Early life stress and iron metabolism in developmental psychoneuroimmunology

Abstract

An estimated 250 million children face adverse health outcomes from early life exposure to severe or chronic social, economic, and nutritional adversity, highlighting/emphasizing the pressing concern about the link between ELS and long-term implications on mental and physical health. There is significant overlap between populations experiencing high levels of chronic stress and those experiencing iron deficiency, spotlighting the potential role of iron as a key mediator in this association. Iron, an essential micronutrient for brain development and immune function, is often depleted in stress conditions. Iron deficiency among the most common nutrient deficiencies in the world. Fetal and infant iron status may thus serve as a crucial intermediary between early chronic psychological stress and subsequent immune system changes to impact neurodevelopment. The review presents a hypothesized pathway between early life stress (ELS), iron deficiency, and neurodevelopment through the hypothalamic-pituitary-adrenocortical (HPA) axis and the IL-6-hepcidin axis. This hypothesis is derived from (1) evidence that stress impacts iron status (2) long-term neurodevelopmental outcomes that are shared by ELS and iron deficiency exposure, and (3) possible mechanisms for how iron may mediate the relation between ELS and iron deficiency through alterations in the developing immune system. The article concludes by proposing future research directions, emphasizing the need for rigorous studies to elucidate how stress and iron metabolism interact to modify the developing immune system. Understanding these mechanisms could open new avenues for improving human health and neurodevelopment for women and children globally, making it a timely and vital area of study in psychoneuroimmunology research.

Graphical abstract

1. Introduction

Hundreds of millions of children face increased risk of worse developmental outcomes due to prenatal and early life stress, including exposure to social, economic, and nutritional adversity (Black et al., 2017). The fetal period and the first few years of life are a window of opportunity to support the foundations of rapidly developing immune systems and brains. This window of opportunity also carries risk, especially for fetuses and children exposed to severe or chronic stressors. Early life stress (ELS) is linked to poor mental and physical health outcomes through disruptions to the mammalian stress response and subsequent alterations in the developing immune system (Hughes et al., 2017; Lupien et al., 2009; Nusslock and Miller, 2016; Reid, 2020b). Extensive research across multiple levels of analysis has mapped ELS to neurodevelopmental outcomes through changes on the hypothalamic-pituitary-adrenal (HPA) axis and the immune system. ELS and circulating inflammatory cytokines have been a primary focus of attention (e.g. (Baumeister et al., 2016),). A separate body of work has also mapped the link between nutritional adversity and neurodevelopmental outcomes, with an emerging focus on inflammatory mechanisms (e.g. (Black et al., 2017; Krebs et al., 2017; Suchdev et al., 2017),). Critically, populations with a high prevalence of nutritional inadequacy overlap with populations with a high prevalence of chronic stress exposure (Reid and Georgieff, 2023). I propose that investigating the pathway between ELS, nutrient metabolism, and the developing immune system merits further exploration in psychoneuroimmunology research. This research should aim to encompass global and diverse populations confronting the dual threats of ELS and nutritional adversity.

As nutritional adversities are vast and multifaceted, I propose focusing on the micronutrient iron as a model to begin to understand how ELS biologically dovetails with nutritional adversity to impact the immune system and neurodevelopment. Iron is critical for brain development (Georgieff, 2017a), an essential nutrient for the immune system (Beard, 2001), and responsive to conditions of stress (Reid and Georgieff, 2023), making it a candidate to better understand the link between ELS and lifelong well-being. Iron deficiency is prevalent in low, middle, and high-income countries, affecting 30–40% of pregnant women and up to 40% of children under five years of age (Auerbach et al., 2021; Stevens et al., 2013). These are the windows of opportunity and risk for ensuring iron sufficiency during rapid changes in immune and brain development.

