/2019] [Accepted: 06/10/2019] [Indexed: 12/14/2022]
Abstract
Adhesion ability to the host is a classical selection criterion for potential probiotic bacteria that could result in a transient colonisation that would help to promote immunomodulatory effects, as well as stimulate gut barrier and metabolic functions. In addition, probiotic bacteria have a potential protective role against enteropathogens through different mechanisms including production of antimicrobial compounds, reduction of pathogenic bacterial adhesion and competition for host cell binding sites. The competitive exclusion by probiotic bacteria has a beneficial effect not only on the gut but also in the urogenital tract and oral cavity. On the other hand, prebiotics may also act as barriers to pathogens and toxins by preventing their adhesion to epithelial receptors. In vitro studies with different intestinal cell lines have been widely used along the last decades to assess the adherence ability of probiotic bacteria and pathogen antagonism. However, extrapolation of these results to in vivo conditions still remains unclear, leading to the need of optimisation of more complex in vitro approaches that include interaction with the resident microbiota to address the current limitations. The aim of this mini review is to provide a comprehensive overview on the potential effect of the adhesive properties of probiotics and prebiotics on the host by focusing on the most recent findings related with adhesion and immunomodulatory and antipathogenic effect on human health.
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Affiliation(s)
- Andrea Monteagudo-Mera
- Biomedical Sciences, School of Biological Sciences, University of Reading, Reading, RG6 6AH, UK.
| | - Robert A Rastall
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, PO Box 226, Reading, RG6 6AP, UK
| | - Glenn R Gibson
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, PO Box 226, Reading, RG6 6AP, UK
| | - Dimitris Charalampopoulos
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, PO Box 226, Reading, RG6 6AP, UK
| | - Afroditi Chatzifragkou
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, PO Box 226, Reading, RG6 6AP, UK.
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28
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Xiao L, van De Worp WR, Stassen R, van Maastrigt C, Kettelarij N, Stahl B, Blijenberg B, Overbeek SA, Folkerts G, Garssen J, Van't Land B. Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells. Eur J Immunol 2019; 49:1001-1014. [PMID: 30900752 PMCID: PMC6619030 DOI: 10.1002/eji.201847971] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 02/19/2019] [Accepted: 03/19/2019] [Indexed: 12/17/2022]
Abstract
Human milk oligosaccharides (HMOS) are a complex mixture of bioactive components supporting the immune development of breastfed‐infants. Dendritic cells (DCs) play a central role in the regulation of immune responses, being specialized in antigen presentation and driving T‐cell priming as well as differentiation. However, little is known about the direct effects of HMOS on human DC phenotypes and functions. Here, we report that HMOS mixture isolated from pooled human milk, induced semi‐maturation of human monocytes‐derived DCs (moDCs), and elevated levels of IL‐10, IL‐27 and IL‐6 but not IL‐12p70 and TNF‐α. Consistently, HMOS‐conditioned human moDCs promoted Treg generation from naïve CD4+ T cells. Interestingly, HMOS limited LPS‐induced maturation of human moDCs, while maintained IL‐10 and IL‐27 secretion and reduced LPS‐induced production of IL‐12p70, IL‐6 and TNF‐α. Furthermore, HMOS+LPS‐stimulated DCs induced a higher frequency of Tregs and increased IL‐10 production, while a reduction in Tbet+Th1 frequency and IFN‐γ production was detected as compared to LPS‐DCs. The regulatory effects of HMOS seemed to be mediated by interactions of HMOS with receptors, including but not limited to TLR4 and DC‐SIGN on human moDCs. In conclusion, HMOS contain tolerogenic factors influencing human moDCs and thereby modulating the development of the neonatal immune system.
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Affiliation(s)
- Ling Xiao
- Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
| | - Wouter Rph van De Worp
- Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.,Department of Respiratory Medicine, NUTRIM, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Roderick Stassen
- Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
| | - Celine van Maastrigt
- Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
| | - Nienke Kettelarij
- Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands
| | - Bernd Stahl
- Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands
| | - Bernadet Blijenberg
- Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands
| | - Saskia A Overbeek
- Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.,Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands
| | - Gert Folkerts
- Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
| | - Johan Garssen
- Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.,Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands
| | - Belinda Van't Land
- Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands.,Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
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29
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Agoston K, Hederos MJ, Bajza I, Dekany G. Kilogram scale chemical synthesis of 2′-fucosyllactose. Carbohydr Res 2019; 476:71-77. [DOI: 10.1016/j.carres.2019.03.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 03/12/2019] [Accepted: 03/14/2019] [Indexed: 12/21/2022]
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30
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El-Hawiet A, Chen Y, Shams-Ud-Doha K, Kitova EN, Kitov PI, Bode L, Hage N, Falcone FH, Klassen JS. Screening natural libraries of human milk oligosaccharides against lectins using CaR-ESI-MS. Analyst 2018; 143:536-548. [PMID: 29239412 DOI: 10.1039/c7an01397c] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Human milk oligosaccharides (HMOs) afford many health benefits to breast-fed infants, such as protection against infection and regulation of the immune system, through the formation of non-covalent interactions with protein receptors. However, the molecular details of these interactions are poorly understood. Here, we describe the application of catch-and-release electrospray ionization mass spectrometry (CaR-ESI-MS) for screening natural libraries of HMOs against lectins. The HMOs in the libraries were first identified based on molecular weights (MWs), ion mobility separation arrival times (IMS-ATs) and collision-induced dissociation (CID) fingerprints of their deprotonated anions. The libraries were then screened against lectins and the ligands identified from the MWs, IMS-ATs and CID fingerprints of HMOs released from the lectin in the gas phase. To demonstrate the assay, four fractions, extracted from pooled human milk and containing ≥35 different HMOs, were screened against a C-terminal fragment of human galectin-3 (hGal-3C), for which the HMOs specificities have been previously investigated, and a fragment of the blood group antigen-binding adhesin (BabA) from Helicobacter pylori, for which the HMO specificities have not been previously established. The structures of twenty-one ligands, corresponding to both neutral and acidic HMOs, of hGal-3C were identified; all twenty-one were previously shown to be ligands for this lectin. The presence of HMO ligands at six other MWs was also ascertained. Application of the assay to BabA revealed nineteen specific HMO structures that are recognized by the protein and HMO ligands at two other MWs. Notably, it was found that BabA exhibits broad specificity for HMOs, and recognizes both neutral HMOs, including non-fucosylated ones, and acidic HMOs. The results of competitive binding experiments indicate that HMOs can interact with BabA at previously unknown binding sites. The affinities of eight purified HMOs for BabA were measured by ESI-MS and found to be in the 103 M-1 to 104 M-1 range.
