A study conducted at the University of Turku showed that greater diversity and proportion of green environments in the residential area were associated with increased diversity in the composition of the oligosaccharides in breastmilk.
More information: Mirkka Lahdenperä et al, Residential green environments are associated with human milk oligosaccharide diversity and composition, Scientific Reports (2023). DOI: 10.1038/s41598-022-27317-1
In this work, we show associations between residential green environment and HMO composition in a Finnish cohort of breastfeeding women. Previously, it has been found that HMO composition is associated with wide scale environmental variables measured as cities, countries, urban/rural areas or seasons 23,24,25.
We demonstrate that greater diversity and proportion of green environments in the residential area were associated with greater HMO diversity and changes in the concentrations of several HMO structural groups as well as individual HMOs.
Some significant differences were detected between secretor and non-secretor mothers (classified by the high abundance or near-absence of the HMO 2′FL), and many of the associations with the residential green environment were stronger in non-secretor mothers. Our results are suggestive of a potential pathway between residential green environments and HMO composition which may have subsequent effects on child health, but this needs to be investigated in further studies (Fig. 2).
Residential green environments with potentially higher microbial diversity could enhance maternal immunity26,27,28,41 and increase the abundance of immunological compounds 32 including HMOs in maternal milk. High microbial diversity in the environment is also likely to increase milk bacterial diversity 42 (or associate with pollutants12 or fungi13) which may further influence HMO composition through interactions within milk 12.
Our results show an association between residential green environment and HMO composition, which might be part of a previously largely unexplored environmental signaling mechanism via maternal milk.
To our knowledge, only one previous study has examined human milk composition in relation to the properties of the residential green environment (with 250 m buffer zone from mother’s home), showing that human milk fungi were not associated with residential NDVI13. Our finding that the strongest associations with HMO diversity and concentrations were observed with VCDI and NI, and weaker associations were observed with NDVI, are in line with this previous study and reflect the fact that NDVI is a generic measure of green vegetation, and its density and vitality, but it does not directly identify vegetation types and plant composition.
Moreover, exposure to green spaces is relatively high in Finland also in urban areas compared to many other European cities43, and only a small percentage of families (5.7%) in our study population lived in low greenness residential areas (NDVI < 0.3). Thus, linking NDVI to specific properties of green environments and HMO composition has its limitations.
Some specific green land cover types or their combinations (e.g. forests, grasslands, shrubs, mires) as well as complex vegetation communities within the green environment have been shown to associate with higher levels of microbiota diversity in air and soil35,44. As our VCDI measure includes six land cover classes indicating green environments (CORINE) and estimates their diversity (Agriculture, Broad-leave forest, Coniferous forest, Mixed forest, Shrub/grassland, Wetlands), the variable is likely to indicate the complexity of vegetation and potentially microbial diversity in the residential area, although specific studies to establish such relationships have to date not been carried out.
Low NI values, in our study, represented mainly impervious asphalt covered residential and industrial areas, while high NI values included non-built areas, e.g., natural bare surfaces, water bodies, wetlands and different types of forests 38. The associations we observed between NI and HMO composition suggests, that not only green spaces but also other natural features of the residential area, such as the presence of water areas and wetlands, may have an important role in HMO composition.
Secondly, we observed positive associations between internal α-2-6-sialylated HMOs (DSLNT, LSTb) and residential green environment. In this context the concentrations increased with increasing VCDI and NI. Thirdly, we found that small HMOs (2′FL, 3FL, 3′SL, 6′SL, and DFLac) and α-1-2-fucosylated HMOs (2′FL, LNFP I) showed negative associations with VCDI and NI.
Although the associations between HMO composition and properties of the residential green environments have to our knowledge not been previously explored, our results are in line with the findings from a study including 11 international cohorts from developed and developing countries 23 (INSPIRE Study).
This study found that the lowest HMO diversities were observed in urban and sub-urban areas of Sweden, USA and Peru and highest HMO diversities in Ghana, Ethiopia, Kenya and Gambia. Our mean diversity value was closer to values observed in other western societies. The INSPIRE study 23 also found that DSLNT concentrations were higher in rural than urban Gambia, similar to our finding that DSLNT increases with VCDI and NI.
Finally, the INSPIRE study found that 2′FL concentration were similarly high compared to our study, around 6000 nmol/ml, in Sweden, USA and Peru and much lower particularly in populations from rural Africa (< 3000 nmol/ml)23. Previous studies have also found substantial variation between geographical locations in the concentrations of fucosylated HMOs45.
It has been suggested that variations in environment, diet and lifestyle all contribute to these observed differences across geographic locations although genetics (and prevalence of secretors) may also explain at least part of these differences in HMOs.
However, observations that human milk immune profiles also differ between the same countries, suggest that exposure to environmental factors including microbiota might drive a part of the differences. For instance, milk immune profiles differed vastly between developed and developing countries as well as rural and urban areas in Gambia in the INSPIRE Study (greater immune response plasticity in developing and rural areas), and this was suggested to result from differential exposure to environmental microbiota between these locations32.
