Exposure to air pollution in the first six months of life impacts a child’s inner world of gut bacteria, or microbiome, in ways that could increase risk of allergies, obesity and diabetes, and even influence brain development, suggests new University of Colorado Boulder research.
The study, published this month in the journal Gut Microbes, is the first to show a link between inhaled pollutants—such as those from traffic, wildfires and industry—and changes in infant microbial health during this critical window of development.
Previous research by the same group found similar results in young adults.
“This study adds to the growing body of literature showing that air pollution exposure, even during infancy, may alter the gut microbiome, with important implications for growth and development,” said senior author Tanya Alderete, assistant professor of Integrative Physiology at CU Boulder.
At birth, an infant hosts little resident bacteria. Over the first two to three years of life, exposure to mother’s milk, solid food, antibiotics and other environmental influences shape which microorganisms take hold. Those microbes, and the metabolites, or byproducts, they produce when they break down food or chemicals in the gut, influence a host of bodily systems that shape appetite, insulin sensitivity, immunity, mood and cognition. While many are beneficial, some microbiome compositions have been associated with Chrohn’s disease, asthma, type 2 diabetes, and other chronic illnesses.
“The microbiome plays a role in nearly every physiological process in the body, and the environment that develops in those first few years of life sticks with you,” said first author Maximilian Bailey, who graduated in May with a master’s in Integrative Physiology and is now a medical student at Stanford University.
For the study, the researchers obtained fecal samples from 103 healthy, primarily breast-fed Latino infants enrolled in the Southern California Mother’s Milk Study and used genetic sequencing to analyze them.
Using their street addresses and data from the U.S. Environmental Protection Agency’s Air Quality System, which records hourly data from monitoring systems, they estimated exposure to PM2.5 and PM10 (fine inhalable particles from things like factories, wildfires and construction sites) and Nitrogen Dioxide (NO2), a gas largely emitted from cars.
“Overall, we saw that ambient air pollution exposure was associated with a more inflammatory gut-microbial profile, which may contribute to a whole host of future adverse health outcomes,” said Alderete.
For instance, infants with the highest exposure to PM2.5 had 60% less Phascolarctobacterium, a beneficial bacterium known to decrease inflammation, support gastrointestinal health and aid in neurodevelopment. Those with the highest exposure to PM10 had 85% more of the microorganism Dialister, which is associated with inflammation.
Disadvantaged communities at higher risk
In a previous study, Alderete found that pregnant Latino women exposed to higher levels of air pollution during pregnancy have babies who grow unusually fast in the first month after birth, putting them at risk for obesity and related diseases later in life.
Infants are particularly vulnerable to the health hazards of air pollution because they breathe faster and their gut microbiome is just taking shape.
“This makes early life a critical window where exposure to air pollution may have disproportionately deleterious health effects,” they write.
Racial minorities and low-income communities, who tend to work, live and attend school in regions closer to busy highways or factories, are at even greater risk. One 2018 Environmental Protection Agency study found that communities of color are exposed to as much as 1.5 times more airborne pollutants than their white counterparts.
“Our findings highlight the importance of addressing the impact of pollution on disadvantaged communities and point to additional steps all families can take to protect their health,” said Alderete, who hopes her research will influence policymakers to move schools and affordable housing projects away from pollution sources.
The authors caution that more research is needed to determine whether changes in the gut in infancy have lasting impacts, and just what those are. More studies are underway.
Meantime, Alderete advises everyone to take these steps to reduce their exposure to both indoor and outdoor pollutants:
Avoid walking outdoors in high traffic zones
Consider a low-cost air-filtration system, particularly for rooms children spend a lot of time in
If you are cooking, open the windows
And for new moms, breastfeed for as long as possible
“Breast milk is a fantastic way to develop a healthy microbiome and may help offset some of the adverse effects from environmental exposures,” Alderete said.
Early life growth trajectories are important determinants of morbidity and mortality across the life course. GRAPHS was a large, cluster-randomized cookstove intervention study that began the intervention during the prenatal period, included a clean-fuel arm, performed serial prenatal and postnatal personal HAP exposure assessments, and measured anthropometric variables at birth and every 3 months thereafter for the first year of life.