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Affiliation(s)
- Amr El-Hawiet
- Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
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31
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Mank M, Welsch P, Heck AJR, Stahl B. Label-free targeted LC-ESI-MS 2 analysis of human milk oligosaccharides (HMOS) and related human milk groups with enhanced structural selectivity. Anal Bioanal Chem 2018; 411:231-250. [PMID: 30443773 DOI: 10.1007/s00216-018-1434-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 10/02/2018] [Accepted: 10/16/2018] [Indexed: 01/19/2023]
Abstract
Human milk (HM) supports the healthy development of neonates and exerts many of its beneficial effects via contained free human milk oligosaccharides (HMOS). These HMOS exhibit a complexity and structural diversity that pose a significant analytical challenge. A detailed characterization of HMOS is essential as every individual structure may have a different function/activity. Certain HMOS isomers may even fundamentally differ in their biological function, and especially their characterization by LC or LC-MS is often impaired by co-elution phenomena. Thus, more efficient analytical methodologies with enhanced structural selectivity are required. Therefore, we developed a negative ion mode LC-ESI-MS2 approach featuring straightforward sample preparation, environmentally friendly EtOH gradient elution, and enhanced, semiquantitative characterization of distinct native HMOS by multiple reaction monitoring (MRM). Our MRM-LC-MS setup takes advantage of highly selective, glycan configuration-dependent collision-induced dissociation (CID) fragments to identify individual neutral and acidic HMOS. Notably, many human milk oligosaccharide isomers could be distinguished in a retention time-independent manner. This contrasts with other contemporary MRM approaches relying on rather unspecific MRM transitions. Our method was used to determine the most abundant human milk tri-, tetra-, penta-, and hexaoses semiquantitatively in a single LC-MS assay. Detected HMO structures included fucosyllactoses (e.g., 2'-FL), lacto-N-difucotetraose (LDFT), lacto-N-tetraoses (LNTs), lacto-N-fucopentaoses (e.g., LNFP I, LNFP II and III), lacto-N-difucohexaoses (LNDFHs) as well as sialyllactoses (SLs) and tentatively assigned blood group A and B tetrasaccharides from which correct human milk type assignment could be also demonstrated. Correctness of milk typing was validated for milk groups I-IV by high pressure anion exchange chromatography (HPAEC) coupled to pulsed amperometric detection (HPAEC-PAD). Graphical Abstract ᅟ.
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Affiliation(s)
- Marko Mank
- Danone Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands.
| | - Philipp Welsch
- Danone Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
| | - Albert J R Heck
- Biomolecular Mass Spectrometry and Proteomics Division, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH, Utrecht, the Netherlands
| | - Bernd Stahl
- Danone Nutricia Research, Uppsalalaan 12, 3584 CT, Utrecht, the Netherlands
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32
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Elwakiel M, Hageman JA, Wang W, Szeto IM, van Goudoever JB, Hettinga KA, Schols HA. Human Milk Oligosaccharides in Colostrum and Mature Milk of Chinese Mothers: Lewis Positive Secretor Subgroups. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:7036-7043. [PMID: 29909634 PMCID: PMC6150670 DOI: 10.1021/acs.jafc.8b02021] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/15/2018] [Accepted: 06/16/2018] [Indexed: 05/24/2023]
Abstract
To study the variability in human milk oligosaccharide (HMO) composition of Chinese human milk over a 20-wk lactation period, HMO profiles of 30 mothers were analyzed using CE-LIF. This study showed that total HMO concentrations in Chinese human milk decreased significantly over a 20-wk lactation period, independent of the mother's SeLe status, although with individual variations. In addition, total acidic and neutral HMO concentrations in Chinese human milk decreased over lactation, and levels are driven by their mother's SeLe status. Analysis showed that total neutral fucosylated HMO concentrations in Chinese human milk were higher in the two secretor groups as compared to the nonsecretor group. On the basis of the total neutral fucosylated HMO concentrations in Chinese human milk, HMO profiles within the Se+Le+ group can be divided into two subgroups. HMOs that differed in level between Se+Le+ subgroups were 2'FL, DF-L, LNFP I, and F-LNO. HMO profiles in Dutch human milk also showed Se+Le+ subgroup division, with 2'FL, LNT, and F-LNO as the driving force.
