Clinical trial NCT01817127: Elucidation of Breast Milk Composition and Structure Over the First Year of Lactation: UC Davis Lactation Study
Official title: Functional Deconstruction of Human Milk Oligosaccharides and Lipids
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Healthy
Gestational Diabetes Mellitus
Type 2 Diabetes Mellitus
Lead sponsor: University of California, Davis
Sponsor class: OTHER
Collaborators: name: California Dairy Research Foundation
First posted: 2013-03-22
Enrollment: 395
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Healthy pregnant women and women diagnosed with gestational diabetes mellitus or type 2 diabetes mellitus.

Brief summary: This observational study is designed to determine how sugars, lipids and proteins in breast milk vary among mothers; is affected by maternal diet, health and microbiota and vary over the course of lactation. Additionally, the study is designed to determine how the structure and composition of complex milk sugars, maternal health status and diet influence the development and maintenance of infant gut microflora.

Detailed description: This study's objectives include: 1) develop a better understanding of the composition and structures of breast milk over the early stages of lactation with specific emphasis on the glycans and lipids; 2) how glycan diversity relates to maternal and infant gut microbiota with an emphasis on bifidobacteria species; 3)how milk composition and structure relate to maternal health and diet.

These samples will be analyzed using comprehensive gas and liquid chromatographic methods, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS); and next generation sequencing, terminal restriction fragment length polymorphism and quantitative polymerase chain reaction.

There are several cohorts to the main study.

Gestational Diabetes Mellitus Cohort. The aim of this study is to investigate the differences between milk composition, infant and maternal gut microbiota from women with and without gestational diabetes mellitus or type 2 diabetes vs. controls.

Fresh Milk Study. The aim of this study is to elucidate the relationship between the expression of glycan metabolizing genes of mammary epithelial cells and levels of milk glycans.

RNA Study. The aim of this study is to compare the RNA of milk fat globule membrane crescents in human milk against epithelial expression profiles in non-human primate milk.

Skin Study. The aim of this study is to provide skin samples from healthy term infants to act as the control group for a different study with preterm infants.

Breast Milk, Gut Microbiome, and Immunity (BMMI) Project. The aim of this study is to provide healthy control samples for the BMMI project. The BMMI project is a multi-investigative project designed to elucidate how maternal nutrient status, and milk composition and structure influence infant gut microbiome from participants in developing countries.

Eligibility criteria: Inclusion Criteria:

* Pregnant women 18 years and older who plan to breastfeed for at least 6 months
* Women who are in good health
* Women with or without diagnosis of gestational diabetes mellitus, or type 2 diabetes mellitus or impaired glucose tolerance

Exclusion Criteria:

* Women who do not plan to breastfeed for at least 6 months
* Women who give birth to pre-term infants
* Women who smoke, either currently or 1 year before becoming pregnant
* Women who have chronic medical conditions or communicable diseases
* Women who take metabolic altering drugs such as corticosteroids or thyroid medication

