Prebiotic GOS and Lactoferrin With Iron Supplements

Iron-deficiency Clinical Trial

Official title:

Prebiotic GOS and Lactoferrin for Beneficial Gut Microbiota With Iron Supplements

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03866837
• Other study ID #: AAAR8900
• Secondary ID: R01DK115449
• Status: Completed
• Phase: N/A
• Start date: January 15, 2020
• Est. completion date: April 30, 2023

Study information

• Verified date: February 2024
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 288
• Est. completion date: April 30, 2023
• Est. primary completion date: April 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Weeks to 27 Weeks

Eligibility

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.

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.

Related Conditions & MeSH terms

• Anemia, Iron-Deficiency
• Iron-deficiency

Intervention

Dietary Supplement:
• Galacto-oligosaccharides
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
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.
• Multiple micronutrient powders with 5 mg iron
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].

Locations

Country	Name	City	State
Kenya	Jomo Kenyatta University of Agriculture and Technology	Nairobi
Switzerland	Swiss Federal Institute of Technology (ETH Zürich)	Zürich

Sponsors (4)

Lead Sponsor	Collaborator
Columbia University	Jomo Kenyatta University of Agriculture and Technology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Swiss Federal Institute of Technology

Countries where clinical trial is conducted

Kenya,  Switzerland, 

References & Publications (27)

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Chen K, Chai L, Li H, Zhang Y, Xie HM, Shang J, Tian W, Yang P, Jiang AC. Effect of bovine lactoferrin from iron-fortified formulas on diarrhea and respiratory tract infections of weaned infants in a randomized controlled trial. Nutrition. 2016 Feb;32(2):222-7. doi: 10.1016/j.nut.2015.08.010. Epub 2015 Sep 3. — View Citation

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Dostal A, Chassard C, Hilty FM, Zimmermann MB, Jaeggi T, Rossi S, Lacroix C. Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats. J Nutr. 2012 Feb;142(2):271-7. doi: 10.3945/jn.111.148643. Epub 2011 Dec 21. — View Citation

Dostal A, Fehlbaum S, Chassard C, Zimmermann MB, Lacroix C. Low iron availability in continuous in vitro colonic fermentations induces strong dysbiosis of the child gut microbial consortium and a decrease in main metabolites. FEMS Microbiol Ecol. 2013 Jan;83(1):161-75. doi: 10.1111/j.1574-6941.2012.01461.x. Epub 2012 Aug 28. — View Citation

Dostal A, Gagnon M, Chassard C, Zimmermann MB, O'Mahony L, Lacroix C. Salmonella adhesion, invasion and cellular immune responses are differentially affected by iron concentrations in a combined in vitro gut fermentation-cell model. PLoS One. 2014 Mar 27;9(3):e93549. doi: 10.1371/journal.pone.0093549. eCollection 2014. — View Citation

Dostal A, Lacroix C, Bircher L, Pham VT, Follador R, Zimmermann MB, Chassard C. Iron Modulates Butyrate Production by a Child Gut Microbiota In Vitro. mBio. 2015 Nov 17;6(6):e01453-15. doi: 10.1128/mBio.01453-15. — View Citation

Dostal A, Lacroix C, Pham VT, Zimmermann MB, Del'homme C, Bernalier-Donadille A, Chassard C. Iron supplementation promotes gut microbiota metabolic activity but not colitis markers in human gut microbiota-associated rats. Br J Nutr. 2014 Jun 28;111(12):2135-45. doi: 10.1017/S000711451400021X. Epub 2014 Feb 21. — View Citation

Jaeggi T, Kortman GA, Moretti D, Chassard C, Holding P, Dostal A, Boekhorst J, Timmerman HM, Swinkels DW, Tjalsma H, Njenga J, Mwangi A, Kvalsvig J, Lacroix C, Zimmermann MB. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut. 2015 May;64(5):731-42. doi: 10.1136/gutjnl-2014-307720. Epub 2014 Aug 20. — View Citation

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Lacroix C, de Wouters T, Chassard C. Integrated multi-scale strategies to investigate nutritional compounds and their effect on the gut microbiota. Curr Opin Biotechnol. 2015 Apr;32:149-155. doi: 10.1016/j.copbio.2014.12.009. Epub 2015 Jan 3. — View Citation

Legrand D. Overview of Lactoferrin as a Natural Immune Modulator. J Pediatr. 2016 Jun;173 Suppl:S10-5. doi: 10.1016/j.jpeds.2016.02.071. — View Citation

Liao Y, Jiang R, Lonnerdal B. Biochemical and molecular impacts of lactoferrin on small intestinal growth and development during early life. Biochem Cell Biol. 2012 Jun;90(3):476-84. doi: 10.1139/o11-075. Epub 2012 Feb 14. — View Citation

Lonnerdal B. Bioactive Proteins in Human Milk: Health, Nutrition, and Implications for Infant Formulas. J Pediatr. 2016 Jun;173 Suppl:S4-9. doi: 10.1016/j.jpeds.2016.02.070. — View Citation