Pregnant individuals and young children exposed to chronic financial stress are more susceptible to iron deficiency likely due to food insecurity and diets lacking sufficient iron (Skalicky et al., 2006). Stress can significantly alter eating behavior: individuals experiencing stress may favor foods high in fat and sugar, which are typically lower in iron (Baskin et al., 2015; Monk et al., 2019). However, even with adequate dietary intake, psychological stress may trigger biological changes that may adversely affect iron status (Reid and Georgieff, 2023). In experimental rodent models, stress led to lower blood iron levels (Teng et al., 2008) and resulted in decreased serum iron, increased liver iron, and altered iron transporter levels, including lower ferroportin in the duodenum and liver (Li et al., 2012; Teng et al., 2008; Wei et al., 2008; Zhao et al., 2008). Stressed rodents also had reduced serum iron, hemoglobin, ferritin, and erythropoietin, along with impaired iron absorption and transporter expression in the small intestine (Chen et al., 2009). In humans, military trainees undergoing weeks of psychological stress exhibited disrupted iron levels (Singh et al., 1991). In the brain, stress in rodents has been linked to decreased iron levels in the hippocampus and prefrontal cortex (Zhang et al., 2023). Stress hormones may disrupt iron metabolism in the brain: corticosterone application in vitro was found to dysregulate iron metabolism in hippocampal neurons (Wang et al., 2010). Thus, there is growing concern that increasing dietary iron intake and oral iron supplementation might not be enough to adequately address the risks of iron deficiency in the context of systemic inflammation, including inflammation produced by chronic psychosocial stress (Reid and Georgieff, 2023).

In this review, I will first present a hypothesized pathway between maternal stress during pregnancy and ELS in infancy, iron deficiency, and neurodevelopment through the HPA axis and the IL-6-hepcidin axis. I then will review the current literature that shows how iron metabolism is altered in stress conditions and focus on how this might occur in the prenatal and early infancy period, reflected in Fig. 1. I will outline possible mechanisms for how iron may mediate the relation between ELS and neurodevelopment through emerging research that focuses on the developing immune system as one of particular interest for PNI research.

Fig. 1.

Hypothesized pathways from stress to iron deficiency to neurodevelopmental outcomes early in life. Following chronic or severe maternal stress during pregnancy, HPA axis dysregulation and subsequent increases in inflammation are hypothesized to trigger the IL-6-hepcidin axis, which alters or inhibits iron flow throughout the maternal milieu and subsequently reduces iron availability to fetal iron endowment and the fetal brain. This in turn increases the risk for iron deficiency in the infant, which is associated with changes to the developing HPA axis, immune system, and epigenetic landscape in the infant which are hypothesized to result in shared neurodevelopmental outcomes between stress and iron deficiency early in life. Even in the context of iron supplementation to the iron deficient infant, iron is prioritized to other tissues and prioritized to the brain last, which puts the infant at risk of the adverse impacts of iron deficiency for neurodevelopment even if the infant is clinically iron replete. It is also possible that stress in infancy carries similar ramifications to iron metabolism through the HPA-IL-6-hepcidin axis that is shown in the maternal side, posing risks of iron deficiency even if the infant was born iron replete. Additional pathways between maternal stress, iron metabolism, and offspring neurodevelopment include (A) stress-induced changes to maternal eating behaviors in pregnancy favoring lower dietary iron consumption, and (B) risks to increased maternal depression. For instance, iron deficiency is a risk factor for maternal depression and reduced iron in the maternal hippocampus and PFC may increase the likelihood of maternal depression and impact offspring neurodevelopment through multiple routes. HPA = hypothalamic-pituitary-adrenocortical axis; PFC = prefrontal cortex; IL6 = interleukin 6; GC = glucocorticoids; GR = glucocorticoid receptors; BDNF = brain derived neurotrophic factor. Figure created using Biorender.

1.1. Stress and iron deficiency: a hypothesized relationship between the HPA axis and the IL-6-hepcidin axis

In conditions of acute, time-limited stress, the mammalian body releases glucocorticoids through the activation of the HPA-axis. As glucocorticoids bind to receptors in monocytes, macrophages, and other immune cells, the cells subsequently reduce the release of pro-inflammatory cytokines and dampen the immune response (Irwin and Cole, 2011). If stress is chronic or severe, the HPA-axis remains activated for prolonged periods of time and does not return to baseline, potentially leading to glucocorticoid receptors (GR) in immune cells becoming resistant to glucocorticoids (Cohen et al., 2012). Consequently, the body fails to effectively down-regulate inflammatory responses with glucocorticoids released by the HPA axis. This results in higher levels of chronic inflammation, leading to higher levels of proinflammatory cytokines such as IL-6 and C-reactive protein (CRP) (Hantsoo et al., 2019; Lopresti, 2020).