Primary outcomes:
measure: Human milk glycans
timeFrame: Change from day 2 to day 366
Secondary outcomes:
measure: Microbiota
timeFrame: 3rd trimester pregnancy and Day 2-Day 366 postpartum
measure: Proteome
timeFrame: Day 2-Day 366 postpartum
measure: Lipidome
timeFrame: Day 2-Day 366 postpartum
measure: Maternal plasma lipids
timeFrame: 3rd trimester pregnancy and 2 months postpartum
measure: Peptidome
timeFrame: 3rd trimester pregnancy and Day 2-Day 366
measure: Metabolome by Nuclear Magnetic Spectroscopy (NMR)
timeFrame: 3rd trimester of pregnancy and D2-Day 366
measure: Metabolome by MS
timeFrame: Day 2-Day 366 postpartum
measure: Secretor status genotyping
timeFrame: 3rd trimester pregnancy and Day 60 postpartum
measure: Maternal fasting and postprandial blood sugar
timeFrame: 3rd trimester of pregnancy and Day 3-7
measure: Maternal plasma lipoprotein size distribution
timeFrame: 3rd trimester of pregnancy and Day 60 postpartum
measure: Human Milk Transcriptomics
timeFrame: 3 and 6 months postpartum
Other outcomes:
measure: Alkaline phosphatase levels
timeFrame: Days 2 through 50
Locations:
city: Davis
country: United States
facility: University of California, Davis
state: California
Study officials:
affiliation: University of California, Davis
name: Bruce German, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Carlito Lebrilla, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: David Mills, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Bart Weimer, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Xiangdong Wu, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Helen Raybould, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Jennifer T. Smilowitz, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Danielle Lemay, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Totten SM, Zivkovic AM, Wu S, Ngyuen U, Freeman SL, Ruhaak LR, Darboe MK, German JB, Prentice AM, Lebrilla CB. Comprehensive profiles of human milk oligosaccharides yield highly sensitive and specific markers for determining secretor status in lactating mothers. J Proteome Res. 2012 Dec 7;11(12):6124-33. doi: 10.1021/pr300769g. Epub 2012 Nov 19.
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citation: Garrido D, Nwosu C, Ruiz-Moyano S, Aldredge D, German JB, Lebrilla CB, Mills DA. Endo-beta-N-acetylglucosaminidases from infant gut-associated bifidobacteria release complex N-glycans from human milk glycoproteins. Mol Cell Proteomics. 2012 Sep;11(9):775-85. doi: 10.1074/mcp.M112.018119. Epub 2012 Jun 27.
citation: Sela DA, Garrido D, Lerno L, Wu S, Tan K, Eom HJ, Joachimiak A, Lebrilla CB, Mills DA. Bifidobacterium longum subsp. infantis ATCC 15697 alpha-fucosidases are active on fucosylated human milk oligosaccharides. Appl Environ Microbiol. 2012 Feb;78(3):795-803. doi: 10.1128/AEM.06762-11. Epub 2011 Dec 2.
citation: Marcobal A, Barboza M, Sonnenburg ED, Pudlo N, Martens EC, Desai P, Lebrilla CB, Weimer BC, Mills DA, German JB, Sonnenburg JL. Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways. Cell Host Microbe. 2011 Nov 17;10(5):507-14. doi: 10.1016/j.chom.2011.10.007. Epub 2011 Oct 27.
citation: Froehlich JW, Barboza M, Chu C, Lerno LA Jr, Clowers BH, Zivkovic AM, German JB, Lebrilla CB. Nano-LC-MS/MS of glycopeptides produced by nonspecific proteolysis enables rapid and extensive site-specific glycosylation determination. Anal Chem. 2011 Jul 15;83(14):5541-7. doi: 10.1021/ac2003888. Epub 2011 Jun 28.
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citation: Zivkovic AM, German JB, Lebrilla CB, Mills DA. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4653-8. doi: 10.1073/pnas.1000083107. Epub 2010 Aug 2.
