Identifying infants vulnerable to the adverse effects of iron supplements

Iron supplements are often given to infants in low-income countries to counteract anaemia. However, high doses of dietary iron can negatively impact the infant gut microbiome. In addition, it has been suggested that iron supplements modify the response to oral antibiotics, particularly reducing their efficacy against enteropathogens. Some of these problems can be addressed by combining iron supplements with a prebiotic in the form of galacto-oligosaccharides (GOS). Research recently published in the journal Nutrients now suggests that specific oligosaccharides found in human milk can act as a ‘natural prebiotic’: the presence or absence of some of these human milk oligosaccharides (HMOs) seems to affect how the infant gut microbiota responds to dietary iron. Identifying the profile of complex sugars in the mothers’ breast milk may help to determine which infants are likely to be more vulnerable to the adverse effects of iron.


Differing responses to iron supplements

The team of researchers was led by dr. Daniela Paganini and prof. dr. Michael Zimmermann at ETH Zurich, Switzerland. The study itself was carried out in Kenya, where virtually all babies are breastfed. Breast milk contains little iron, and once the infants start to be weaned between 6 and 24 months of age, many of them are given iron supplements. This is because the foods these infants start to eat contain insufficient iron to prevent anaemia. Previous research has shown that these infants differ in their response to iron, not only in terms of efficacy for anaemia, but also regarding side effects. Some infants get diarrhoea while others do not; and when iron is given together with prebiotics to reduce side effects, some infants benefit more than others. The results of the new study suggest that the composition of their mothers’ milk, in particular the HMO profile, may play a role in this.

The varied functions of human milk oligosaccharides

The solid components of milk include digestible fats and sugars, but also a varied group of complex indigestible oligosaccharides that act as prebiotics. Although these HMOs have little nutritional value, once inside the infant gut HMOs can modulate the immune system and the gut microbiome, thereby helping to prevent pathogen binding and infections. The most common HMOs are the neutral fucosylated and non-fucosylated oligosaccharides. But not all breast milk contains specific fucosylated oligosaccharides. This is due to a homozygous mutation in the FUT2 gene, which encodes the α-1-2-fucosyltransferase enzyme. Women with such a mutation are known as non-secretors as they cannot produce certain HMOs. The difference in milk composition between secretors and non-secretors is thought to also influence the infant’s health. Approximately 20% of women worldwide are thought to be non-secretors, but this proportion is known to vary from country to country.

Investigating the impact of maternal HMO profiles in Kenya

Despite increasing knowledge on HMOs, data on the breast milk composition of women in Sub-Saharan Africa is limited. Until now, it was also unclear whether variations in HMO composition might have an effect on the way in which infants respond to iron supplements and/or prebiotics in the form of GOS.

The researchers therefore set out to determine the secretor/non-secretor status and HMO profiles of lactating mothers in rural Kenya. They looked at whether this had an effect on the infant’s gut microbiome and on the infant’s response to a daily dose of iron, given either alone or together with GOS. Data was collected and analysed from 75 mother–infant pairs who were taking part in a 4-month intervention trial. The infants (aged 6.5–9.5 months) were spread over three intervention groups that received no iron or GOS, iron only, or iron and GOS. The supplements were supplied to the mothers in the form of a daily sachet containing a micronutrient powder, which could be added to the infants’ food.

Maternal secretor status affects the infants’ response to iron fortification

Analysis of human milk oligosaccharide composition in maternal breast milk to determine secretor status revealed that 28% of the mothers were non-secretors, indicating that the prevalence of secretors in this region might be higher than average. HMO profiles of maternal breast milk samples showed clear differences between the secretor and non-secretor mothers: as expected, milk from the non-secretors contained no α-1-2-linked fucosylated oligosaccharides. When the infants’ stool samples were analysed using 16S rDNA sequencing and quantitative polymerase chain reaction (qPCR) for selected pathogenic bacteria, maternal secretor status was found to have no impact on the composition of the infant gut microbiome.

However, the researchers then looked at the three intervention groups separately and saw three key differences between infants of secretor and non-secretor mothers. Firstly, in the ‘no iron or GOS’ control group, the infants of non-secretor mothers were more likely to get diarrhoea. Secondly, in the ‘iron only’ group, the infants of non-secretor mothers had a greater decrease over the 4-month period in the relative abundance of protective bacteria. Thirdly, in the ‘iron and GOS’ group, infants of non-secretor mothers benefited the most from the co-provision of GOS: these infants maintained protective bacteria, and had a significant increase in body iron stores over the 4-month period, while no such increase was seen in the infants of secretor mothers.

Future studies needed to determine the effect of giving iron together with specific HMOs

The results suggest that the HMO profile may modulate the way in which the infant gut microbiome responds to supplementary iron. In addition, compared with infants of secretor mothers, infants of non-secretor mothers appear to be more vulnerable to the adverse effect of iron. But this extra vulnerability also means that they likely derive greater benefit from the co-provision of prebiotics in the form of GOS. Identifying such vulnerable infants is a new step towards a more specific approach of safely preventing anaemia. A possible direction of future research, therefore, is to determine the effect of specific HMOs (those that are missing from the milk of non-secretor mothers) on the infant gut microbiota during the provision of supplementary iron. More research is needed on whether these specific HMOs may be more effective than GOS when it comes to counteracting iron’s harmful effects on the composition of the gut microbiome.

Should you wish to discuss the above, please contact Guus Kortman, Gut Microbiology and Nutrition Scientist or Business Development Manager Ioana Iorga.
Collaborating institutes

This research was conducted by researchers from Switzerland, Kenya and the Netherlands.

– Department of Health Sciences and Technology, ETH Zurich.
– Department of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich.

– Department of Medical Epidemiology, College of Health Sciences, Jomo Kenyatta University of Agriculture and Technology, Nairobi.

The Netherlands:
– NIZO, Ede.


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