Iron Supplementation and Microbiome in Preterm Infants: Risks of Dysbiosis and Pathogen Enrichment Original paper
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Metals
Metals
Heavy metals play a significant and multifaceted role in the pathogenicity of microbial species.
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Iron (Fe)
Iron (Fe)
OverviewIron is a pivotal nutrient at the host–pathogen interface. Virtually all microbes (with rare exceptions like Borrelia) require iron for processes from DNA synthesis to respiration. [1] In human hosts, free iron is vanishingly scarce due to “nutritional immunity,” wherein iron is locked up in hemoproteins or tightly bound by transport proteins.[2] This metal tug-of-war […]
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
What was studied?
This longitudinal observational study investigated how different enteral iron supplementation (EIS) dosages affect the intestinal microbiome of very low birth weight (VLBW) preterm infants. Infants were stratified into groups receiving 3–3.9, 4–4.9, 5–5.9, or ≥6 mg/kg/day of elemental iron. Using 16S rRNA V4 gene sequencing, bacterial taxonomy and predicted functional pathways were analyzed from stool samples collected before and after EIS initiation. The study also employed the Piphillin software to infer functional capacities such as ferroptosis and epithelial invasion from the microbiome. Linear mixed-effects models were used to determine associations between EIS dose and microbial parameters, adjusting for multiple clinical covariates.
Who was studied?
The study cohort comprised 80 VLBW infants (average gestational age: 28.1 ± 2.4 weeks; average birth weight: 1103 ± 210 g) from a single tertiary academic center. A total of 342 stool samples were collected over the first two months of life, including 105 samples before and 237 after EIS initiation. Inclusion criteria restricted the cohort to infants under 1500 g birth weight without major anomalies, and all received iron supplementation as per clinical protocols. Infants varied in sex, mode of delivery, feeding type (maternal breast milk, formula, or mixed), and antibiotic exposure.
Most important findings
Infants receiving higher EIS doses (≥6 mg/kg/day) exhibited a statistically significant increase in the abundance of Proteus spp. and Bifidobacterium, and a reduction in alpha diversity (Shannon index) compared to lower-dose groups. These alterations are indicative of gut dysbiosis. Notably, Proteus enrichment was associated with formula feeding, earlier initiation of EIS, and female sex. Predicted functional potential using KEGG pathway analysis revealed a higher abundance of pathways related to ferroptosis and bacterial epithelial invasion, particularly in the highest dose group two weeks after iron initiation. This finding aligns with mechanistic literature suggesting that iron-rich environments enhance bacterial pathogenicity. These microbial alterations occurred despite adjustments for confounding factors, including gestational age, antibiotic use, anemia, feeding mode, and maternal BMI.
| Microbial/Functional Marker | EIS Dose Effect (Group 6 vs. others) | Statistical Significance |
|---|---|---|
| Proteus abundance | Significantly increased | p <0.001 |
| Bifidobacterium | Also increased (vs. group 3) | p = 0.028 |
| Shannon Index (diversity) | Significantly reduced | p <0.001 |
| Ferroptosis pathways | Increased in high-dose group | Inferred via KEGG pathways |
| Epithelial invasion genes | Enriched in high-dose group (week 2 post-EIS) | Inferred via KEGG pathways |
Key implications
This study provides compelling evidence that high-dose enteral iron supplementation may disrupt microbial homeostasis in VLBW infants, contributing to intestinal dysbiosis marked by reduced diversity and pathogenic enrichment. The enrichment of Proteus—a known opportunistic pathogen—and functional potentials for epithelial invasion underscore potential risks for enteric inflammation or sepsis in this vulnerable population. These findings advocate for caution in the upper dosing range of EIS and suggest the need for individualized dosing regimens. They also emphasize the importance of integrating microbiome considerations into neonatal nutritional protocols, especially where pathogen proliferation and barrier integrity are clinical concerns.
Citation
Ho TB, Sarkar A, Szalacha L, Groer MW. Intestinal Microbiome in Preterm Infants Influenced by Enteral Iron Dosing.J Pediatr Gastroenterol Nutr. 2021;72(5):e132–e138. doi:10.1097/MPG.0000000000003033.