Infant Microbiota and Probiotic Intake Study

Healthy Clinical Trial

— IMPRINT  

Official title:

Infant Supplementation With Probiotic Bifidobacterium Longum Subsp. Infantis Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02457338
• Other study ID #: 631099
• Status: Active, not recruiting
• Phase: N/A
• Start date: November 1, 2014
• Est. completion date: June 7, 2027

Study information

• Verified date: November 2023
• 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 by C-section or vaginal delivery who only consume breastmilk with a probiotic for 21 consecutive days increases levels of bacteria in infants' stool.

Description:

The purpose of this clinical trial is to determine the effects of supplementing the probiotic Bifidobacterium longum subsp. infantis for the first 21 days of life in healthy term breastfed infants delivered via C-section or vaginal delivery on gut bacteria composition during, 1 week, and 1 month after supplementation compared with matched-control term infants receiving standard care. The investigators' specific aim is to compare the fecal microbiota (total B. infantis, total Bifidobacterium, total bacteria and composition of microbiota) between the supplement and control groups.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 120
• Est. completion date: June 7, 2027
• Est. primary completion date: July 15, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 21 Years to 45 Years

Eligibility

Inclusion Criteria:

• Healthy, non-smoking women and their infants

• Who are pregnant in their third trimester OR have delivered by C-section or vaginal birth within the past 7 days

• Patients who live within a 20-mile radius from University of California Davis Medical Center (UCDMC) or a 20-mile radius from UC Davis Campus in Davis, California.

• Plan to exclusively breastfeed their infants for at least 3 months

• Infants: 0-7 days old, delivered by C-section or vaginal delivery, born >37 weeks gestation, without medical complications that would preclude breastfeeding or alter gut microbiota

Exclusion Criteria:

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

• Infants who have taken antibiotics for more than 72 hours of life

• Infants who have consume formula feedings after day 7 of life

• Mothers and their infants who are not discharged from the hospital by day 4 of life due to complications

• Plan to administer probiotics to infants or use of probiotics other than the study supplement by infants anytime throughout the study duration

• Women who have had any breast surgery or injury within the past 5 years that would reduce the chance of successful exclusive breastfeeding

• Mothers who have a chronic metabolic disease or obesity

Related Conditions & MeSH terms

• Healthy

Intervention

Dietary Supplement:
• Bifidobacterium

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 (27)

Bager P, Simonsen J, Nielsen NM, Frisch M. Cesarean section and offspring's risk of inflammatory bowel disease: a national cohort study. Inflamm Bowel Dis. 2012 May;18(5):857-62. doi: 10.1002/ibd.21805. Epub 2011 Jul 7. — 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

Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11971-5. doi: 10.1073/pnas.1002601107. Epub 2010 Jun 21. — View Citation

Frese SA, Hutton AA, Contreras LN, Shaw CA, Palumbo MC, Casaburi G, Xu G, Davis JCC, Lebrilla CB, Henrick BM, Freeman SL, Barile D, German JB, Mills DA, Smilowitz JT, Underwood MA. Persistence of Supplemented Bifidobacterium longum subsp. infantis EVC001 — 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. — View Citation

Garrido D, Dallas DC, Mills DA. Consumption of human milk glycoconjugates by infant-associated bifidobacteria: mechanisms and implications. Microbiology (Reading). 2013 Apr;159(Pt 4):649-664. doi: 10.1099/mic.0.064113-0. Epub 2013 Mar 4. — 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-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. — 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

Henrick BM, Hutton AA, Palumbo MC, Casaburi G, Mitchell RD, Underwood MA, Smilowitz JT, Frese SA. Elevated Fecal pH Indicates a Profound Change in the Breastfed Infant Gut Microbiome Due to Reduction of Bifidobacterium over the Past Century. mSphere. 2018 — View Citation

Karav S, Casaburi G, Frese SA. Reduced colonic mucin degradation in breastfed infants colonized by Bifidobacterium longum subsp. infantis EVC001. FEBS Open Bio. 2018 Sep 17;8(10):1649-1657. doi: 10.1002/2211-5463.12516. eCollection 2018 Oct. — 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. doi: 10.1021/jf0710480. Epub 2007 Oct 5. — View Citation

Pei Z, Heinrich J, Fuertes E, Flexeder C, Hoffmann B, Lehmann I, Schaaf B, von Berg A, Koletzko S; Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics (LISAplus) Study Group. Cesarean delivery and risk of childhood obesity. J Pediatr. 2014 May;164(5):1068-1073.e2. doi: 10.1016/j.jpeds.2013.12.044. Epub 2014 Feb 5. — 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. doi: 10.1542/peds.2005-2824. — View Citation

