Prebiotic GOS and Lactoferrin With Iron Supplements

Not Applicable

Completed

• Conditions: Iron-deficiency
• Interventions: Dietary Supplement: Bovine lactoferrin; Dietary Supplement: Galacto-oligosaccharides; Dietary Supplement: Multiple micronutrient powders with 5 mg iron

• Registration Number: NCT03866837
• Lead Sponsor: Columbia University

Brief Summary

The ultimate goal of this research is to develop a means to safely administer iron supplements to infants in settings with a high infection burden. The investigators will conduct a randomized clinical trial in 6 month-old Kenyan infants in conjunction with mechanistic microbiota studies using a novel long-term continuous polyfermenter platform inoculated with immobilized fecal microbiota from Kenyan infants. Oral iron supplements are associated with a significant 15% increase in the rate of diarrhea in children in malaria-endemic areas. The most recent studies have shown that prebiotic galacto-oligosaccharides (GOS) can provide partial amelioration of the adverse effects of iron supplementation by enhancing the growth of barrier populations of bifidobacteria and lactobacilli. The investigators hypothesize that the combination of GOS with bovine lactoferrin, adding iron sequestration as well as antimicrobial and immunomodulatory activities, will provide almost complete protection against the adverse effects of added iron on the intestinal microbiota.

Detailed Description

Iron deficiency, the principal cause of anemia globally, affects more than two billion individuals, predominantly infants, children and women of childbearing age. Iron deficiency impairs cognitive and behavioral development in childhood, compromises immune responsiveness, decreases physical performance, and when severe, increases mortality among infants, children and pregnant women. Effective prevention and treatment of iron deficiency uses iron supplements or fortificants to increase oral iron intake. Generally, only a small fraction of the added iron is absorbed in the upper small intestine, with 80% or more passing into the colon. Because iron is an essential micronutrient for growth, proliferation, and persistence for most intestinal microbes, the increase in iron availability has profound effects on the composition and metabolism of intestinal microbiota. In particular, iron is a prime determinant of colonization and virulence for most enteric gram-negative bacteria, includingmSalmonella, Shigella and pathogenic Escherichia coli. Commensal intestinal microorganisms, principally of the genera Bifidobacterium and Lactobacillus, require little or no iron, provide a barrier effect and can inhibit pathogen growth by a variety of methods, including sequestration of iron, competition for nutrients and for intestinal epithelial sites stabilization of intestinal barrier function, and production of antibacterial peptides and organic acids that lower the pH. Increases in unabsorbed iron can promote the growth of virulent enteropathogens that overwhelm barrier strains and disrupt the gut microbiota.

We hypothesize that the combination of prebiotic GOS with bovine lactoferrin (bLF), adding iron sequestration, antimicrobial and immunomodulatory activities, will provide virtually complete protection against the adverse effects of added iron on the intestinal microbiota. Our research has two specific aims:

1. to conduct a randomized, controlled double-blind 9-month clinical trial in 6-month old Kenyan infants comparing the effects on gut microbiome composition among groups receiving in-home fortification for 6 months with micronutrient powders containing 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]) and (i) galacto-oligosaccharides (GOS; 7.5 g), (ii) bovine lactoferrin (bLF, 1.0 g), (iii) GOS (7.5 g) and bLF (1.0 g), and (iv) no GOS or bLF. Each infant will then be followed for an additional 3 months to determine the longer-term effects of the treatments.

2. to examine mechanisms of iron, prebiotic GOS and iron-sequestering bLF on microbiota composition, enteropathogen development, microbiota functions and metabolic activity, and inflammatory potential in vitro with treatments paralleling those in Specific Aim 1, using immobilized fecal microbiota from Kenyan infants to inoculate our established long-term continuous polyfermenter intestinal model (PolyFermS) to mimic Kenyan infant colon conditions, together with cellular studies.

Combining in vivo clinical and in vitro approaches will help guide formulation of safer iron supplements and fortificants and improve our understanding of the mechanisms whereby prebiotic GOS and iron-sequestering bLF support commensal microbiota to prevent iron-induced overgrowth by opportunistic enteropathogens.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2019-03-04
• Study First Submitted QC: 2019-03-06
• Study First Posted: 2019-03-07
• Study Start: 2020-01-15
• Primary Completion: 2023-04-30
• Study Completion: 2023-04-30
• Results First Submitted: 2024-11-25
• Status Verified: 2024-12
• Results First Submitted QC: 2024-12-17
• Last Update Submitted: 2024-12-17
• Results First Posted: 2025-01-08
• Last Update Posted: 2025-01-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 288

Inclusion Criteria

• vaginal or cesarean delivery
• an infant age of 6 months (±3 weeks)
• mother ≥15 years of age
• infant still breastfeeding
• anticipated residence in the area for the study duration.

