title: Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants.
abstract: 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.
  
  
  BACKGROUND
  NCT01111864.
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Jaeggi
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Guus A M
authors.initials: GA
authors.lastname: Kortman
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Diego
authors.initials: D
authors.lastname: Moretti
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Chassard
authors.affiliation: International Center for Behavioural Studies, Mombasa, Kenya.
authors.forename: Penny
authors.initials: P
authors.lastname: Holding
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dostal
authors.affiliation: NIZO Food Research B.V., Ede, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Boekhorst
authors.affiliation: NIZO Food Research B.V., Ede, The Netherlands.
authors.forename: Harro M
authors.initials: HM
authors.lastname: Timmerman
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.affiliation: Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Harold
authors.initials: H
authors.lastname: Tjalsma
authors.affiliation: Department of Food, Technology and Nutrition, University of Nairobi, Nairobi, Kenya.
authors.forename: Jane
authors.initials: J
authors.lastname: Njenga
authors.affiliation: Department of Food, Technology and Nutrition, University of Nairobi, Nairobi, Kenya.
authors.forename: Alice
authors.initials: A
authors.lastname: Mwangi
authors.affiliation: University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Jane
authors.initials: J
authors.lastname: Kvalsvig
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lacroix
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Zimmermann
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000517:prevention & control; D001419:Bacteria / Q000302:isolation & purification; D003968:Diarrhea, Infantile / Q000139:chemically induced / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004760:Enterocolitis / Q000139:chemically induced* / Q000382:microbiology; D005243:Feces / Q000737:chemistry; D005527:Food, Fortified / Q000009:adverse effects*; D006801:Humans; D007223:Infant; D007422:Intestines / Q000382:microbiology*; D019266:Iron, Dietary / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism; D064307:Microbiota / Q000187:drug effects*; D018977:Micronutrients / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D019266:Iron, Dietary; D039841:Leukocyte L1 Antigen Complex; D018977:Micronutrients
keywords: Enteric Bacterial Microflora; Enteropathogenic E Coli; Gut Inflammation; Infant Gut; Iron Nutrition