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Affiliation(s)
- M. Elwakiel
- Laboratory
of Food Chemistry, and Food Quality and Design Group, Wageningen University & Research, Bornse Weilanden 9, Wageningen 6708 WG, The Netherlands
| | - J. A. Hageman
- Biometris-Applied
Statistics, Wageningen University &
Research, Droevendaalsesteeg
1, Wageningen 6708 PB, The Netherlands
| | - W. Wang
- Inner
Mongolia Yili Industrial Group Co., Ltd., Jinshan Road 8, Hohhot 010110, China
| | - I. M. Szeto
- Inner
Mongolia Yili Industrial Group Co., Ltd., Jinshan Road 8, Hohhot 010110, China
| | - J. B. van Goudoever
- Department
of Pediatrics, Emma Children’s Hospital
− AMC, Meibergdreef
9, Amsterdam 1100 DD, The Netherlands
| | - K. A. Hettinga
- Laboratory
of Food Chemistry, and Food Quality and Design Group, Wageningen University & Research, Bornse Weilanden 9, Wageningen 6708 WG, The Netherlands
| | - H. A. Schols
- Laboratory
of Food Chemistry, and Food Quality and Design Group, Wageningen University & Research, Bornse Weilanden 9, Wageningen 6708 WG, The Netherlands
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Özcan E, Sela DA. Inefficient Metabolism of the Human Milk Oligosaccharides Lacto- N-tetraose and Lacto- N-neotetraose Shifts Bifidobacterium longum subsp. infantis Physiology. Front Nutr 2018; 5:46. [PMID: 29900174 PMCID: PMC5989456 DOI: 10.3389/fnut.2018.00046] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/09/2018] [Indexed: 12/14/2022] Open
Abstract
Human milk contains a high concentration of indigestible oligosaccharides, which likely mediated the coevolution of the nursing infant with its gut microbiome. Specifically, Bifidobacterium longum subsp. infantis (B. infantis) often colonizes the infant gut and utilizes these human milk oligosaccharides (HMOs) to enrich their abundance. In this study, the physiology and mechanisms underlying B. infantis utilization of two HMO isomers lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT) was investigated in addition to their carbohydrate constituents. Both LNT and LNnT utilization induced a significant shift in the ratio of secreted acetate to lactate (1.7–2.0) in contrast to the catabolism of their component carbohydrates (~1.5). Inefficient metabolism of LNnT prompts B. infantis to shunt carbon toward formic acid and ethanol secretion. The global transcriptome presents genomic features differentially expressed to catabolize these two HMO species that vary by a single glycosidic linkage. Furthermore, a measure of strain-level variation exists between B. infantis isolates. Regardless of strain, inefficient HMO metabolism induces the metabolic shift toward formic acid and ethanol production. Furthermore, bifidobacterial metabolites reduced LPS-induced inflammation in a cell culture model. Thus, differential metabolism of milk glycans potentially drives the emergent physiology of host-microbial interactions to impact infant health.
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Affiliation(s)
- Ezgi Özcan
- Department of Food Science, University of Massachusetts, Amherst, MA, United States
| | - David A Sela
- Department of Food Science, University of Massachusetts, Amherst, MA, United States.,Department of Microbiology, University of Massachusetts, Amherst, MA, United States.,Department of Microbiology and Physiological Systems and Center for Microbiome Research, University of Massachusetts Medical School, Worcester, MA, United States
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Challenges in Separations of Proteins and Small Biomolecules and the Role of Modern Mass Spectroscopy Tools for Solving Them, as Well as Bypassing Them, in Structural Analytical Studies of Complex Biomolecular Mixtures. SEPARATIONS 2018. [DOI: 10.3390/separations5010011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Thurl S, Munzert M, Boehm G, Matthews C, Stahl B. Systematic review of the concentrations of oligosaccharides in human milk. Nutr Rev 2018; 75:920-933. [PMID: 29053807 PMCID: PMC5914348 DOI: 10.1093/nutrit/nux044] [Citation(s) in RCA: 273] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Context Oligosaccharides are the third largest solid component in human milk. These diverse compounds are thought to have numerous beneficial functions in infants, including protection against infectious diseases. The structures of more than 100 oligosaccharides in human milk have been elucidated so far. Objective The aim of this review was to identify the main factors that affect the concentrations of oligosaccharides in human milk and to determine whether it is possible to calculate representative and reliable mean concentrations. Data Sources A comprehensive literature search on oligosaccharide concentrations in human milk was performed in 6 electronic databases: BIOSIS, Current Contents Search, Embase, Lancet Titles, MEDLINE and PubMed. Study Selection The initial search resulted in 1363 hits. After the elimination of duplicates, the literature was screened. The application of strict inclusion criteria resulted in 21 articles selected. Data Extraction Oligosaccharide concentrations, both mean values and single values, reported in the literature were sorted by gestational age, secretor status of mothers, and defined lactation periods. Results Mean concentrations, including confidence limits, of 33 neutral and acidic oligosaccharides reported could be calculated. Concentrations of oligosaccharides in human milk show variations that are dependent on both the secretor type of the mother and the lactation period as examined by analyses of variance. In addition, large interlaboratory variations in the data were observed. Conclusions Worldwide interlaboratory quantitative analyses of identical milk samples would be required to identify the most reliable methods of determining concentrations of oligosaccharides in human milk. The data presented here contribute to the current knowledge about the composition and quantities of oligosaccharides in human milk and may foster greater understanding of the biological functions of these compounds.