Prior E, Santhakumaran S, Gale C, Philipps LH, Modi N, Hyde MJ. Breastfeeding after cesarean delivery: a systematic review and meta-analysis of world literature. Am J Clin Nutr. 2012 May;95(5):1113-35. doi: 10.3945/ajcn.111.030254. Epub 2012 Mar 28. — View 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. — 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 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. — 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, Mills DA. Nursing our microbiota: molecular linkages between bifidobacteria and milk oligosaccharides. Trends Microbiol. 2010 Jul;18(7):298-307. doi: 10.1016/j.tim.2010.03.008. Epub 2010 Apr 19. — 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. — View 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. — View Citation

Smilowitz JT, Moya J, Breck MA, Cook C, Fineberg A, Angkustsiri K, Underwood MA. Erratum to: Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial. BMC Pedi — 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

Underwood MA, Kalanetra KM, Bokulich NA, Mirmiran M, Barile D, Tancredi DJ, German JB, Lebrilla CB, Mills DA. Prebiotic oligosaccharides in premature infants. J Pediatr Gastroenterol Nutr. 2014 Mar;58(3):352-60. doi: 10.1097/MPG.0000000000000211. — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Infant fecal B. infantis	Measure the change from baseline, during supplementation, and post supplementation	baseline, days 10, 14, 17, 21, 25, 29, 32, 40, 50, 60
Primary	Infant fecal Bifidobacterium	Measure the change from baseline, during supplementation, and post supplementation	baseline, days 10, 14, 17, 21, 25, 29, 32, 40, 50, 60
Primary	Infant fecal total bacteria	Measure the change from baseline, during supplementation, and post supplementation	baseline, days 10, 14, 17, 21, 25, 29, 32, 40, 50, 60
Primary	Infant fecal microbiota	Measure the change from baseline, during supplementation, and post supplementation	baseline, days 10, 14, 17, 21, 25, 29, 32, 40, 50, 60
Primary	Incidence of Adverse Events and Treatments	Gastrointestinal symptoms and related symptoms (discomfort passing bowel movements, vomiting, constipation, colic or irritability) before, during and after B. infantis supplementation will be determined and reported daily by parental self-report questionnaire. 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.	Baseline-days 60
Primary	Incidence of Adverse Events and Treatments	Gastrointestinal symptoms and related symptoms (diarrhea, vomiting, constipation, colic, irritability) after B. infantis supplementation will be determined and reported parental self-report questionnaire. 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.	Months 4, 6, 8, 10, 12, 18 and 24
Secondary	Infant fecal bacteria oligosaccharide consumption	Compare the oligosaccharides in human milk against the oligosaccharides in infant feces before, during, and after B. infantis supplementation by using liquid chromatography Chip-TOP mass spectrometry.	days 7, 14, 21, 32, 60
Secondary	Infant fecal sialic acid concentrations	Measure the change in infant fecal sialic acid concentrations before, during, and after B. infantis supplementation in infant stool samples using enzymatic assay.	baseline, days 10, 14, 17, 21, 25, 29, 32, 40, 50, 60
Secondary	Maternal fecal B. infantis, Bifidobacterium, total bacteria, and microbiota composition	Compare the maternal fecal B. infantis, bifidobacterium, total bacteria, and microbiota composition with changes in infant fecal microbiota	baseline, day 60
Secondary	Infant weight	Determine the change in weight across the study duration using a digital infant scale and change in gut microbiota	birth, hospital discharge, days 15, 33, 61
Secondary	Fecal inflammatory mediators	Compare GI function between infants in the B. infantis and control groups through the measurement of fecal inflammatory mediators.	Baseline-days 60
Secondary	Fecal gut barrier function barrier markers	Compare GI function between infants in the B. infantis and control groups through the measurement of GI barrier function markers.	Baseline-days 60
Secondary	Fecal lipopolysaccharide	Compare GI function between infants in the B. infantis and control groups through the measurement of fecal lipopolysaccharide binding.	Baseline-days 60
Secondary	Fecal short-chain fatty acids	Determine the relationship between fecal microbiota composition and fecal short chain fatty acids	Baseline-days 60
Secondary	Fecal microbiome-Follow-up	next generation sequencing	Months 4, 6, 8, 10, 12
Secondary	Fecal B. infantis-Follow-up	Q Polymerase Chain Reaction (PCR)	Months 4, 6, 8, 10, 12
Secondary	Fecal Bifidobacterium-Follow-up	Q PCR	Months 4, 6, 8, 10, 12

External Links

•   University of California, Davis Foods for Health Institute