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Exclusion Criteria

• inability to provide informed consent
• hemoglobin < 70 g/L
• Z scores for weight-for-age (WAZ) or weight-for-height (WHZ) <3,
• any maternal or infant chronic illness
• administration of any infant vitamin or mineral supplements for the past 2 months
• history of infant antibiotic treatment within 7 days before study enrollment.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Study group B: bLF	Bovine lactoferrin	This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]), bovine lactoferrin (bLF), 1.0 g.
Study group B: bLF	Multiple micronutrient powders with 5 mg iron	This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]), bovine lactoferrin (bLF), 1.0 g.
Study group C: GOS + bLF	Bovine lactoferrin	This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]), galacto-oligosaccharides (GOS), 7.5 mg, and bovine lactoferrin (bLF), 1.0 g.
Study group C: GOS + bLF	Multiple micronutrient powders with 5 mg iron	This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]), galacto-oligosaccharides (GOS), 7.5 mg, and bovine lactoferrin (bLF), 1.0 g.
Study group A: GOS	Galacto-oligosaccharides	This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]) and galacto-oligosaccharides (GOS), 7.5 mg.
Study group D	Multiple micronutrient powders with 5 mg iron	This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]) alone, with no galacto-oligosaccharides (GOS), and no bovine lactoferrin (bLF).
Study group A: GOS	Multiple micronutrient powders with 5 mg iron	This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]) and galacto-oligosaccharides (GOS), 7.5 mg.
Study group C: GOS + bLF	Galacto-oligosaccharides	This study group will receive daily in-home fortification for 6 months with multiple micronutrient powders with 5 mg iron (as sodium iron EDTA \[2.5 mg\] and ferrous fumarate \[2.5 mg\]), galacto-oligosaccharides (GOS), 7.5 mg, and bovine lactoferrin (bLF), 1.0 g.

Primary Outcome Measures

Name	Time	Method
Ratio of Harmful to Beneficial Bacterial Genera in Fecal Microbiota as Determined by Quantitative Polymerase Chain Reaction (qPCR) at 1 Month	1 month	The primary outcome measure will be the ratio of the abundances of potentially harmful (enteropathogenic and/or enterotoxigenic E. coli, C. difficile, members of the C. perfringens group, B. cereus, S. aureus, sum of Shigella spp., and Salmonella) to beneficial (bifidobacteria and the group of Lactobacillus/Leuconostoc/Pediococcus spp.) bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 1 month.

Secondary Outcome Measures

Name	Time	Method
Ratio of Harmful to Beneficial Bacterial Genera in Fecal Microbiota as Determined by Quantitative Polymerase Chain Reaction (qPCR) at 6 Months	6 months	A key secondary outcome measure will be the ratio of the abundances of potentially harmful (enteropathogenic and/or enterotoxigenic E. coli, C. difficile, members of the C. perfringens group, B. cereus, S. aureus, sum of Shigella spp., and Salmonella) to beneficial (bifidobacteria and the group of Lactobacillus/Leuconostoc/Pediococcus spp.) bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 6 months.
Ratio of Harmful to Beneficial Bacterial Genera in Fecal Microbiota as Determined by Quantitative Polymerase Chain Reaction (qPCR) at 9 Months	9 months	A key secondary outcome measure will be the ratio of the abundances of potentially harmful (enteropathogenic and/or enterotoxigenic E. coli, C. difficile, members of the C. perfringens group, B. cereus, S. aureus, sum of Shigella spp., and Salmonella) to beneficial (bifidobacteria and the group of Lactobacillus/Leuconostoc/Pediococcus spp.) bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 9 months.
Microbiota Composition as Determined by Quantitative Polymerase Chain Reaction (qPCR).	1, 6 and 9 months	A secondary outcome measure will be the microbiota composition among study groups as determined by quantitative polymerase chain reaction (qPCR) measures of the abundances of potentially harmful (enteropathogenic and/or enterotoxigenic E. coli, C. difficile, members of the C. perfringens group, B. cereus, S. aureus, sum of Shigella spp., and Salmonella) and of beneficial (bifidobacteria and the group of Lactobacillus/Leuconostoc/Pediococcus spp.) bacterial genera at 1, 6, and 9 months. This outcome is reported as the mean log10 fold change from the beneficial to harmful bacteria ratio (BHR) of the baseline microbiota composition, abbreviated as "log10 FC in BHR".
Number of Participants Who Experienced Diarrhea	Up to 9 months	A secondary outcome measure will be the prevalence of diarrhea among study groups.
Number of Participants Who Experienced Malaria	Up to 9 months	A secondary outcome measure will be the prevalence of malaria among study groups.
Proportion of Participants Who Experienced Anemia	Baseline, 1 month, 6 months, 9 months	A secondary outcome measure will be the proportion of participants with anemia among study groups, defined as Hemoglobin \< 11.5 g/L by laboratory diagnosis.
Proportion of Participants Who Experienced Iron Deficiency	Baseline, 1 month, 6 months, 9 months	A secondary outcome measure will be the proportion of participants with iron deficiency among study groups, defined as plasma Ferritin \< 12 µg/L or/and soluble transferrin receptor (sTfR) \> 8.3 mg/L
Proportion of Participants Who Experienced Iron Deficiency Anemia (IDA)	Baseline, 1 month, 6 months, 9 months	A secondary outcome measure will be the proportion of participants with iron deficiency anemia among study groups, defined as Hemoglobin \< 11.5 g/L and Soluble transferrin receptor (sTfR) \> 8.3 mg/L
Proportion of Participants Who Experienced Inflammation	Baseline, 1 month, 6 months, 9 months	A secondary outcome measure will be the proportion of participants with inflammation among study groups, defined as C-reactive protein (CRP) \> 5 mg/L
Number of Participants Who Experienced Respiratory Tract Infections	Up to 9 months	A secondary outcome measure will be the prevalence of Respiratory tract infections among study groups.
Other Illnesses	Up to 9 months	A secondary outcome measure will be the prevalence of other illnesses among study groups.

Trial Locations

Locations (2)

Jomo Kenyatta University of Agriculture and Technology; 🇰🇪 Nairobi, Kenya

Swiss Federal Institute of Technology (ETH Zürich); 🇨🇭 Zürich, Switzerland