Prebiotic GOS and Lactoferrin With Iron Supplements
Condition: Iron-deficiency
MeSH terms: Anemia, Iron-Deficiency; Iron Deficiencies
Study type: Interventional

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.
    

Intervention name(s): Galacto-oligosaccharides; Bovine lactoferrin; Multiple micronutrient powders with 5 mg iron
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): Galacto-oligosaccharides are classified as Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration, are components of cow's milk and have been used repeatedly in clinical trials without adverse effects.; Bovine lactoferrin is classified as Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration, is a component of cow's milk and has been used repeatedly in clinical trials without adverse effects.; The multiple micronutrient powders are composed of Vitamin A, 400 μg; Vitamin D, 5 μg; Tocopherol Equivalents, 5 mg; Thiamine, 0.5 mg; Riboflavin, 0.5 mg; Vitamin B6, 0.5 mg; Folic Acid, 90 μg; Niacin, 6 mg; Vitamin B12, 0.9 μg; Vitamin C, 30 mg; Copper, 0.56 mg; Iodine, 90 μg; Selenium, 17 μg; Zinc, 4.1 mg; Phytase, 190 FTU; Iron, 5 mg [(as Ferrous fumarate, 2.5 mg and sodium iron ethylenediaminetetraacetate (NaFeEDTA), 2.5 mg].
Intervention MeSH terms: Micronutrients; Trace Elements; Lactoferrin
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: The study is a single-center, double-blinded, randomized, 9-month clinical trial with a 2X2 factorial design to determine the efficacy of galacto-oligosaccharides and bovine lactoferrin in preserving a beneficial gut microbiota during iron supplementation in Kenyan infants.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Iron-deficiency; Iron supplementation; Galacto-oligosaccharides; Lactoferrin; Ferrous fumarate; Clinical trial; Microbiome; PolyFermS; Polyfermenter intestinal model