Our findings add to evidence from studies that classified HAP exposure on the basis of self-reported use of different types of cooking or heating fuels and provide quantitative evidence for the effect of early life HAP exposure, as indexed by CO and PM2.5 exposure, on infant growth trajectories. Specifically, these data suggest that increasing prenatal exposure impairs length growth and increases risk for stunting, whereas increasing postnatal exposure impairs HC, MUAC, and WLZ growth over the first year of life. Further, this work provides evidence that an LPG cookstove intervention begun during pregnancy may improve HC and MUAC growth trajectories.
These data add to a growing literature supporting an association between HAP exposure and poor growth in infancy. Prior evidence supports an association between prenatal HAP exposure and birth weight (Amegah et al. 2014; Balakrishnan et al. 2018; Quinn et al 2021). For example, Wylie et al. (2017a) estimated that a 1-unit log increase in PM2.5 was associated with a mean decrease in birth weight of 270g. Two cookstove intervention trials have suggested that a prenatally introduced cookstove may improve birth weight (Thompson et al. 2011; Alexander et al. 2018). Evidence beyond birth anthropometrics has been limited to studies employing questionnaires to ascertain HAP exposure, finding that households burning unclean fuels are more likely to have stunted or underweight children.
The data provided herein thus extends these observations and finds higher early life CO and PM2.5 exposures are associated with increased risk for poorer length, HC, MUAC, and LAZ growth trajectories and assignment to the lowest LAZ trajectory, consistent with a definition of stunted. A prenatally introduced LPG cookstove, which we previously found to be associated with a 47% reduction (95% CI: 34, 57%) in CO and 32% lower (95% CI: 26, 38%) PM2.5 exposures (Chillrud et al. 2021), was associated with improved MUAC and HC growth trajectories relative to trajectories in control children whose mothers used 3-stone fires throughout pregnancy and the first year of the child’s life.
Despite substantial progress in reducing early childhood mortality, mortality for children <5 years of age remains disproportionately high in sub-Saharan Africa. Stunting alone is responsible for 164,000 deaths and 14.3 million DALYs each year in children <5 years of age (GBD 2019 Risk Factors Collaborators 2020). Causes of faltered early childhood growth are multifactorial, and emerging evidence suggests the importance of early life environmental exposures, including air pollution, beginning prenatally (Zheng et al. 2016). Suboptimal growth, even with mild impairments, increases risk for all-cause mortality and infectious disease mortality, specifically owing to respiratory infections and diarrheal disease (Olofin et al. 2013). Our findings, which are based on a cluster-randomized intervention, extend existing evidence of deleterious effects of HAP on birth weight to include evidence of adverse effects on early childhood growth trajectories, with implications for morbidity and mortality across the life course.
These data suggest that increased prenatal HAP, as indexed by both CO and PM2.5 exposures, was associated with impairments in length growth, whereas increasing postnatal PM2.5 exposure was associated with impairments in WLZ and MUAC trajectories. The underlying mechanisms are unknown. Length is considered a more chronic measure of health, whereas weight is considered a more acute measure of health; however, a plausible underlying link seen in both stunted and wasted children is reduced muscle mass (Briend et al. 2015). HAP exposure may induce inflammation; inflammation may promote insulin resistance, thereby reducing available nutrients for muscle metabolism (Fernández-Real and Ricart 1999; Oluwole et al. 2013). Stunted children often have a history of prior wasting episodes, reflecting the importance of sufficient energy stores to promote length growth (Briend et al. 2015; Pelletier 1994). An attenuated effect of growth hormone on insulin-like growth factor 1 production is seen in wasting and may prevent length growth, resulting in smaller length and LAZ (Freemark 2015). Overall, the finding that prenatal and postnatal HAP exposures are associated with stunting and wasting, respectively, suggests that children with higher early life HAP exposures have a shift in global development toward a frailer phenotype, which in turn is associated with the increased risk for future morbidity and mortality.
Prenatal HAP may alter functioning of the placenta, the maternal–fetal interface, which regulates the in utero environment and plays a central role in programming future development (Saenen et al. 2019). Prenatal HAP exposure may induce thrombotic placental lesions in those highly exposed, which may impair placental functioning, thus contributing to adverse fetal outcomes (Wylie et al. 2017b). Ambient air pollution research in the INfancia y Medio Ambiente Spanish birth cohort demonstrated a 6% decrease in z-score for length by 6 months of age per 10-μg/m3 increase in prenatal (first trimester) NO2 exposure, mediated partly through placental mitochondrial DNA (mtDNA) content, a biomarker of oxidative stress (Clemente et al. 2017). GRAPHS analyses similarly found that higher prenatal HAP exposure was associated with a lower cord blood mtDNA copy number and shorter cord blood mononuclear cell telomere length, with effects mitigated by the LPG intervention, supporting a role of oxidative stress in prenatal HAP pathogenesis (Kaali et al. 2018, 2021).
