Iron in Micronutrient Powder Promotes an Unfavorable Gut Microbiota in Kenyan Infants

Abstract

Iron supplementation may have adverse health effects in infants, probably through manipulation of the gut microbiome. Previous research in low-resource settings have focused primarily on anemic infants. This was a double blind, randomized, controlled trial of home fortification comparing multiple micronutrient powder (MNP) with and without iron. Six-month-old, non- or mildly anemic, predominantly-breastfed Kenyan infants in a rural malaria-endemic area were randomized to consume: (1) MNP containing 12.5 mg iron (MNP+Fe, n = 13); (2) MNP containing no iron (MNP−Fe, n = 13); or (3) Placebo (CONTROL, n = 7), from 6–9 months of age. Fecal microbiota were profiled by high-throughput bacterial 16S rRNA gene sequencing. Markers of inflammation in serum and stool samples were also measured. At baseline, the most abundant phylum was Proteobacteria (37.6% of rRNA sequences). The proteobacterial genus Escherichia was the most abundant genus across all phyla (30.1% of sequences). At the end of the intervention, the relative abundance of Escherichia significantly decreased in MNP−Fe (−16.05 ± 6.9%, p = 0.05) and CONTROL (−19.75 ± 4.5%, p = 0.01), but not in the MNP+Fe group (−6.23 ± 9%, p = 0.41). The second most abundant genus at baseline was Bifidobacterium (17.3%), the relative abundance of which significantly decreased in MNP+Fe (−6.38 ± 2.5%, p = 0.02) and CONTROL (−8.05 ± 1.46%, p = 0.01), but not in MNP-Fe (−4.27 ± 5%, p = 0.4445). Clostridium increased in MNP-Fe only (1.9 ± 0.5%, p = 0.02). No significant differences were observed in inflammation markers, except for IL-8, which decreased in CONTROL. MNP fortification over three months in non- or mildly anemic Kenyan infants can potentially alter the gut microbiome. Consistent with previous research, addition of iron to the MNP may adversely affect the colonization of potential beneficial microbes and attenuate the decrease of potential pathogens.

The Benefits and Risks of Iron Supplementation in Pregnancy and Childhood

“…The explanation may reside in the gut bacterial microbiome. In two separate studies of African infants, the regular consumption of iron-fortified biscuits and iron-fortified food powders shifted the profile of the gut microbiota from one in which more beneficial bifidobacteria barrier strains presided to one where pathogenic enterobacteria strains prevailed (132). Recent preclinical models also suggest that pathogenic shifts in the gut microbiome are associated not only with diarrheal illness but also with an increased risk of a range of respiratory viruses, including respiratory syncytial virus and pneumococcal pneumonia (117).…”

Approaches for Reducing the Risk of Early-Life Iron Deficiency-Induced Brain Dysfunction in Children

“…Although the mechanism behind the lower morbidity associated with delayed iron therapy is unclear, it follows that the greater percentage iron incorporation that we observed with delayed treatment would be accompanied by less unabsorbed iron in the intestinal lumen. In multiple studies of iron-fortified micronutrient powder, unabsorbed iron has been associated with a shift in the composition of the intestinal microbiome of young children living in malaria-endemic areas, shifting from predominant beneficial barrier strains (e.g., bifidobacteriaceae), to more pathogenic strains (e.g., enterobacteria), and leading to intestinal inflammation [ 75 , 76 , 77 ].…”

Data needed to respond appropriately to anemia when it is a public health problem

“…Malaria is a cause of anemia as well as causing inflammation and important to measure when assessing the etiology of anemia. Recent evidence indicates that unabsorbed iron may be detrimental to the gut microflora, Given iron absorption regulation, iron‐replete individuals may have more unabsorbed supplemental iron in the upper and lower gastrointestinal tract. This evidence further illustrates the value of characterizing a population's iron status prior to giving preventive iron interventions.…”

“…However, low blood Hb concentration is influenced by multiple health conditions other than inadequate iron intake such as malaria, HIV, inflammation, gastrointestinal bleeding (e.g., intestinal parasites or peptic ulcer disease), nonmodifiable genetic blood disorders and hemoglobinopathies, multiple micronutrient deficiencies, and physiologic state (e.g., pregnancy and menstruation). Iron provided to populations without iron deficiency (ID) may lead to unnecessary health risks in the context of infection, because bacteria and parasites propagate in iron‐rich environments. Therefore, assessment of context‐specific data is required to understand and respond appropriately to the drivers of low Hb.…”