Iron is tightly regulated by inflammation, as both the mammalian immune system and microbial pathogens require iron to grow and function. For this reason, iron plays a key role in infection susceptibility through the hypoferremic response which is an essential facet of the innate immune system that limits iron availability to invading pathogens by sequestering iron within cells and tissues (Cassat and Skaar, 2013). Hepcidin, along with its receptor and the iron transporter ferroportin, regulates iron absorption, storage, and distribution. Inflammatory responses, especially IL-6, increase hepcidin levels, reducing iron availability (Ganz and Nemeth, 2009). IL-6, crucial for hepcidin synthesis, increases with acute and chronic stress (Bower and Kuhlman, 2023; Marsland et al., 2017; Nemeth et al., 2004). This process helps control infections and adjusts iron supply to red blood cell precursors, contributing to the anemia often seen in infections and inflammatory conditions (Ganz and Nemeth, 2009). Consequently, iron is withheld from pathogens with the tradeoff of limiting iron for erythropoiesis and contributing to anemia (Nemeth and Ganz, 2023). Research in adult rats supports the hypothesis suggesting that inflammatory and hepcidin pathways connect stress and iron deficiency: IL-6 and hepcidin expression increased under stress and normalized following IL-6 monoclonal antibody treatment (Zhao et al., 2008). In a study of adolescent Indian boys, self-reported stress was positively associated with IL-6 and hepcidin concentrations (Augustine et al., 2014). Therefore, early life stress may not only sustain inflammation but may also disrupt iron homeostasis, compounding the body's vulnerability to infections and contributing to conditions that impact neurodevelopment such as iron deficiency anemia.

1.2. Evidence of stress and iron connections in the context of pregnancy and early life

Pregnancy poses a significant risk for developing iron deficiency due to increased iron demands of the fetoplacental unit and maternal blood volume expansion (Sangkhae et al., 2023). Low-income and racially- and ethnically-minoritized women are at especially high risk of iron deficiency in pregnancy (Brannon and Taylor, 2017). Maternal iron deficiency in pregnancy compromises fetal and neonatal iron levels and is linked to fetal iron deficiency (for review, see (Sangkhae et al., 2023)). Maternal iron deficiency in pregnancy also increases risks for cognitive deficits and impaired immune function in offspring (Arija et al., 2019; Coe et al., 2007; Georgieff, 2011). In the context of stress, our preliminary analyses in a pregnant cohort of Black women found an association between heightened cortisol response to a laboratory stressor and reduced serum ferritin levels in the third trimester (Reid and Keenan, 2023).

Iron transport to the fetus hinges on its transfer across the placenta. Maternal, placental, and fetal signals regulate placental and fetal iron homeostasis (Sangkhae et al., 2023). In iron-deficient pregnancies, the placenta adapts to sustain its iron content during iron scarcity, potentially compromising fetal iron, to sustain placental metabolic functions that indirectly support fetal development (Sangkhae et al., 2023). In healthy pregnancies, hepcidin is suppressed, which is crucial for ensuring adequate iron supply to the fetus through placental iron transport (Sangkhae et al., 2023). In conditions that result in inflammation and heightened hepcidin levels, maternal iron transfer to the placenta is reduced (Young et al., 2012). Thus, chronic stress may override pregnancy's suppression of maternal hepcidin.

Accordingly, we can look to the large literature on maternal immune activation to generate hypotheses on how stress and inflammation together may impact offspring iron endowment and ultimately neurodevelopment. Maternal immune activation in pregnancy is implicated in the pathogenesis of multiple psychopathologies and insults to neurodevelopment (Estes and McAllister, 2016), and may operate along iron metabolism pathways. For example, in mice, using lipopolysaccharide (LPS) injection to induce acute systemic inflammation resulted in increased hepcidin and iron deficiency in the dam and fetus (Fisher et al., 2020; Sangkhae et al., 2020). Similarly, in human pregnancies complicated by infection or inflammation, fetuses exhibit elevated cord blood plasma hepcidin levels and iron deficiency (Sangkhae et al., 2023). Perhaps more relevant to stress and its association with inflammation, chronic maternal inflammation due to excess adipose tissue and obesity heightens the risk of infant anemia (Yin et al., 2020). This is thought to be due to prolonged elevation of hepcidin levels in obese women, which ultimately lead to iron restriction (Sangkhae et al., 2023). More research is needed into the mechanisms of how stress leads to worse iron status in the neonate. Nevertheless, as prenatal maternal stress is associated with increased and chronic maternal inflammation (Coussons-Read et al., 2007), it as a potential pathway connecting stress to iron insufficiency for the maternal and fetal side alike.