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Affiliation(s)
- Stephan Thurl
- Department of Food Technology, Fulda University of Applied Sciences, Fulda, Germany
| | - Manfred Munzert
- Bavarian State Research Centre for Agriculture, Freising, Germany
| | | | | | - Bernd Stahl
- Danone Nutricia Research, Utrecht, the Netherlands
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Ayechu-Muruzabal V, van Stigt AH, Mank M, Willemsen LEM, Stahl B, Garssen J, Van't Land B. Diversity of Human Milk Oligosaccharides and Effects on Early Life Immune Development. Front Pediatr 2018; 6:239. [PMID: 30250836 PMCID: PMC6140589 DOI: 10.3389/fped.2018.00239] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 08/07/2018] [Indexed: 12/12/2022] Open
Abstract
One of the well-known features of human milk, is the capacity to protect against the risk and impact of neonatal infections, as well as to influence the onset of allergic and metabolic disease manifestations. The major objective of this review is to provide a detailed overview regarding the role of human milk, more specifically the diversity in human milk oligosaccharides (HMOS), on early life immune development. Novel insights in immune modulatory effects of HMOS obtained by in vitro as well as in vivo studies, adds to the understanding on how early life nutrition may impact immune development. Extensive description and analysis of single HMOS contributing to the diversity within the composition provided during breastfeeding will be discussed with specific emphasis on immune development and the susceptibility to neonatal and childhood infections.
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Affiliation(s)
- Veronica Ayechu-Muruzabal
- Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Arthur H van Stigt
- Pediatric Immunology, Laboratory of Translational Immunology, The Wilhelmina Children's Hospital, University Medical Center, Utrecht, Netherlands
| | - Marko Mank
- Department of Immunology and Department of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, Netherlands
| | - Linette E M Willemsen
- Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Bernd Stahl
- Department of Immunology and Department of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.,Department of Immunology and Department of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, Netherlands
| | - Belinda Van't Land
- Pediatric Immunology, Laboratory of Translational Immunology, The Wilhelmina Children's Hospital, University Medical Center, Utrecht, Netherlands.,Department of Immunology and Department of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, Netherlands
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Thongaram T, Hoeflinger JL, Chow J, Miller MJ. Human milk oligosaccharide consumption by probiotic and human-associated bifidobacteria and lactobacilli. J Dairy Sci 2017; 100:7825-7833. [PMID: 28780103 DOI: 10.3168/jds.2017-12753] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 06/14/2017] [Indexed: 01/04/2023]
Abstract
Human milk contains high concentrations of nondigestible complex oligosaccharides (human milk oligosaccharides; HMO) that reach the colon and are subsequently fermented by the infant gut microbiota. Using a high-throughput, low-volume growth determination, we evaluated the ability of 12 lactobacilli and 12 bifidobacteria strains, including several commercial probiotics, to ferment HMO and their constituent monomers. Of the 24 strains tested, only Bifidobacterium longum ssp. infantis ATCC 15697 and Bifidobacterium infantis M-63 were able to ferment 3'-sialyllactose, 6'-sialyllactose, 2'-fucosyllactose, and 3'-fucosyllactose. Bifidobacterium infantis M-63 degraded almost 90% of the 2'-fucosyllactose but left most of the fucose in the supernatant, as detected by HPLC. Among bifidobacteria, only the B. infantis strains and Bifidobacterium breve ATCC 15700 were able to ferment lacto-N-neotetraose (LNnT). Among lactobacilli, Lactobacillus acidophilus NCFM was found to be the most efficient at utilizing LNnT. The extracellular β-galactosidase (lacL, LBA1467) of L. acidophilus NCFM cleaves the terminal galactose of LNnT for growth, leaving lacto-N-triose II in the media as detected by HPLC. Inactivation of lacL abolishes growth of L. acidophilus NCFM on LNnT. These results contribute to our knowledge of HMO-microbe interactions and demonstrate the potential for synbiotic combinations of pre- and probiotics.
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Affiliation(s)
- Taksawan Thongaram
- Department of Food Science and Human Nutrition, University of Illinois, Urbana 61801
| | - Jennifer L Hoeflinger
- Department of Food Science and Human Nutrition, University of Illinois, Urbana 61801
| | | | - Michael J Miller
- Department of Food Science and Human Nutrition, University of Illinois, Urbana 61801.
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Vandenplas Y, Ludwig T, Bouritius H, Alliet P, Forde D, Peeters S, Huet F, Hourihane J. Randomised controlled trial demonstrates that fermented infant formula with short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides reduces the incidence of infantile colic. Acta Paediatr 2017; 106:1150-1158. [PMID: 28328065 PMCID: PMC5485044 DOI: 10.1111/apa.13844] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 11/28/2016] [Accepted: 03/17/2017] [Indexed: 12/20/2022]
Abstract
AIM We examined the effects on gastrointestinal (GI) tolerance of a novel infant formula that combined specific fermented formula (FERM) with short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS), with a 9:1 ratio and concentration of 0.8 g/100 mL. METHODS This prospective, double-blind, randomised, controlled trial comprised 432 healthy, term infants aged 0-28 days whose parents decided to not start, or discontinued, breastfeeding. Infant formula with scGOS/lcFOS+50%FERM, scGOS/lcFOS+15%FERM, 50%FERM and scGOS/lcFOS were tested. Parents completed standardised seven-day diaries on GI symptoms, crying, sleeping and stool characteristics each month until the infants were 17 weeks. RESULTS All the formulas were well tolerated. At four weeks, the overall incidence of infantile colic was significantly lower (8%) with scGOS/lcFOS+50%FERM than scGOS/lcFOS (20%, p = 0.034) or 50%FERM (20%, p = 0.036). Longitudinal modelling showed that scGOS/lcFOS+50%FERM-fed infants also displayed a persistently lower daily crying duration and showed a consistent stool-softening effect than infants who received formula without scGOS/lcFOS. CONCLUSION The combination of fermented formula with scGOS/lcFOS was well tolerated and showed a lower overall crying time, a lower incidence of infantile colic and a stool-softening effect in healthy term infants. These findings suggest for the first time that a specific infant formula has a preventive effect on infantile colic in formula-fed infants.