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citation: Ninonuevo MR, Ward RE, LoCascio RG, German JB, Freeman SL, Barboza M, Mills DA, Lebrilla CB. Methods for the quantitation of human milk oligosaccharides in bacterial fermentation by mass spectrometry. Anal Biochem. 2007 Feb 1;361(1):15-23. doi: 10.1016/j.ab.2006.11.010. Epub 2006 Nov 27.
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citation: Ninonuevo MR, Perkins PD, Francis J, Lamotte LM, LoCascio RG, Freeman SL, Mills DA, German JB, Grimm R, Lebrilla CB. Daily variations in oligosaccharides of human milk determined by microfluidic chips and mass spectrometry. J Agric Food Chem. 2008 Jan 23;56(2):618-26. doi: 10.1021/jf071972u. Epub 2007 Dec 19.
citation: LoCascio RG, Ninonuevo MR, Freeman SL, Sela DA, Grimm R, Lebrilla CB, Mills DA, German JB. Glycoprofiling of bifidobacterial consumption of human milk oligosaccharides demonstrates strain specific, preferential consumption of small chain glycans secreted in early human lactation. J Agric Food Chem. 2007 Oct 31;55(22):8914-9. doi: 10.1021/jf0710480. Epub 2007 Oct 5.
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citation: Chu CS, Ninonuevo MR, Clowers BH, Perkins PD, An HJ, Yin H, Killeen K, Miyamoto S, Grimm R, Lebrilla CB. Profile of native N-linked glycan structures from human serum using high performance liquid chromatography on a microfluidic chip and time-of-flight mass spectrometry. Proteomics. 2009 Apr;9(7):1939-51. doi: 10.1002/pmic.200800249.
citation: Hong P, Ninonuevo MR, Lee B, Lebrilla C, Bode L. Human milk oligosaccharides reduce HIV-1-gp120 binding to dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN). Br J Nutr. 2009 Feb;101(4):482-6. doi: 10.1017/s0007114508025804.
citation: Lewis ZT, Bokulich NA, Kalanetra KM, Ruiz-Moyano S, Underwood MA, Mills DA. Use of bifidobacterial specific terminal restriction fragment length polymorphisms to complement next generation sequence profiling of infant gut communities. Anaerobe. 2013 Feb;19:62-9. doi: 10.1016/j.anaerobe.2012.12.005. Epub 2012 Dec 20.
citation: Garrido D, Ruiz-Moyano S, Jimenez-Espinoza R, Eom HJ, Block DE, Mills DA. Utilization of galactooligosaccharides by Bifidobacterium longum subsp. infantis isolates. Food Microbiol. 2013 Apr;33(2):262-70. doi: 10.1016/j.fm.2012.10.003. Epub 2012 Oct 22.
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citation: Yang Y, Rader E, Peters-Carr M, Bent RC, Smilowitz JT, Guillemin K, Rader B. Ontogeny of alkaline phosphatase activity in infant intestines and breast milk. BMC Pediatr. 2019 Jan 3;19(1):2. doi: 10.1186/s12887-018-1379-1.
citation: Nijman RM, Liu Y, Bunyatratchata A, Smilowitz JT, Stahl B, Barile D. Characterization and Quantification of Oligosaccharides in Human Milk and Infant Formula. J Agric Food Chem. 2018 Jul 5;66(26):6851-6859. doi: 10.1021/acs.jafc.8b01515. Epub 2018 Jun 20.
citation: Bever CS, Rand AA, Nording M, Taft D, Kalanetra KM, Mills DA, Breck MA, Smilowitz JT, German JB, Hammock BD. Effects of triclosan in breast milk on the infant fecal microbiome. Chemosphere. 2018 Jul;203:467-473. doi: 10.1016/j.chemosphere.2018.03.186. Epub 2018 Mar 28.
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citation: Lewis ZT, Davis JC, Smilowitz JT, German JB, Lebrilla CB, Mills DA. The impact of freeze-drying infant fecal samples on measures of their bacterial community profiles and milk-derived oligosaccharide content. PeerJ. 2016 Jan 21;4:e1612. doi: 10.7717/peerj.1612. eCollection 2016.
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citation: Spevacek AR, Smilowitz JT, Chin EL, Underwood MA, German JB, Slupsky CM. Infant Maturity at Birth Reveals Minor Differences in the Maternal Milk Metabolome in the First Month of Lactation. J Nutr. 2015 Aug;145(8):1698-708. doi: 10.3945/jn.115.210252. Epub 2015 Jun 3.
