High-Dose Enteral Iron Supplementation in Infants With Very Low Birth Weight Associated With Intestinal Dysbiosis

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Investigators compared differences in microbiome composition among infants with very low birth weights receiving varying enteral iron supplementation doses.

In infants with very low birth weight (VLBW), higher enteral iron supplementation (EIS) doses were associated with a less diverse microbiome, higher abundances of Proteus and Bifidobacterium, and a higher potential for epithelial invasion, according to a study published in The Journal of Pediatric Gastroenterology and Nutrition.

Stool samples from 80 infants born at an average gestational age of 28.1±2.4 weeks and average weight of 1103±210 g were collected: 105 samples were collected before EIS and 237 samples after. The average initial EIS dose was 4.8±1.1 mg/kg/day. Infants were stratified into groups based on their initial dose, the lowest being 3.0-3.9 mg/kg/dayand highest ≥6 mg/kg/day.

After controlling for age at stool collection, the number of days on EIS had a weak positive correlation with the percentages of Proteobacteria and Escherichia, and a weak negative correlation with Firmicutes.

Infants in the highest dose group had post supplementation samples with significantly higher Proteus abundance compared against all other groups. Feeding type (β =2.080; P =.016) and age when supplementation began (β = -0.349; P =.025) were also significant predictors, suggesting that lower human milk consumption is associated with higher Proteus abundance, and the later supplementation is started, the smaller the difference in Proteus abundance becomes. Compared with the highest dose group, the lowest dose group had significantly lower Bifidobacterium abundance (β= -7.244; P =.028).

At 2 weeks post-supplementation, the strongest and most consistently predicted differences were a lower number of ferroptosis pathways in intestinal bacteria in the lowest dose group and a greater number of pathways in bacterial invasion of epithelial cells in the highest dose group.

As far as limitations, this study did not take serum blood samples to examine systemic influences of EIS dosing. Additionally, the timing of EIS was varied. Finally, the study was not powered to detect a relationship between clinical outcomes and microbiome changes in each dose group.

Investigators concluded that, “…high-dose EIS was associated with traits of intestinal dysbiosis, increase in Proteus and a less diverse gut microbiome, but with a higher presence of Bifidobacteria in VLBW infants.” They added, “These observations suggest potential harms of high-dose EIS and the need for further studies to identify the optimal EIS dosage that can prevent iron deficiency without increasing pathogenic bacterial growth.”


Ho T, 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.