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Affiliation(s)
- Yvan Vandenplas
- Department of Pediatrics; UZ, Vrije Universiteit Brussel; Brussels Belgium
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39
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Gross JH. Matrix-Assisted Laser Desorption/Ionization. Mass Spectrom (Tokyo) 2017. [DOI: 10.1007/978-3-319-54398-7_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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40
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Partly Fermented Infant Formulae With Specific Oligosaccharides Support Adequate Infant Growth and Are Well-Tolerated. J Pediatr Gastroenterol Nutr 2016; 63:e43-53. [PMID: 27472478 PMCID: PMC5051523 DOI: 10.1097/mpg.0000000000001360] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Fermented formulae (FERM) and a specific mixture of 90% short-chain galacto-oligosaccharides and 10% long-chain fructo-oligosaccharides (scGOS/lcFOS; 9:1) have a potential beneficial effect on gastrointestinal function and microbiota development in infants. The present study assessed the safety and tolerance of the combination of partly fermented infant milk formulae and scGOS/lcFOS compared with either 1 feature, in healthy term infants. METHODS Four hundred thirty-two infants were enrolled before 28 days of age and followed up to 17 weeks of age and assigned to 1 of the 4 groups: (i) formula with scGOS/lcFOS, (ii) scGOS/lcFOS + 15% FERM, (iii) scGOS/lcFOS + 50% FERM, or (iv) 50% fermented formula (50% FERM). Primary outcome was daily weight gain during intervention (equivalence criterion: difference in daily weight gain ≤3 g/day). Infants' anthropometrics, formula intake, number, and type of (serious) AEs were monitored monthly. Stool samples were collected at baseline and after 17 weeks for analysis of physiological and microbiological parameters. RESULTS Equivalence of weight gain per day was demonstrated in both the intention-to-treat and per-protocol population, with a mean weight gain (SD) of 29.7 (6.1), 28.2 (4.8), 28.5 (5.0), and 28.7 (5.9) g/day for the groups i to iv respectively. No differences were observed in other growth parameters, formula intake, and the number or severity of AEs. In all scGOS/lcFOS-containing formulae, a beneficial effect of scGOS/lcFOS was observed, indicated by the lower pH, lower Clostridium difficile levels, and higher secretory immunoglobulin A levels. CONCLUSIONS The partly fermented infant milk formulae containing the specific mixture scGOS/lcFOS were well-tolerated and resulted in normal growth in healthy infants.
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Lowry CA, Smith DG, Siebler PH, Schmidt D, Stamper CE, Hassell JE, Yamashita PS, Fox JH, Reber SO, Brenner LA, Hoisington AJ, Postolache TT, Kinney KA, Marciani D, Hernandez M, Hemmings SMJ, Malan-Muller S, Wright KP, Knight R, Raison CL, Rook GAW. The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health. Curr Environ Health Rep 2016; 3:270-86. [PMID: 27436048 PMCID: PMC5763918 DOI: 10.1007/s40572-016-0100-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The hygiene or "Old Friends" hypothesis proposes that the epidemic of inflammatory disease in modern urban societies stems at least in part from reduced exposure to microbes that normally prime mammalian immunoregulatory circuits and suppress inappropriate inflammation. Such diseases include but are not limited to allergies and asthma; we and others have proposed that the markedly reduced exposure to these Old Friends in modern urban societies may also increase vulnerability to neurodevelopmental disorders and stress-related psychiatric disorders, such as anxiety and affective disorders, where data are emerging in support of inflammation as a risk factor. Here, we review recent advances in our understanding of the potential for Old Friends, including environmental microbial inputs, to modify risk for inflammatory disease, with a focus on neurodevelopmental and psychiatric conditions. We highlight potential mechanisms, involving bacterially derived metabolites, bacterial antigens, and helminthic antigens, through which these inputs promote immunoregulation. Though findings are encouraging, significant human subjects' research is required to evaluate the potential impact of Old Friends, including environmental microbial inputs, on biological signatures and clinically meaningful mental health prevention and intervention outcomes.