citation: Beck KL, Weber D, Phinney BS, Smilowitz JT, Hinde K, Lonnerdal B, Korf I, Lemay DG. Comparative Proteomics of Human and Macaque Milk Reveals Species-Specific Nutrition during Postnatal Development. J Proteome Res. 2015 May 1;14(5):2143-57. doi: 10.1021/pr501243m. Epub 2015 Apr 6.
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citation: Dallas DC, Smink CJ, Robinson RC, Tian T, Guerrero A, Parker EA, Smilowitz JT, Hettinga KA, Underwood MA, Lebrilla CB, German JB, Barile D. Endogenous human milk peptide release is greater after preterm birth than term birth. J Nutr. 2015 Mar;145(3):425-33. doi: 10.3945/jn.114.203646. Epub 2014 Dec 24.
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citation: O'Sullivan A, Farver M, Smilowitz JT. The Influence of Early Infant-Feeding Practices on the Intestinal Microbiome and Body Composition in Infants. Nutr Metab Insights. 2015 Dec 16;8(Suppl 1):1-9. doi: 10.4137/NMI.S29530. eCollection 2015.
citation: Totten SM, Wu LD, Parker EA, Davis JC, Hua S, Stroble C, Ruhaak LR, Smilowitz JT, German JB, Lebrilla CB. Rapid-throughput glycomics applied to human milk oligosaccharide profiling for large human studies. Anal Bioanal Chem. 2014 Dec;406(30):7925-35. doi: 10.1007/s00216-014-8261-2. Epub 2014 Oct 31.
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citation: Smilowitz JT, Gho DS, Mirmiran M, German JB, Underwood MA. Rapid measurement of human milk macronutrients in the neonatal intensive care unit: accuracy and precision of fourier transform mid-infrared spectroscopy. J Hum Lact. 2014 May;30(2):180-9. doi: 10.1177/0890334413517941. Epub 2014 Jan 14.
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citation: Smilowitz JT, Lebrilla CB, Mills DA, German JB, Freeman SL. Breast milk oligosaccharides: structure-function relationships in the neonate. Annu Rev Nutr. 2014;34:143-69. doi: 10.1146/annurev-nutr-071813-105721. Epub 2014 May 15.
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citation: Smilowitz JT, Totten SM, Huang J, Grapov D, Durham HA, Lammi-Keefe CJ, Lebrilla C, German JB. Human milk secretory immunoglobulin a and lactoferrin N-glycans are altered in women with gestational diabetes mellitus. J Nutr. 2013 Dec;143(12):1906-12. doi: 10.3945/jn.113.180695. Epub 2013 Sep 18.
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citation: Ruiz-Moyano S, Totten SM, Garrido DA, Smilowitz JT, German JB, Lebrilla CB, Mills DA. Variation in consumption of human milk oligosaccharides by infant gut-associated strains of Bifidobacterium breve. Appl Environ Microbiol. 2013 Oct;79(19):6040-9. doi: 10.1128/AEM.01843-13. Epub 2013 Jul 26.
citation: Dallas DC, Guerrero A, Khaldi N, Castillo PA, Martin WF, Smilowitz JT, Bevins CL, Barile D, German JB, Lebrilla CB. Extensive in vivo human milk peptidomics reveals specific proteolysis yielding protective antimicrobial peptides. J Proteome Res. 2013 May 3;12(5):2295-304. doi: 10.1021/pr400212z. Epub 2013 Apr 24.
citation: Dallas DC, Martin WF, Strum JS, Zivkovic AM, Smilowitz JT, Underwood MA, Affolter M, Lebrilla CB, German JB. N-linked glycan profiling of mature human milk by high-performance microfluidic chip liquid chromatography time-of-flight tandem mass spectrometry. J Agric Food Chem. 2011 Apr 27;59(8):4255-63. doi: 10.1021/jf104681p. Epub 2011 Mar 18.
citation: Goonatilleke E, Huang J, Xu G, Wu L, Smilowitz JT, German JB, Lebrilla CB. Human Milk Proteins and Their Glycosylation Exhibit Quantitative Dynamic Variations during Lactation. J Nutr. 2019 Aug 1;149(8):1317-1325. doi: 10.1093/jn/nxz086.