Milk Oriented Microbiota

Microbial Colonization Clinical Trial

— MOM  

Official title:

Establishing a Milk Oriented Microbiota in Healthy Term Infants

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03222804
• Other study ID #: 738191
• Status: Withdrawn
• Phase: N/A
• First received: July 7, 2017
• Last updated: March 9, 2018
• Start date: May 2017
• Est. completion date: March 6, 2018

Study information

• Verified date: March 2018
• Source: University of California, Davis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if supplementing healthy term infants delivered vaginally who consume breast milk, formula, or both with a probiotic for 21 consecutive days increases levels of bacteria in infants' stool.

Description:

The purpose of phase 1 of this two phase clinical trial is to determine: 1) the effect of decreasing levels of human milk oligosaccharides on fecal B.infantis during and after 21 days of supplementation with Evolve activated B.infantis using exclusively breastfed, mixed-fed and exclusively formula-fed infants; 2) determine the effect of Evolve activated B.infantis on fecal B.infantis levels in exclusively breastfed infants compared to pre-supplementation levels.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: March 6, 2018
• Est. primary completion date: March 6, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 21 Years to 45 Years

Eligibility

Inclusion Criteria:

• Women with infants age 8 to 12 weeks

• Term infants born >37 weeks gestation

• Mother-infant pairs who live within a 20-mile radius from UC Davis campus in Davis, CA or within a 20-mile UCDMC

• Women and infants who live in one location

• Infants born vaginally

• Infants who are either exclusively formula-fed, exclusively breastfed or mixed-fed

• Women who are mixed and formula feeding their infants who are willing to switch infant formulas and use the study's infant formula (Earth's Best Organic Infant Formula With Iron, Earth's Best) throughout the first two months of the study

• Women who are breastfeeding but introduce infant formula to their infants during the first two months of the study who are willing to use the study's infant formula (Earth's Best Organic Infant Formula With Iron, Earth's Best) for the first two months of the study

Exclusion Criteria:

• Women who have lived in the United States or other developed nation for less than 10 consecutive years

• Multiple infants born to one mother

• Plan to feed infants solid foods before infants turn 5 months of age

• Family history of cow milk or soy allergy and/or infants allergic to cow milk protein or soy

• Infants born by C-section

• Infants born with medical complications such as: respiratory distress syndrome, birth defects, and infection

• Infants who have taken antibiotics 4 weeks before enrollment and more than one course of antibiotics since birth

• Infants who have taken probiotics since birth

• Plan to administer probiotics to infants or use of probiotics other than the study supplement by infants for the first two months of the study

• Mothers who have a chronic metabolic disease or obesity

• Mothers who currently smoke or plan to resume smoking during the study period

• Infants who consume solid foods or other liquids other than breastmilk, infant formula or water

Related Conditions & MeSH terms

• Communicable Diseases
• Infection
• Microbial Colonization

Intervention

Dietary Supplement:
• Bifidobacterium
Each B. infantis (strain: BIEVC001) dose will be provided in one 625 mg sachet delivering 156 mg of live bacteria at a dose of 9x10^9 CFU plus 469 mg of pharmaceutical-grade lactose as the excipient and dispensed to participants by the study personnel.

Locations

Country	Name	City	State
United States	University of California, Davis Medical Center	Sacramento	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, Davis	Evolve BioSystems, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (56)

Alfaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD005496. doi: 10.1002/14651858.CD005496.pub3. Review. Update in: Cochrane Database Syst Rev. 2014;4:CD005496. — View Citation

Allen SJ, Jordan S, Storey M, Thornton CA, Gravenor M, Garaiova I, Plummer SF, Wang D, Morgan G. Dietary supplementation with lactobacilli and bifidobacteria is well tolerated and not associated with adverse events during late pregnancy and early infancy. J Nutr. 2010 Mar;140(3):483-8. doi: 10.3945/jn.109.117093. Epub 2010 Jan 20. — View Citation

Bager P, Wohlfahrt J, Westergaard T. Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin Exp Allergy. 2008 Apr;38(4):634-42. doi: 10.1111/j.1365-2222.2008.02939.x. Epub 2008 Feb 11. — View Citation

Barile D, Guinard J, Meyrand M, German JB. Examining bioactive components of milk: complex oligosaccharides. AgroFood. 2011;22(4):12-6.

Barile D, Marotta M, Chu C, Mehra R, Grimm R, Lebrilla CB, German JB. Neutral and acidic oligosaccharides in Holstein-Friesian colostrum during the first 3 days of lactation measured by high performance liquid chromatography on a microfluidic chip and time-of-flight mass spectrometry. J Dairy Sci. 2010 Sep;93(9):3940-9. doi: 10.3168/jds.2010-3156. — View Citation

Barile D, Meyrand M, Lebrilla CB, German JB. Examining bioactive components of milk Sources of complex oligosaccharides (Part 2). Agro Food Industry Hi-Tech. 2011;22(4):37-9.