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Affiliation(s)
- Christopher A Lowry
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA.
| | - David G Smith
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA
| | - Philip H Siebler
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA
| | - Dominic Schmidt
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA
| | - Christopher E Stamper
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA
| | - James E Hassell
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA
| | - Paula S Yamashita
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA
| | - James H Fox
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA
| | - Stefan O Reber
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, D-89081, Ulm, Germany
| | - Lisa A Brenner
- Departments of Psychiatry, Physical Medicine & Rehabilitation, University of Colorado, Anschutz School of Medicine, Aurora, CO, 80045, USA
- Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Denver, CO, 80220, USA
| | - Andrew J Hoisington
- Department of Civil and Environmental Engineering, United States Air Force Academy, Colorado Springs, CO, 80840, USA
| | - Teodor T Postolache
- University of Maryland School of Medicine, Baltimore, MD, USA
- Rocky Mountain MIRECC, Denver, CO, 80220, USA
- VISN 5 MIRECC, Baltimore, MD, 21201, USA
| | - Kerry A Kinney
- Civil, Architectural and Environmental Engineering, University of Texas Austin, Austin, TX, 78712, USA
| | | | - Mark Hernandez
- Department of Civil, Environmental and Architectural Engineering, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Sian M J Hemmings
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, 7505, South Africa
| | - Stefanie Malan-Muller
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, 7505, South Africa
| | - Kenneth P Wright
- Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, 1725 Pleasant Street, Boulder, CO, 80309-0354, USA
| | - Rob Knight
- Departments of Pediatrics and Computer Science and Engineering, and Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, 92093, USA
| | - Charles L Raison
- School of Human Ecology and School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Graham A W Rook
- Center for Clinical Microbiology, UCL (University College London), WC1E 6BT, London, UK
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Zhang Y, Wang J, Liu J, Han J, Xiong S, Yong W, Zhao Z. Combination of ESI and MALDI mass spectrometry for qualitative, semi-quantitative and in situ analysis of gangliosides in brain. Sci Rep 2016; 6:25289. [PMID: 27142336 PMCID: PMC4855142 DOI: 10.1038/srep25289] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 04/14/2016] [Indexed: 01/04/2023] Open
Abstract
Gangliosides are a family of complex lipids that are abundant in the brain. There is no doubt the investigations about the distribution of gangliosides in brian and the relationship between gangliosides and Alzheimer’s disease is profound. However, these investigations are full of challenges due to the structural complexity of gangliosides. In this work, the method for efficient extraction and enrichment of gangliosides from brain was established. Moreover, the distribution of gangliosides in brain was obtained by matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI). It was found that 3-aminoquinoline (3-AQ) as matrix was well-suited for MALDI MS analysis of gangliosides in negative ion mode. In addition, the pretreatment by ethanol (EtOH) cleaning brain section and the addition of ammonium formate greatly improved the MS signal of gangliosides in the brain section when MALDI MSI analysis was employed. The distribution of ganliosides in cerebral cortex, hippocampus and cerebellum was respectively acquired by electrospray ionization (ESI) MS and MALDI MSI, and the data were compared for reliability evaluation of MALDI MSI. Further, applying MALDI MSI technology, the distribution of gangliosides in amyloid precursor protein transgenic mouse brain was obtained, which may provide a new insight for bioresearch of Alzheimer’s disease (AD).
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Affiliation(s)
- Yangyang Zhang
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing Mass Spectrum Center, Beijing, China
| | - Jun Wang
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Jian'an Liu
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing Mass Spectrum Center, Beijing, China
| | - Juanjuan Han
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing Mass Spectrum Center, Beijing, China
| | - Shaoxiang Xiong
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing Mass Spectrum Center, Beijing, China
| | - Weidong Yong
- Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Zhenwen Zhao
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing Mass Spectrum Center, Beijing, China.,Graduate School, University of Chinese Academy of Sciences, Beijing, China
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Qu S, Barrett-Wilt G, Fonseca LM, Rankin SA. A profile of sphingolipids and related compounds tentatively identified in yak milk. J Dairy Sci 2016; 99:5083-5092. [PMID: 27085416 DOI: 10.3168/jds.2015-10431] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 02/20/2016] [Indexed: 01/11/2023]
Abstract
This work characterized a fraction of constituents in yak milk within the realm of approximately 1,000 to 3,000 Da using matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry. Eleven samples of yak milk powder from the Sichuan province of China were received by the Department of Food Science, University of Wisconsin-Madison, and stored at room temperature until analysis. Sample preparation involved delipidation and deproteinization of yak milk samples and cold ethanol precipitation. Subsequently, MALDI time-of-flight mass spectrometry was performed in positive ion, reflector mode (AB Sciex TOF/TOF 4800 MALDI; AB Sciex, Foster City, CA). The instrument was first calibrated with the manufacturer's 6-peptide mixture, and each spectrum was internally calibrated using the accurate mass of ACTH Fragment 18-39 standard peptide (protonated mass at m/z 2464.199) present in each sample. Laser power was adjusted for the calibration standards and for each sample so that the signal obtained for the most-abundant ion in each spectrum could be maximized, or kept below ~2×10(4) to preserve spectral quality. Structure and name based on mass were matched using the Metlin metabolite database (https://metlin.scripps.edu/index.php). Results of the current work for yak milk powder showed a large variety of sphingolipid structures with clusters around 1,200, 1,600, and 2,000 Da. The profiling matched several glycosphingolipids, such as gangliosides GA1, GD1a, GD1b, GD3, GM1, GM2, GM3, and GT2 and several other unique moieties, including deaminated neuraminic acid (KDN) oligosaccharides, and fucose containing gangliosides. Matrix preparation and MALDI time-of-flight parameters were important factors established in this work to allow high resolution profiling of complex sphingolipids in yak powder milk.
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Affiliation(s)
- S Qu
- Department of Food Science, Mass Spectrometry/Proteomics Facility, University of Wisconsin-Madison 53706
| | - G Barrett-Wilt
- Biotechnology Center, Mass Spectrometry/Proteomics Facility, University of Wisconsin-Madison 53706
| | - L M Fonseca
- Department of Food Science, Mass Spectrometry/Proteomics Facility, University of Wisconsin-Madison 53706; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasília BEX 18183-12-3, Brazil; School of Veterinary Medicine, Universidade Federal de Minas Gerais, Belo Horizonte MG 31270-901, Brazil
| | - S A Rankin
- Department of Food Science, Mass Spectrometry/Proteomics Facility, University of Wisconsin-Madison 53706.
