Iron Fortification Adversely Affects the Gut Microbiome, Increases Pathogen Abundance and Induces Intestinal Inflammation in Kenyan Infants
Open accessAbstract
Background: In-home iron fortification for infants in developing countries is recommended for control of anaemia, but low absorption typically results in >80% of the iron passing into the colon. Iron is essential for growth and virulence of many pathogenic enterobacteria. We determined the effect of high and low dose in-home iron fortification on the infant gut microbiome and intestinal inflammation. Methods: We performed two double-blind randomised controlled trials in 6-month-old Kenyan infants (n=115) consuming home-fortified maize porridge daily for 4 months. In the first, infants received a micronutrient powder (MNP) containing 2.5 mg iron as NaFeEDTA or the MNP without iron. In the second, they received a different MNP containing 12.5 mg iron as ferrous fumarate or the MNP without the iron. The primary outcome was gut microbiome composition analysed by 16S pyrosequencing and targeted real-time PCR (qPCR). Secondary outcomes included faecal calprotectin (marker of intestinal inflammation) and incidence of diarrhoea. We analysed the trials separately and combined. Results: At baseline, 63% of the total microbial 16S rRNA could be assigned to Bifidobacteriaceae but there were high prevalences of pathogens, including Salmonella Clostridium difficile , Clostridium perfringens , and pathogenic Escherichia coli . Using pyrosequencing, +FeMNPs increased enterobacteria, particularly Escherichia / Shigella (p=0.048), the enterobacteria/bifidobacteria ratio (p=0.020), and Clostridium (p=0.030). Most of these effects were confirmed using qPCR; for example, +FeMNPs increased pathogenic E. coli strains (p=0.029). +FeMNPs also increased faecal calprotectin (p=0.002). During the trial, 27.3% of infants in +12.5 mgFeMNP required treatment for diarrhoea versus 8.3% in −12.5 mgFeMNP (p=0.092). There were no study-related serious adverse events in either group. Conclusions: In this setting, provision of iron-containing MNPs to weaning infants adversely affects the gut microbiome, increasing pathogen abundance and causing intestinal inflammation. Trial registration number: NCT01111864.
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Studies investigating iron supplementation in Kenyan infants found increased levels of Enterobacteriaceae and decreased levels of Lactobacillus and Bifidobacterium.
“Studies investigating the effect of iron supplementation in Kenyan infants also found increased levels of Enterobacteriaceae and decreased levels of Lactobacillus and Bifidobacterium [42].”
From Oral Iron Supplementation—Gastrointestinal Side Effects and the Impact on the Gut Microbiota (2021) · cites this paper as [42]
The Results and ‘What are the new findings?’ sections report increased enterobacteria and decreased bifidobacteria with iron fortification in Kenyan infants. The Kenyan results report a higher enterobacteria-to-lactobacilli ratio, not a decrease in lactobacilli themselves; the Discussion attributes a decrease in lactobacilli to a separate trial in schoolchildren in Côte d’Ivoire. Page numbers are not available in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn Sub-Saharan Africa, iron supplementation to infants and young children increased morbidity and mortality from infections, possibly because of iron-induced growth of Plasmodium or expansion of pathogenic E. coli.
“In Sub-Saharan Africa for example, iron supplementation to infants and young children increased morbidity and mortality from infections, possibly because of iron-induced growth of Plasmodium, the causative agent of malaria, or expansion of pathogenic E. coli (Jaeggi et al., 2014;Sazawal et al., 2006;Tang et al., 2017).”
From Iron in infection and immunity (2020) · cites this paper as Jaeggi et al., 2014
The Results (Figure 1 Trial profile; page unavailable) report higher pathogenic E. coli concentrations at the endpoint in Kenyan infants receiving iron fortification. The Discussion (page unavailable) describes a possible link to diarrhoea, but says the increase in treated diarrhoea in this study was only a trend and that the disease risk remains uncertain. The paper does not establish increased infection mortality or iron-induced growth of Plasmodium. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome but not all studies found altered composition of intestinal flora and increased inflammation in children treated to prevent or reverse iron deficiency.
“Motivated to understand the connection between iron supplementation and diarrhoeal illness in African children, some but not all studies found an altered composition of the intestinal flora and increased inflammation in children who were treated to prevent or reverse iron deficiency61–63.”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [62]
Human breastmilk transmits lactoferrin, an iron-binding glycoprotein, to protect the undeveloped infant gut from pathogen colonization, and iron supplementation in infants can increase pathogen growth and intestinal inflammation.
“Human breastmilk transmits lactoferrin, an iron-binding glycoprotein, to protect the undeveloped infant gut from pathogen colonization, and iron supplementation in infants can increase pathogen growth and intestinal inflammation (52).”