Barile D, Rastall RA. Human milk and related oligosaccharides as prebiotics. Curr Opin Biotechnol. 2013 Apr;24(2):214-9. doi: 10.1016/j.copbio.2013.01.008. Epub 2013 Feb 19. Review. — View Citation

Bekkali N, Hamers SL, Reitsma JB, Van Toledo L, Benninga MA. Infant stool form scale: development and results. J Pediatr. 2009 Apr;154(4):521-526.e1. doi: 10.1016/j.jpeds.2008.10.010. Epub 2008 Dec 3. — View Citation

Benno Y, Sawada K, Mitsuoka T. The intestinal microflora of infants: composition of fecal flora in breast-fed and bottle-fed infants. Microbiol Immunol. 1984;28(9):975-86. — View Citation

Bezirtzoglou E, Tsiotsias A, Welling GW. Microbiota profile in feces of breast- and formula-fed newborns by using fluorescence in situ hybridization (FISH). Anaerobe. 2011 Dec;17(6):478-82. doi: 10.1016/j.anaerobe.2011.03.009. Epub 2011 Apr 8. — View Citation

Degnan FH. The US Food and Drug Administration and probiotics: regulatory categorization. Clin Infect Dis. 2008 Feb 1;46 Suppl 2:S133-6; discussion S144-51. doi: 10.1086/523324. — View Citation

Dewey KG, Heinig MJ, Nommsen LA, Lonnerdal B. Maternal versus infant factors related to breast milk intake and residual milk volume: the DARLING study. Pediatrics. 1991 Jun;87(6):829-37. — View Citation

Eggesbø M, Botten G, Stigum H, Nafstad P, Magnus P. Is delivery by cesarean section a risk factor for food allergy? J Allergy Clin Immunol. 2003 Aug;112(2):420-6. — View Citation

Floch MH, Montrose DC. Use of probiotics in humans: an analysis of the literature. Gastroenterol Clin North Am. 2005 Sep;34(3):547-70, x. Review. — View Citation

Galdeano CM, de Moreno de LeBlanc A, Vinderola G, Bonet ME, Perdigón G. Proposed model: mechanisms of immunomodulation induced by probiotic bacteria. Clin Vaccine Immunol. 2007 May;14(5):485-92. Epub 2007 Mar 14. Review. — View Citation

Garrido D, Barile D, Mills DA. A molecular basis for bifidobacterial enrichment in the infant gastrointestinal tract. Adv Nutr. 2012 May 1;3(3):415S-21S. doi: 10.3945/an.111.001586. Review. — View Citation

Garrido D, Kim JH, German JB, Raybould HE, Mills DA. Oligosaccharide binding proteins from Bifidobacterium longum subsp. infantis reveal a preference for host glycans. PLoS One. 2011 Mar 15;6(3):e17315. doi: 10.1371/journal.pone.0017315. — View Citation

Garrido D, Nwosu C, Ruiz-Moyano S, Aldredge D, German JB, Lebrilla CB, Mills DA. Endo-ß-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. — View 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. — View Citation

Garrido D, Ruiz-Moyano S, Mills DA. Release and utilization of N-acetyl-D-glucosamine from human milk oligosaccharides by Bifidobacterium longum subsp. infantis. Anaerobe. 2012 Aug;18(4):430-5. doi: 10.1016/j.anaerobe.2012.04.012. Epub 2012 May 9. — View Citation

Gratz SW, Mykkanen H, El-Nezami HS. Probiotics and gut health: a special focus on liver diseases. World J Gastroenterol. 2010 Jan 28;16(4):403-10. Review. — View Citation

Haarman M, Knol J. Quantitative real-time PCR assays to identify and quantify fecal Bifidobacterium species in infants receiving a prebiotic infant formula. Appl Environ Microbiol. 2005 May;71(5):2318-24. — View Citation

Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, Wagendorp AA, Klijn N, Bindels JG, Welling GW. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J Pediatr Gastroenterol Nutr. 2000 Jan;30(1):61-7. — View Citation

Klaenhammer TR, Kleerebezem M, Kopp MV, Rescigno M. The impact of probiotics and prebiotics on the immune system. Nat Rev Immunol. 2012 Oct;12(10):728-34. doi: 10.1038/nri3312. Review. — View Citation