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Mantovani V, Galeotti F, Maccari F, Volpi N. Recent advances on separation and characterization of human milk oligosaccharides. Electrophoresis 2016; 37:1514-24. [PMID: 26801168 DOI: 10.1002/elps.201500477] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 12/03/2015] [Accepted: 12/04/2015] [Indexed: 01/14/2023]
Abstract
Free human milk oligosaccharides (HMOs) are unique due to their highly complex nature and important emerging biological and protective functions during early life such as prebiotic activity, pathogen deflection, and epithelial and immune cell modulation. Moreover, four genetically determined heterogeneous HMO secretory groups are known to be based on their structure and composition. Over the years, several analytical techniques have been applied to characterize and quantitate HMOs, including nuclear magnetic resonance spectroscopy, high-performance liquid chromatography (HPLC), high pH anion-exchange chromatography, off-line and on-line mass spectrometry (MS), and capillary electrophoresis (CE). Even if these techniques have proven to be efficient and simple, most glycans have no significant UV absorption and derivatization with fluorophore groups prior to separation usually results in higher sensitivity and an improved chromatographic/electrophoretic profile. Consequently, the analysis by HPLC/CE of derivatized milk oligosaccharides with different chromophoric active tags has been developed. However, UV or fluorescence detection does not provide specific structural information and this is a key point in particular related to the highly complex nature of the milk glycan mixtures. As a consequence, for a specific determination of complex mixtures of oligomers, analytical separation is usually required with evaluation by means of MS, which has been successfully applied to HMOs, resulting in efficient compositional analysis and profiling in various milk samples. This review aims to give an overview of the current state-of-the-art techniques used in HMO analysis.
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Affiliation(s)
- Veronica Mantovani
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Fabio Galeotti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Francesca Maccari
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicola Volpi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
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45
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O'Neill EC, Field RA. Enzymatic synthesis using glycoside phosphorylases. Carbohydr Res 2015; 403:23-37. [PMID: 25060838 PMCID: PMC4336185 DOI: 10.1016/j.carres.2014.06.010] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 05/29/2014] [Accepted: 06/09/2014] [Indexed: 01/10/2023]
Abstract
Carbohydrate phosphorylases are readily accessible but under-explored catalysts for glycoside synthesis. Their use of accessible and relatively stable sugar phosphates as donor substrates underlies their potential. A wide range of these enzymes has been reported of late, displaying a range of preferences for sugar donors, acceptors and glycosidic linkages. This has allowed this class of enzymes to be used in the synthesis of diverse carbohydrate structures, including at the industrial scale. As more phosphorylase enzymes are discovered, access to further difficult to synthesise glycosides will be enabled. Herein we review reported phosphorylase enzymes and the glycoside products that they have been used to synthesise.
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Affiliation(s)
- Ellis C O'Neill
- Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK
| | - Robert A Field
- Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
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46
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47
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Abstract
The important roles played by human milk oligosaccharides (HMOS), the third major component of human milk, in the health of breast-fed infants have been increasingly recognized, as the structures of more than 100 different HMOS have now been elucidated. Despite the recognition of the various functions of HMOS as prebiotics, antiadhesive antimicrobials, and immunomodulators, the roles and the applications of individual HMOS species are less clear. This is mainly due to the limited accessibility to large amounts of individual HMOS in their pure forms. Current advances in the development of enzymatic, chemoenzymatic, whole-cell, and living-cell systems allow for the production of a growing number of HMOS in increasing amounts. This effort will greatly facilitate the elucidation of the important roles of HMOS and allow exploration into the applications of HMOS both as individual compounds and as mixtures of defined structures with desired functions. The structures, functions, and enzyme-catalyzed synthesis of HMOS are briefly surveyed to provide a general picture about the current progress on these aspects. Future efforts should be devoted to elucidating the structures of more complex HMOS, synthesizing more complex HMOS including those with branched structures, and developing HMOS-based or HMOS-inspired prebiotics, additives, and therapeutics.