Our data suggest that the associations with residential green environments may vary by maternal genetics (secretor vs non-secretor). The associations observed in this study were often stronger in the non-secretor mothers, and the directions of some associations were opposite in secretors and non-secretors. Non-secretor mothers are capable of producing only small amounts of 2′FL and LNFP-I but their HMO profile differs from secretor mothers also by the amounts of several other HMO components.
In our study, secretor status was significantly linked with 17/19 individual HMO components. The non-secretor phenotype is more prevalent in Africa, Central Asia, Far East and Pacific regions compared to other regions, and this is suggested to be due to the fact that such trait might have provided protection against certain viruses or other pathogens in these areas21. The variation in HMO composition among women has in fact been suggested to result from both genetic and environmental variation that respond to different selective pressures 21.
In our study, secretor mothers lived in greener environments compared to non-secretor mothers (50% vs. 43% lived in the greenest areas (NDVI > 0.6)), suggesting the strength of the HMO associations with green environments may also differ with the exposure levels to green environment. Further studies are needed to understand whether the susceptibility to respond to environmental cues depends on the genetics, and exposure levels, and how these associations reflect on infant health.
Accumulating evidence suggests that some of the associations we found between residential green environment and HMO composition may be further connected to beneficial composition of infant fecal microbiota and improved infant health outcomes. Higher HMO diversity with higher VCDI and NI potentially increases gut microbiota diversity as HMOs are linked to gut microbiota composition through acting as prebiotics 19,46.
Gut microbiota diversity has been reported to be greater in microbe rich environments 26,29, and living areas with diverse vegetation cover (higher diversity of yard shrub species) were negatively associated with dysbiotic shifts in the gut microbiota 47. Higher gut microbiota diversity in early life has been associated with reduced risk of health concerns such as asthma 48 and allergic diseases 49.
Furthermore, higher HMO diversity and higher concentrations of HMOs have been connected directly to lower risks of several diseases in infancy (e.g. necrotizing enterocolitis (NEC)50,51, bacterial and viral infections 52 and immune-mediated diseases 20,53). Moreover, Lagström et al. 2020 found in this same study population that higher HMO diversity but lower concentrations of 2’FL were associated with lower height and weight in early childhood in Finland 40.
These results thus suggest that higher HMO diversity and lower concentrations of 2′FL with higher VCDI and NI may protect from obesity development in children in this western population. In order to bring clarity to these debated topics further studies are needed to investigate the specific links between residential green environments, gut microbiota diversity and infant health outcomes taking into account the variation in HMO composition.
There are some important issues that need to be considered when interpreting the results and implications of the present study. Firstly, although we speculate that the residential green environment may be associated with HMO composition via environmental microbial diversity, there are other routes that could have led to these associations.
Residential green environment may modify the HMO composition by e.g. increasing physical activity of mothers and relieving their mental stress 30,54. We did not have information from mother’s physical activity levels at the time of milk collection. However, we tested associations between HMOs and residential socioeconomic disadvantage, which has been connected to increased risk of mental disorders55, and found no clear evidence of a link between the two.
Secondly, the effect sizes between residential green environment and HMO composition were relatively small, not allowing corrections for multiple testing. However, it should be noted that the use of corrections is debated 56. Thirdly, we only had one milk sample from each mother so we could not investigate within mother variation in HMO composition in relation to changing residential location, which would have made the study stronger.
Finally, less than 50% of mothers were known to exclusively breastfeed their children at the time of milk collection, which may have impacted the HMO composition. However, we have adjusted the analyses with lactation status, as well as many other confounding factors known to be associated with HMO composition and we therefore believe these variables are unlikely to confound the results between residential green environment and HMO composition.
Furthermore, our study benefits from detailed information on maternal and child characteristics, objectively determined accurate place of residence linked to specific measures on the surrounding green environment and similar findings from two different buffer zones around the homes of mothers and their children (250 m × 250 m and 750 m × 750 m grid sizes).
The findings were also similar in models with only secretor status as an adjusted variable, suggesting that the results from this study are robust. Furthermore, the participating families, whose children were born in 2008–2010, lived in a geographically concentrated area in Southwest Finland. Thus, the data is explicit in space and time, increasing the validity of the findings in this homogenous study population.
In conclusion, our results demonstrate that HMO diversity increased and the concentrations of individual HMOs and HMO groups changed with increased exposure to residential green environments. The findings are important for future studies on infant health as HMOs have a crucial role in the development of the neonatal immune system.
The findings emphasize the need to understand the biological pathways that lead to the development of health and disease via both direct and indirect contact with the physical environment, including via exposure to diverse milk compositional profiles across different environments. Our results imply that increased everyday contacts with nature might be beneficial for breastfeeding mothers by increasing HMO diversity. These findings also point to the need of new nature-based clinical trials.
Overall further studies with a focus on the properties of residential green environment, but also taking into account house and indoor characteristics, and HMO composition in maternal milk, are needed. These should be conducted across different populations and climates, in order to determine which characteristics of the residential environment and which exposure times provide the greatest public-health benefits and contribute to a balanced infant immunity and to improved health outcomes.