Kleessen B, Bunke H, Tovar K, Noack J, Sawatzki G. Influence of two infant formulas and human milk on the development of the faecal flora in newborn infants. Acta Paediatr. 1995 Dec;84(12):1347-56. — View Citation

Lewis ZT, Totten SM, Smilowitz JT, Popovic M, Parker E, Lemay DG, Van Tassell ML, Miller MJ, Jin YS, German JB, Lebrilla CB, Mills DA. Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants. Microbiome. 2015 Apr 10;3:13. doi: 10.1186/s40168-015-0071-z. eCollection 2015. — View Citation

LoCascio RG, Desai P, Sela DA, Weimer B, Mills DA. Broad conservation of milk utilization genes in Bifidobacterium longum subsp. infantis as revealed by comparative genomic hybridization. Appl Environ Microbiol. 2010 Nov;76(22):7373-81. doi: 10.1128/AEM.00675-10. Epub 2010 Aug 27. — View 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. Epub 2007 Oct 5. — View Citation

Macfarlane GT, Steed H, Macfarlane S. Bacterial metabolism and health-related effects of galacto-oligosaccharides and other prebiotics. J Appl Microbiol. 2008 Feb;104(2):305-44. doi: 10.1111/j.1365-2672.2007.03520.x. Review. — View Citation

Marcobal A, Barboza M, Froehlich JW, Block DE, German JB, Lebrilla CB, Mills DA. Consumption of human milk oligosaccharides by gut-related microbes. J Agric Food Chem. 2010 May 12;58(9):5334-40. doi: 10.1021/jf9044205. — View Citation

Matsuki T, Watanabe K, Tanaka R, Fukuda M, Oyaizu H. Distribution of bifidobacterial species in human intestinal microflora examined with 16S rRNA-gene-targeted species-specific primers. Appl Environ Microbiol. 1999 Oct;65(10):4506-12. — View Citation

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 Dec 20;14:306. doi: 10.1186/s12887-014-0306-3. — View Citation

Mitsuoka T, Kaneuchi C. Ecology of the bifidobacteria. Am J Clin Nutr. 1977 Nov;30(11):1799-810. — View Citation

Negele K, Heinrich J, Borte M, von Berg A, Schaaf B, Lehmann I, Wichmann HE, Bolte G; LISA Study Group. Mode of delivery and development of atopic disease during the first 2 years of life. Pediatr Allergy Immunol. 2004 Feb;15(1):48-54. — View Citation

Neville MC, Keller R, Seacat J, Lutes V, Neifert M, Casey C, Allen J, Archer P. Studies in human lactation: milk volumes in lactating women during the onset of lactation and full lactation. Am J Clin Nutr. 1988 Dec;48(6):1375-86. — View Citation

Ninonuevo MR, Park Y, Yin H, Zhang J, Ward RE, Clowers BH, German JB, Freeman SL, Killeen K, Grimm R, Lebrilla CB. A strategy for annotating the human milk glycome. J Agric Food Chem. 2006 Oct 4;54(20):7471-80. — View Citation

Niñonuevo 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. Epub 2007 Dec 19. — View 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. Epub 2006 Nov 27. — View Citation

Pelucchi C, Chatenoud L, Turati F, Galeone C, Moja L, Bach JF, La Vecchia C. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology. 2012 May;23(3):402-14. doi: 10.1097/EDE.0b013e31824d5da2. Review. — View Citation

Penders J, Gerhold K, Stobberingh EE, Thijs C, Zimmermann K, Lau S, Hamelmann E. Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood. J Allergy Clin Immunol. 2013 Sep;132(3):601-607.e8. doi: 10.1016/j.jaci.2013.05.043. Epub 2013 Jul 27. — View Citation

Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, van den Brandt PA, Stobberingh EE. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006 Aug;118(2):511-21. — View Citation

Penders J, Vink C, Driessen C, London N, Thijs C, Stobberingh EE. Quantification of Bifidobacterium spp., Escherichia coli and Clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time PCR. FEMS Microbiol Lett. 2005 Feb 1;243(1):141-7. — View Citation

Renz-Polster H, David MR, Buist AS, Vollmer WM, O'Connor EA, Frazier EA, Wall MA. Caesarean section delivery and the risk of allergic disorders in childhood. Clin Exp Allergy. 2005 Nov;35(11):1466-72. — View Citation

Rosenfeldt V, Benfeldt E, Valerius NH, Paerregaard A, Michaelsen KF. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr. 2004 Nov;145(5):612-6. — View Citation

Sela DA, Chapman J, Adeuya A, Kim JH, Chen F, Whitehead TR, Lapidus A, Rokhsar DS, Lebrilla CB, German JB, Price NP, Richardson PM, Mills DA. The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18964-9. doi: 10.1073/pnas.0809584105. Epub 2008 Nov 24. — View 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 a-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. — View Citation