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Affiliation(s)
- Xi Chen
- Department of Chemistry, University of California, Davis, California, USA
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48
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Meli F, Puccio G, Cajozzo C, Ricottone GL, Pecquet S, Sprenger N, Steenhout P. Growth and safety evaluation of infant formulae containing oligosaccharides derived from bovine milk: a randomized, double-blind, noninferiority trial. BMC Pediatr 2014; 14:306. [PMID: 25527244 PMCID: PMC4297447 DOI: 10.1186/s12887-014-0306-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 12/02/2014] [Indexed: 12/25/2022] Open
Abstract
Background A limited number of nondigestible oligosaccharides are available for use in infant formula. This study evaluated growth and safety in infants fed formula supplemented with a mixture of bovine milk-derived oligosaccharides (BMOS). This mixture, which was generated from whey permeate, contains galactooligosaccharides and other oligosaccharides from bovine milk, such as 3′- and 6′-sialyllactose. We hypothesized that growth in infants fed BMOS-supplemented formula would be noninferior to that in infants fed standard formula. Methods Healthy term infants ≤14 days old were randomly assigned to standard formula (control; n = 84); standard formula with BMOS (IF-BMOS; n = 99); or standard formula with BMOS and probiotics (Bifidobacterium longum, Lactobacillus rhamnosus) (IF-BMOS + Pro; n = 98). A breastfed reference group was also enrolled (n = 30). The primary outcome was mean weight gain/day from enrollment to age 4 months (noninferiority margin: −3.0 g/day). Results 189 (67.3%) formula-fed infants were included in the primary analysis. Mean differences in weight gain between the control and IF-BMOS and IF-BMOS + Pro groups were <1 g/day, with 97.5% confidence intervals above −3.0 g/day, indicating noninferior weight gain in the BMOS formula groups. Compared with control, infants in the BMOS groups had more frequent (p < 0.0001) and less hard (p = 0.0003) stools. No significant differences were observed between the control and BMOS groups in caregivers’ reports of flatulence, vomiting, spitting up, crying, fussing, and colic. When based on clinical evaluation by the investigator, the incidence of colic was higher (p = 0.01) in IF-BMOS than in control; the incidence of investigator-diagnosed colic was not significantly different in control and IF-BMOS + Pro (p = 0.15). Stool bifidobacteria and lactobacilli counts were higher with IF-BMOS + Pro compared with control (p < 0.05), whereas Clostridia counts were lower (p < 0.05) in both BMOS groups compared with control. Conclusions Infant formula containing BMOS either with or without probiotics provides adequate nutrition for normal growth in healthy term infants. Further studies are needed to fully explore the digestive tolerance of BMOS formula. Trial registration ClinicalTrials.gov NCT01886898. Registered 24 June 2013.
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Affiliation(s)
- Ferdinando Meli
- Dipartimento Materno Infantile, Unità Operativa di Neonatologia, Università degli Studi di Palermo, Palermo, Italy.
| | - Giuseppe Puccio
- Dipartimento Materno Infantile, Unità Operativa di Neonatologia, Università degli Studi di Palermo, Palermo, Italy.
| | - Cinzia Cajozzo
- Dipartimento Materno Infantile, Unità Operativa di Neonatologia, Università degli Studi di Palermo, Palermo, Italy.
| | - Giovanni Licata Ricottone
- Dipartimento Materno Infantile, Unità Operativa di Neonatologia, Università degli Studi di Palermo, Palermo, Italy.
| | - Sophie Pecquet
- Nestlé Nutrition, Nestec Ltd, 22 av Reller, 1800, Vevey, Switzerland.
| | - Norbert Sprenger
- Nestlé Research Center, Nestec Ltd, Vers-chez-les-Blanc, 1000, Lausanne 26, Switzerland.
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49
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Scholtens PAMJ, Goossens DAM, Staiano A. Stool characteristics of infants receiving short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides: A review. World J Gastroenterol 2014; 20:13446-13452. [PMID: 25309075 PMCID: PMC4188896 DOI: 10.3748/wjg.v20.i37.13446] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 05/09/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
Human milk is considered to be the optimal source of infant nutrition. Some of the benefits of breastfeeding have been ascribed to human milk oligosaccharides (HMO). For instance, HMO can affect faecal characteristics such as stool consistency and stool frequency. Such effects on stool characteristics can be beneficial for young infants as hard stools and even constipation is common in that age group. Prebiotics in infant milk formulas have been introduced to exert similar functionalities. A specific mixture of prebiotics consists of a combination of short chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS) in a ratio of 9:1. This specific mixture has been developed to closely resemble the molecular size composition of HMO. Many studies have been done with scGOS/lcFOS, and indicators for digestive comfort have often been included as secondary outcomes. This review summarizes the effects of scGOS/lcFOS (9:1) on stool consistency, stool frequency and transit time in healthy term and preterm infants. In several of the studies with scGOS/lcFOS in a ratio of 9:1 in infant milk formulas, positive effects of this mixture on stool characteristics such as stool consistency and stool frequency were observed. As stool consistency was shown to be correlated to whole gut transit time, scGOS/lcFOS can be hypothesised to have a role in reducing the risk of constipation.
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50
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Wammes LJ, Mpairwe H, Elliott AM, Yazdanbakhsh M. Helminth therapy or elimination: epidemiological, immunological, and clinical considerations. THE LANCET. INFECTIOUS DISEASES 2014; 14:1150-1162. [PMID: 24981042 DOI: 10.1016/s1473-3099(14)70771-6] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Deworming is rightly advocated to prevent helminth-induced morbidity. Nevertheless, in affluent countries, the deliberate infection of patients with worms is being explored as a possible treatment for inflammatory diseases. Several clinical trials are currently registered, for example, to assess the safety or efficacy of Trichuris suis ova in allergies, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, and autism, and the Necator americanus larvae for allergic rhinitis, asthma, coeliac disease, and multiple sclerosis. Studies in animals provide strong evidence that helminths can not only downregulate parasite-specific immune responses, but also modulate autoimmune and allergic inflammatory responses and improve metabolic homoeostasis. This finding suggests that deworming could lead to the emergence of inflammatory and metabolic conditions in countries that are not prepared for these new epidemics. Further studies in endemic countries are needed to assess this risk and to enhance understanding of how helminths modulate inflammatory and metabolic pathways. Studies are similarly needed in non-endemic countries to move helminth-related interventions that show promise in animals, and in phase 1 and 2 studies in human beings, into the therapeutic development pipeline.
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Affiliation(s)
- Linda J Wammes
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Harriet Mpairwe
- MRC/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda
| | - Alison M Elliott
- MRC/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda; London School of Hygiene and Tropical Medicine, London, UK
| | - Maria Yazdanbakhsh
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands.
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