Manzoni P. Clinical Benefits of Lactoferrin for Infants and Children. J Pediatr. 2016 Jun;173 Suppl:S43-52. doi: 10.1016/j.jpeds.2016.02.075. — View Citation

Ochoa TJ, Chea-Woo E, Baiocchi N, Pecho I, Campos M, Prada A, Valdiviezo G, Lluque A, Lai D, Cleary TG. Randomized double-blind controlled trial of bovine lactoferrin for prevention of diarrhea in children. J Pediatr. 2013 Feb;162(2):349-56. doi: 10.1016/j.jpeds.2012.07.043. Epub 2012 Aug 30. — View Citation

Paganini D, Uyoga MA, Zimmermann MB. Iron Fortification of Foods for Infants and Children in Low-Income Countries: Effects on the Gut Microbiome, Gut Inflammation, and Diarrhea. Nutrients. 2016 Aug 12;8(8):494. doi: 10.3390/nu8080494. — View Citation

Pasricha SR, Hayes E, Kalumba K, Biggs BA. Effect of daily iron supplementation on health in children aged 4-23 months: a systematic review and meta-analysis of randomised controlled trials. Lancet Glob Health. 2013 Aug;1(2):e77-e86. doi: 10.1016/S2214-109X(13)70046-9. Epub 2013 Jul 24. Erratum In: Lancet Glob Health. 2014 Mar 2(3):e144. — View Citation

Payne AN, Chassard C, Banz Y, Lacroix C. The composition and metabolic activity of child gut microbiota demonstrate differential adaptation to varied nutrient loads in an in vitro model of colonic fermentation. FEMS Microbiol Ecol. 2012 Jun;80(3):608-23. doi: 10.1111/j.1574-6941.2012.01330.x. Epub 2012 Mar 27. — View Citation

Payne AN, Zihler A, Chassard C, Lacroix C. Advances and perspectives in in vitro human gut fermentation modeling. Trends Biotechnol. 2012 Jan;30(1):17-25. doi: 10.1016/j.tibtech.2011.06.011. Epub 2011 Jul 20. — View Citation

Rai D, Adelman AS, Zhuang W, Rai GP, Boettcher J, Lonnerdal B. Longitudinal changes in lactoferrin concentrations in human milk: a global systematic review. Crit Rev Food Sci Nutr. 2014;54(12):1539-47. doi: 10.1080/10408398.2011.642422. — View Citation

Tanner SA, Zihler Berner A, Rigozzi E, Grattepanche F, Chassard C, Lacroix C. In vitro continuous fermentation model (PolyFermS) of the swine proximal colon for simultaneous testing on the same gut microbiota. PLoS One. 2014 Apr 7;9(4):e94123. doi: 10.1371/journal.pone.0094123. eCollection 2014. — View Citation

Troesch B, Egli I, Zeder C, Hurrell RF, de Pee S, Zimmermann MB. Optimization of a phytase-containing micronutrient powder with low amounts of highly bioavailable iron for in-home fortification of complementary foods. Am J Clin Nutr. 2009 Feb;89(2):539-44. doi: 10.3945/ajcn.2008.27026. Epub 2008 Dec 23. — View Citation

Zihler Berner A, Fuentes S, Dostal A, Payne AN, Vazquez Gutierrez P, Chassard C, Grattepanche F, de Vos WM, Lacroix C. Novel Polyfermentor intestinal model (PolyFermS) for controlled ecological studies: validation and effect of pH. PLoS One. 2013 Oct 30;8(10):e77772. doi: 10.1371/journal.pone.0077772. eCollection 2013. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ratio of harmful to beneficial bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 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.	1 month
Secondary	Ratio of harmful to beneficial bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 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.	6 months
Secondary	Ratio of harmful to beneficial bacterial genera in fecal microbiota as determined by quantitative polymerase chain reaction (qPCR) at 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.	9 months
Secondary	Microbiota composition as determined by quantitative polymerase chain reaction (qPCR).	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.	1, 6 and 9 months
Secondary	Diarrhea	A secondary outcome measure will be the prevalence of diarrhea among study groups	1, 6 and 9 months
Secondary	Malaria	A secondary outcome measure will be the prevalence of malaria among study groups	1, 6 and 9 months
Secondary	Anemia	A secondary outcome measure will be the prevalence of anemia among study groups	1, 6 and 9 months
Secondary	Iron deficiency	A secondary outcome measure will be the prevalence of iron deficiency among study groups	1, 6 and 9 months
Secondary	Iron deficiency anemia	A secondary outcome measure will be the prevalence of iron deficiency anemia among study groups	1, 6 and 9 months
Secondary	Inflammation	A secondary outcome measure will be the prevalence of inflammation among study groups	1, 6 and 9 months
Secondary	Respiratory tract infections	A secondary outcome measure will be the prevalence of inflammation among study groups	1, 6 and 9 months
Secondary	Other illnesses	A secondary outcome measure will be the prevalence of other illnesses among study groups	1, 6 and 9 months