Postnatal PM2.5 exposure was negatively associated with MUAC and WLZ trajectories, and the LPG intervention was associated with improvement in MUAC trajectories compared with control. Visualization of the modeled latent class trajectories (Figure 2) suggests that they are distinct at birth, with changes in slope over the first year of life. We thus hypothesize that higher postnatal HAP exposure may worsen MUAC and WLZ growth over the first year of life, suggesting a subacute or acute effect on chronic impairment, as seen in other studies (Garenne et al. 2009; Isanaka et al. 2011). HAP is a major risk factor for infections in early childhood, specifically acute lower respiratory infection (ALRI), and one intervention study found that a cookstove intervention may reduce risk for severe ALRI (GBD 2015 Risk Factors Collaborators 2016; Smith et al. 2011).
Therefore, it is plausible that children with higher HAP exposures were more susceptible to repeated infections, resulting in poorer MUAC and WLZ trajectories (Briend et al. 2015). Emerging evidence suggests that inhaled pollutants alter gut microbiome alpha- and beta-diversity and function (Kish et al. 2013; Mutlu et al. 2018), which in turn may modify the lower airway microbiome and immune response, increasing the risk for respiratory disease (Huang and Boushey 2015; Lee-Sarwar et al. 2019). An altered gut microbiome may also increase inflammation and gut permeability (Mutlu et al. 2011), affecting nutrient absorption, with implications for childhood growth. It is also plausible that our LPG intervention indirectly affected health by, for example, reducing time a mother spent gathering fuel and increasing time spent on other activities, such as breastfeeding (96% of LPG mothers breastfed for >12 months vs. 84% of improved biomass mothers and 78% of open fire/control mothers; Table 1) or income-generating activities (Williams et al. 2020).
Previously published associations between early life air pollution exposure and head growth suggest prenatal exposure reduces fetal biparietal diameter as measured by ultrasound or HC at birth; however, results are inconsistent (van den Hooven et al. 2012). Although data from LMICs are scarce, an urban Tanzanian cohort did not find an association between prenatal PM2.5 or CO and HC at birth (Wylie et al. 2017a). Similarly, our results did not demonstrate an association between prenatal HAP exposure and HC trajectory but, rather, suggest that postnatal CO increased the risk for reduced HC growth trajectory.
The LPG intervention was associated with better HC growth trajectories, as compared with control. The implications of impaired head growth in this population are unknown, but studies of postnatal head growth in at-risk populations, such as preterm infants, suggest head growth may be associated with neurocognitive outcomes (Ghods et al. 2011). Analyses from the Helsinki Birth Cohort Study demonstrated that decreased HC at birth was associated with lower verbal, visuospatial, and arithmetic abilities by 20 years of age (Räikkönen et al. 2009).
Supporting evidence from high-income countries suggests a link between air pollution exposure (largely traffic related) and cognition; air pollution exposure during childhood may impair neurodevelopment and academic achievement (Clifford et al. 2016). Higher air pollution exposure has also been associated with white matter hyperintensities in the prefrontal cortex (Calderón-Garcidueñas et al. 2008). Animal mechanistic studies point to a role of neuroinflammation and lipid peroxidation in air pollution-induced cognitive deficits (Block and Calderón-Garcidueñas 2009; Calderón-Garcidueñas et al. 2008). Characterizing neurodevelopmental outcomes in this cohort would allow us to better understand the implications of reduced HC growth and the potential benefit of a clean cookstove intervention.
The LPG intervention was associated with better MUAC and HC trajectories; however, we did not find evidence of association with improved length growth. It is plausible that the sensitive window for programming length was prior to our mid-gestation intervention. First trimester polycyclic aromatic hydrocarbon exposure has been shown to have the largest effect on fetal growth ratio and birth length, as compared with other trimesters (Block and Calderón-Garcidueñas 2009). Further, we note overlap in prenatal exposures by study arm and that all arms had average PM2.5 exposures above the WHO interim guidance of 35 μg/m3; a larger prenatal exposure differential or a greater reduction in exposure levels may be required to see health effects. Finally, the effects of intervention on health may have benefited from an effect of the intervention unrelated to exposure (e.g., longer breastfeeding duration) to which weight gain and head growth may be more sensitive.