From The gut microbiota at the intersection of diet and human health (2018) · cites this paper as [52]
Dietary iron has less than 20% absorption efficiency, leaving most ingested iron in the intestinal lumen for the microbiota.
“Dietary iron has less than 20% absorption efficiency leaving the bulk of iron intake within the intestinal lumen to the microbiota (Jaeggi et al., 2015).”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Jaeggi et al., 2015
Dietary iron drives changes to the microbiota that may increase susceptibility to infection.
“Yet, studies examining the effects of dietary iron suggest iron drives changes to the microbiota that may result in increased susceptibility to infection ((Constante et al., 2017; Jaeggi et al., 2015); Figure 3).”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Jaeggi et al., 2015
Iron supplementation trials in infants in low- to middle-income countries showed increased incidence of diarrhoeal disease.
“Iron supplementation trials in infants in low‐ to middle‐income countries showed increased incidence of diarrhoeal disease. 152 , 153 , 154 , 155”
From The battle for iron in enteric infections (2020) · cites this paper as [154]
One consistent result from in vivo studies is an iron-induced skew away from commensals such as lactobacilli or Bifidobacterium species, which have low iron requirements, towards Enterobacteriaceae.
“Althuogh complex, one consistent result from in vivo studies is an iron‐induced skew away from commensals such as lactobacilli or Bifidobacterium species, 154 , 157 , 158 which have low iron requirements, 53 towards Enterobacteriaceae (the bacterial family which includes Salmonella sp.).”
From The battle for iron in enteric infections (2020) · cites this paper as [154]
Iron supplementation in a cohort of Kenyan children increased the abundance of pathogens such as Bacillus cereus, Staphylococcus aureus, Clostridium difficile, C. perfringens, and Salmonella, potentially contributing to gut inflammation.
“For example, iron supplementation in a cohort of Kenyan children increased the abundance of pathogens such as Bacillus cereus, Staphylococcus aureus, Clostridium difficile, C. perfringens, and Salmonella, potentially contributing to gut inflammation (156)”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [156]
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Self-citationIron in the Tumor Microenvironment-Connecting the Dots
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BackgroundOral iron acutely elevates bacterial growth in human serum
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BackgroundMethodResultInfluentialKortman, G. A. M., Dutilh, B. E., Maathuis, A. J. H., Engelke, U. F., Boekhorst, J., Keegan, K. P., Nielsen, F. G. G., Betley, J., Weir, J. C., Kingsbury, Z., et al. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.01481 · Cited by 73 · see citing works
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- Authors
- Jaeggi, T., Kortman, G. A. M., Moretti, D., Chassard, C., Holding, P., Dostal, A., Boekhorst, J., Timmerman, H. M., Swinkels, D. W., Tjalsma, H., Njenga, J., Mwangi, A., Kvalsvig, J., Lacroix, C., & Zimmermann, M. B.
- Affiliations
- ETH Zurich (CH)
- Radboud University Medical Center (NL)
- International Center for Behavioural Studies, Mombasa, Kenya
- Nederlands Instituut Voor Zuivel Oonderzoek (NL)
- University of Nairobi (KE)
- University of KwaZulu-Natal (ZA)
- Corresponding author
- Jaeggi, Tanja
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2014-08-20
- Volume
- 64
- Issue
- 5
- Pages
- 731-742
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2138003397
- Cited by
- 622
- References
- 71
- Citations by year
- 2026: 32 · 2025: 48 · 2024: 61 · 2023: 58 · 2022: 55 · 2021: 58 · 2020: 69 · 2019: 58 · 2018: 56 · 2017: 57 · 2016: 44 · 2015: 21 · 2014: 4
- FWCI
- 17.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- European Commission (211484, 2007–2013)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD064921)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Nursing › Nutrition and Dietetics › Infant Nutrition and Health
- Health Sciences › Nursing › Nutrition and Dietetics › Child Nutrition and Water Access
- Keywords
- iron fortification, infant gut microbiota, micronutrient powders, intestinal inflammation, fecal calprotectin, diarrhea, pathogenic Escherichia coli, Clostridium difficile, Clostridium perfringens, Enterobacteriaceae, Bifidobacteriaceae, anemia prevention, iron dosage, maize porridge
- MeSH terms
- Bacteria, Diarrhea, Infantile, Dose-Response Relationship, Drug, Double-Blind Method, Enterocolitis, Feces, Food, Fortified, Humans, Infant, Intestines, Anemia, Iron-Deficiency, Micronutrients, Iron, Dietary, Leukocyte L1 Antigen Complex, Microbiota
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