Maternal stress exposure in pregnancy has now been associated with offspring iron status across multiple studies, possibly due to stress's impact on fetal iron endowment through inflammation and hepcidin. One study demonstrated that mothers in an area subjected to rocket attacks during pregnancy had offspring with lower cord blood ferritin levels compared to those living outside of rocket attack areas (Armony-Sivan et al., 2013). The association between maternal stress and reduced offspring iron status was replicated in a study of 493 mother-infant pairs, where higher maternal stress, violence exposure, and anxiety were linked to lower cord blood ferritin in infants (Campbell et al., 2020). Pregnant women with elevated stress levels had one-year-old infants who were at greater risk for low plasma ferritin (Rendina et al., 2018). This is especially important in the third trimester of pregnancy, when the human fetus accumulates most of its iron endowment (Sangkhae et al., 2023). Reduced iron endowment in the fetus leads to increased risk of iron deficiency in infancy, as the rapidly growing neonate and infant places large demands on iron in the first few years of life (Cusick et al., 2018). This risk was observed in an animal model of prenatal stress: pregnant rhesus macaques exposed to stress gave birth to infant monkeys with lower iron levels as they grew (Coe et al., 2007).

Unfortunately, the risk to the iron deficient infant remains even with dietary iron supplementation. Elegant research shows that in an iron deficient state, iron is prioritized to red blood cells first and the brain (see (Cusick et al., 2018) for review). Thus, even when clinical markers of iron deficiency normalize, the infant brain can remain functionally iron deficient (Cusick et al., 2018). Even in the context of iron replete neonates, our work in a cohort of healthy, iron-replete infants found that infants with accumulated family stressors during the first year of life had poorer iron status and were at higher risk of being classified as either having iron deficiency or iron deficiency anemia (Reid et al., 2022). Thus, reduced iron endowment either through maternal stress leading to reduced fetal iron loading or through stress in infancy may carry ramifications for reduced iron availability to the rapidly growing brain. Taken together, the intricate relationship between maternal stress, inflammation, and iron regulation highlights the critical need for targeted PNI research that seeks to understands how maternal stress can significantly impact fetal iron endowment and subsequent infant iron status, ultimately affecting neurodevelopmental outcomes and long-term health.

1.3. Long term outcomes of stress and iron deficiency

1.3.1. Iron's impacts on the immune system

The immune system and its development in contexts of stress has been a key area of focus for PNI research on ELS and neurodevelopmental outcomes (O'Connor et al., 2014; Slopen et al., 2015; Yirmiya and Goshen, 2011; Yuan et al., 2019). In addition to iron acting as a direct mediator between ELS and the brain, iron deficiency that arises from contexts of stress may carry long-lasting implications for development through its impact on the immune system. Adequate iron is required for a wide range of immune and metabolic processes that include the proper functioning of physical barriers and immune cells, immune cell differentiation, and immune cell growth (Gombart et al., 2020; Haryanto et al., 2015). In the innate immune system, iron influences the reactive oxygen species that kill pathogens, cytokine production and action, cellular iron homeostasis, immune cell proliferation, monocyte and macrophage differentiation, and lymphocyte malnutrition (Gombart et al., 2020; Haryanto et al., 2015; Maggini et al., 2018). Iron also affects cytokines secretion and transcription factor activities involved in the immune response (Brittenham, 2012; Nairz et al., 2014). In the adaptive immune response, iron is important in T lymphocyte differentiation and proliferation (Maggini et al., 2018). Iron may influence the adaptive immune responses by its impact on immune cell differentiation and function as cofactors for epigenetic enzymes involved in histone and DNA demethylation (Chen et al., 2022).