Potential mechanisms that might explain sex-specific differences in associations between child growth and prenatal or postnatal HAP exposures are not clear. Prior studies have reported differences in associations between prenatal ambient air pollution exposures and fetal growth by sex; however, few have extended these observations to postnatal growth (Rosofsky et al. 2020).
Previous analyses of GRAPHS data have suggested stronger associations between prenatal HAP exposures and infant lung function in girls compared with boys, and stronger associations between prenatal HAP exposures and biomarkers of oxidative stress in boys than girls (Kaali et al. 2018; Lee et al. 2019). Our exploratory analyses suggest that sex-related differences in associations between growth outcomes and prenatal or postnatal HAP exposures may differ by pollutant. Specifically, prenatal CO exposure was associated with lower length trajectories in boys but not girls, whereas prenatal PM2.5 exposure was associated with lower length trajectories in girls but not boys. However, an important limitation of these findings is the reduced sample size in the PM2.5 analyses. Further work is needed to confirm these findings.
We note several strengths of our study. We leveraged the GRAPHS cohort, derived from a cluster-randomized stove intervention deployed mid-gestation and maintained through the first year of life, with serially measured prenatal and postnatal personal HAP exposures. Our well-characterized cohort included anthropometric measurements every 3 months beginning at birth, allowing us to construct growth trajectories for a number of important growth metrics. Ultrasound-established gestational dating ensured our cohort of nonsmoking pregnant women received the intervention prior to 24 wk of gestation and provided accurate GAs at delivery for our cohort, which we additionally adjusted for in sensitivity analyses. Questionnaires captured a number of important personal- and household-level covariates.
We also acknowledge limitations. Given the cost and field logistics of performing serial personal exposure measures in a resource-poor setting, we were unable to measure CO and PM2.5 exposures continuously, although we note that our exposure strategy involved repeated CO measures in both prenatal and postnatal periods. Each observed (personal) short-term measured exposure therefore provides an unbiased estimate of a participant’s exposure during the observed interval, and repeated sampling improves the ability of short-term personal exposures to estimate long-term exposures (McCracken et al. 2009). We also note that pollution sources outside of cooking may have contributed to these exposures.
Our primary exposure was CO; PM2.5 was measured only in a subset of participants, limiting our ability to investigate PM2.5 and sex-specific effects. Some maternal characteristics differed by study arm and, although we adjust for these variables in multivariable analyses, findings should be interpreted with caution despite the randomized trial design. We report multiple comparisons and therefore some results may appear significant due to chance. For example, we perform 10 regressions with our primary pollutant CO, and only our results for prenatal CO on stunting and postnatal CO on HC would remain significant after Bonferroni correction. Maternal BMI was measured after enrollment and therefore during pregnancy. Prepregnancy maternal BMI would be a more accurate measure of maternal size; however, this data was not available. We measured anthropometric variables once at each assessment; measurement in duplicate or triplicate may have reduced measurement error.
In particular, the larger standard deviations for length and HC measurements may be related to population heterogeneity but more likely suggest measurement error, which may bias findings to the null. We did not measure nutrition intake or enteric infections; however, note that we did adjust for household wealth index, which we conceptualized as an antecedent of nutrition and enteric infections in early life (Akombi et al. 2019). Further, we prospectively and serially assessed breastfeeding practices over the first year of life and additional adjustment for breastfeeding duration did not substantively change our results (Fekadu et al. 2015). Finally, we note that our CO exposure distribution was lower than reported in other HAP studies, possibly owing to the outdoor nature of cooking in our cohort compared with indoor cooking in others, and larger or additional effects may be seen in a more exposed population.
If these results are replicated elsewhere, they would suggest that increased early life HAP may increase risk for poorer growth trajectories over childhood. Primary strategies for reducing child mortality focus on widespread implementation of low-cost technologies, such as immunization, oral rehydration therapy, and antibiotics; however, poor growth and disease have multiple etiologies and an optimal strategy may involve a combination of environmental, health, and nutritional interventions. Future work is needed to confirm these findings and better characterize the future health implications of the identified impaired growth trajectories.
reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629028/
More information: Maximilian J. Bailey et al, Postnatal exposure to ambient air pollutants is associated with the composition of the infant gut microbiota at 6-months of age, Gut Microbes (2022). DOI: 10.1080/19490976.2022.2105096