Sela DA, Li Y, Lerno L, Wu S, Marcobal AM, German JB, Chen X, Lebrilla CB, Mills DA. An infant-associated bacterial commensal utilizes breast milk sialyloligosaccharides. J Biol Chem. 2011 Apr 8;286(14):11909-18. doi: 10.1074/jbc.M110.193359. Epub 2011 Feb 2. Erratum in: J Biol Chem. 2011 Jul 1;286(26):23620. — View Citation

Sela DA. Bifidobacterial utilization of human milk oligosaccharides. Int J Food Microbiol. 2011 Sep 1;149(1):58-64. doi: 10.1016/j.ijfoodmicro.2011.01.025. Epub 2011 Jan 26. Review. — View Citation

Stark PL, Lee A. The microbial ecology of the large bowel of breast-fed and formula-fed infants during the first year of life. J Med Microbiol. 1982 May;15(2):189-203. — View Citation

Tao N, DePeters EJ, Freeman S, German JB, Grimm R, Lebrilla CB. Bovine milk glycome. J Dairy Sci. 2008 Oct;91(10):3768-78. doi: 10.3168/jds.2008-1305. — View Citation

Tao N, DePeters EJ, German JB, Grimm R, Lebrilla CB. Variations in bovine milk oligosaccharides during early and middle lactation stages analyzed by high-performance liquid chromatography-chip/mass spectrometry. J Dairy Sci. 2009 Jul;92(7):2991-3001. doi: 10.3168/jds.2008-1642. — View Citation

Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR. A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy. 2008 Apr;38(4):629-33. doi: 10.1111/j.1365-2222.2007.02780.x. — View 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. — View Citation

Underwood MA, Kalanetra KM, Bokulich NA, Lewis ZT, Mirmiran M, Tancredi DJ, Mills DA. A comparison of two probiotic strains of bifidobacteria in premature infants. J Pediatr. 2013 Dec;163(6):1585-1591.e9. doi: 10.1016/j.jpeds.2013.07.017. Epub 2013 Aug 29. — View Citation

Yoshioka H, Iseki K, Fujita K. Development and differences of intestinal flora in the neonatal period in breast-fed and bottle-fed infants. Pediatrics. 1983 Sep;72(3):317-21. — View Citation

Zivkovic AM, Lewis ZT, German JB, Mills DA. Establishment of a milk-oriented microbiota (MOM) in early life: How babies meet their MOMs. . Functional Food Reviews. 2013;5:3-12.

* Note: There are 56 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Infant fecal B. infantis	The change in infant fecal B. infantis before, during and after supplementation.	Change from baseline to day 280
Primary	Infant fecal Bifidobacterium	The change in infant fecal Bifidobacterium before, during, and after supplementation.	Change from baseline to day 280
Primary	Infant fecal total bacteria	The change in infant fecal total bacteria before, during and after supplementation.	Change from baseline to day 280
Primary	Infant fecal microbiome	The change in infant fecal microbiome before, during and after supplementation.	Change from baseline to day 280
Primary	Infant gastrointestinal symptoms	Gastrointestinal symptoms and related symptoms (discomfort passing bowel movements, vomiting, constipation, colic or irritability) before, during and after supplementation will be determined and reported daily by parental self-report questionnaire.	Change from baseline to day 50
Primary	Infant health status	General health status of the infant such as occurrence of any illness, health care visits for sickness, fever, antibiotic and medication use and parental assessments of infant's overall health.	Change from baseline to day 280
Secondary	Maternal secretor status	Determine the relationship between human milk oligosaccharides in breast milk and infant fecal microbiome.	Change from baseline to day 280
Secondary	Infant fecal sialic acid concentrations	The change in infant fecal sialic acid and fucose concentrations before, during and after supplementation in infant stool samples.	Change from baseline to day 280
Secondary	Infant fecal microbiome and lifestyle	Determine the relationship between the following factors determined by self-report questionnaires: parity, maternal and infant antibiotic intake and maternal use of antimicrobials, infant intake of formula; and the change infant fecal microbiome.	Change from baseline to day 280
Secondary	Infant weight	Determine the relationship between infant weight and change in fecal microbiome.	Change from baseline to day 280
Secondary	Infant fecal short chain fatty acids	Determine the relationship between fecal short chain fatty acids and fecal microbiome.	Change from baseline to day 280
Secondary	Infant gastrointestinal function	Determine the relationship between GI function (fecal inflammatory, GI barrier mediators, LPS) and fecal microbiome.	Change from baseline to day 280