Iron deficiency can dampen the innate and adaptive arms of antiviral immunity (Gombart et al., 2020) and is associated with immune system deficiencies (Drakesmith et al., 2021; Ganz and Nemeth, 2015; Stoffel et al., 2020). Iron deficiency impairs an organism's immune response, leading to decreased mitogen response, lowered natural killer cell activity, reduced lymphocyte ability to kill bacteria, and diminished interleukin-6 production (Calder, 2013). Individuals with iron deficiency have weaker antibody responses to vaccinations (Jiang et al., 2019; Stoffel et al., 2020). Children with anemia exhibit diminished inflammatory and immune responses (Ekiz et al., 2005). Randomized controlled trials in infants show that iron supplementation in the context of iron deficiency enhances infants' antibody response to vaccines (Stoffel et al., 2020). Iron supplementation may play a role in reducing the risk of childhood respiratory tract infections (Chen et al., 2013), and iron supplementation is associated with modulating immune function and reducing the severity of infections (Muñoz et al., 2007).

In recent years, a growing area of research has begun to shed light on how ELS and iron deficiency may have long-lasting effects on the developing immune system. A seminal study in nonhuman primates demonstrated that maternal stress during fetal development could lead to reduced iron levels in the offspring (Coe et al., 2007). More importantly, these lower iron levels were associated with subsequent changes in the offspring's innate immune system, specifically affecting NK cells (Coe et al., 2007). This finding establishes a direct link between early-life iron insufficiency and long-term alterations to the immune system. In my previous study conducted with a Chilean cohort, infants randomly assigned to receive iron supplementation showed reduced levels of peripheral CRP during adolescence, even after the supplementation trial had concluded (Reid et al., 2020). Additionally, I found that early iron status correlated with adolescent monocyte counts (Reid, 2020a). Higher serum ferritin levels at 6 months of age and randomization to receive iron supplementation between 6 and 12 months of age were both associated with lower monocyte counts (Reid, 2020a). Serum ferritin in infancy statistically mediated the relationship between family-level stressors in the first year of life and adolescent monocyte count (Reid, 2020a). This research indicates that early-life stress can lead to poor iron status, which may later be linked to increased inflammation and higher monocyte counts. As these are the first human studies supporting the association between stress, iron, and the immune system, they are preliminary but intriguing paths to follow for future research. Iron deficiency resulting from early-life stress may significantly impair both innate and adaptive immune responses, leading to long-term developmental consequences.

1.3.2. Shared neurodevelopmental impacts

Insufficient iron and ELS impact the foundation of the developing brain, affecting brain function, behavior, and psychopathology risk (Reid and Georgieff, 2023). Insufficient iron during gestation is associated with worse recognition memory, slower neural processing speed, poor offspring-mother bonding, and poor maternal interaction (Amin et al., 2010; Geng et al., 2015; Siddappa et al., 2004; Wachs et al., 2005). Pre- and postnatally, insufficient iron is associated with alterations in the hippocampus, dendritic structure, brain metabolism, myelination, and neurotransmitter function (Barks et al., 2018; Beard, 2001; Black et al., 2011; Lozoff et al., 2006). Similarly, stress exposure pre- and postnatally is associated with cortical thinning and decreased cognitive functioning, alterations in synaptic signaling, and changes in gene expression in the hippocampus and amygdala that are associated with anxious and depressive phenotypes (Sandman et al., 2018; Turecki and Meaney, 2016; Ishikawa et al., 2015). Other outcomes of early stress include reduced dendritic arborization in the prefrontal cortex and hippocampus, changes in hippocampal synaptic plasticity, and diminished spatial memory learning (Bagot et al., 2009; Monroy et al., 2010; Smith and Pollak, 2022; Turecki and Meaney, 2016).

Behavior is also affected by early iron deficiency, including motor dysfunction, altered social and affective behavior, and reduced memory performance (Jabès et al., 2015; Lozoff et al., 2008; Riggins et al., 2009). In parallel, fetal and early life stress are associated with impaired learning, worse attention regulation, impaired executive function, increased anxiety, increased depressive behaviors, and increased emotional reactivity (Gunnar and Reid, 2019; Swales et al., 2018; Vallée et al., 1999). Both exposures also carry an increased risk for long-term psychopathology, including autism spectrum disorder, schizophrenia, and increased risk of anxiety, depression, and attention deficit hyperactivity disorder (Chan et al., 2018; Doom et al., 2018; Insel et al., 2008; Lukowski et al., 2010; O'Donnell et al., 2014; Schmidt et al., 2014; Van den Bergh et al., 2020). Whether these neurodevelopmental outcomes arise from parallel impacts or interplay between insufficient iron and ELS exposure is a nascent area of research.

There are likely multiple potential mechanisms that may mediate the lasting effects of iron status on immune function, behavior, and neuronal function. HPA axis development may play a role, as children who were iron deficient in infancy exhibited blunted HPA response to stressors (Felt et al., 2012). Insufficient maternal iron in pregnancy has been associated in rodent models with altered glucocorticoid levels and glucocorticoid receptors (GR) in offspring, which subsequently lead to reduced BDNF in the hippocampus and reduced neurogenesis (Ranade et al., 2013). Rodent models have also found evidence of changes to the epigenetic landscape after early iron deficiency, including expression changes in synaptic plasticity genes and BDNF in the hippocampus (Georgieff, 2017b; Tran et al., 2015). The relationship between iron metabolism and long-term changes to brain and immune functioning has been further elaborated in murine models. Emerging evidence suggests that iron deficiency in neonatal mice leads to an increased expression of proinflammatory cytokine gene pathways in the adult brain, even after iron levels are normalized (Personal communication, Phu Tran, 2023). Early life stress and iron deficiency may also contribute to the development of Alzheimer's disease later in life by promoting neuroinflammation, oxidative stress, and altering the expression of genes linked to Alzheimer's disease pathogenesis (Hoeijmakers et al., 2017, 2018; Carlson et al., 2008; Pappolla et al., 1992). Though more work is needed, these studies highlight possible cellular and molecular impacts of early stress and iron deficiency. Both insufficient iron and ELS profoundly impact development, affecting brain structure, function, behavior, and increasing the risk of psychopathology. These findings highlight the importance of understanding the potential parallel and interactive mechanisms within PNI research through which iron deficiency and ELS shape long-term neurodevelopmental outcomes.

2. Conclusion

This review seeks to initiate the exploration of the complex relationship/connection between prenatal and early life stress, disruptions in iron metabolism, and consequent alterations in brain and immune system development. Non-infectious, chronic psychological stress, mediated by glucocorticoid regulation and the hypothalamic-pituitary-adrenocortical (HPA) axis, could result in iron sequestration and reduced maternal iron absorption, even with adequate intake (Monk et al., 2013; Suchdev et al., 2017). Chronic, severe stress affects how the HPA axis functions (Lupien et al., 2009). HPA axis functioning may affect iron metabolism through increased inflammation and its effect on hepcidin, an essential iron regulator (Reid and Georgieff, 2023).

There are far more questions than answers in this domain. Can the impact of early life stress on the developing brain and immune system be modulated through iron metabolism? How does developmental timing of stress affect its impact on iron metabolism and immune development? Is there a degree of stress and HPA axis dysregulation that triggers the IL-6-hepcidin axis? How does this vary across developmental stages? How do ELS and iron deficiency create lasting effects on the developing immune system and contribute to neurodevelopment? Addressing these questions will not only expand our understanding but also guide interventions to mitigate the long-term impacts of ELS and nutritional deficiencies.

Research going forward across human and pre-clinical animal models is required to rigorously explore how stress affects iron metabolism and immune function in early life, and how these interactions shape long-term health. This research is interesting not just for applications in higher-income countries, but also could have the potential to redefine PNI within a global context, addressing health disparities arising from iron deficiency and ELS in various populations. As young children, infants, and pregnant people in the global majority experience the dual burdens of stress and iron deficiency, the recognition of iron's pivotal role in modulating the effects of ELS on the immune system and brain development underscores the urgency – and potential utility – of this research. PNI research is uniquely positioned to investigate the intersection of stress and iron metabolism in the developing immune system, offering opportunities improvement in health and neurodevelopmental outcomes globally.

AI statement

During the preparation of this work the author used ChatGPT and Grammarly to improve grammar and readability of the manuscript. After using this tool/service, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.

CRediT authorship contribution statement

Brie M. Reid: Writing – review & editing, Writing – original draft, Visualization, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Data availability

No data was used for the research described in the article.