Evolutionary Significance of the Neuroendocrine Stress Axis on Vertebrate Immunity and the Influence of the Microbiome on Early-Life Stress Regulation and Health Outcomes

Abstract

Stress is broadly defined as the non-specific biological response to changes in homeostatic demands and is mediated by the evolutionarily conserved neuroendocrine networks of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Activation of these networks results in transient release of glucocorticoids (cortisol) and catecholamines (epinephrine) into circulation, as well as activation of sympathetic fibers innervating end organs. These interventions thus regulate numerous physiological processes, including energy metabolism, cardiovascular physiology, and immunity, thereby adapting to cope with the perceived stressors. The developmental trajectory of the stress-axis is influenced by a number of factors, including the gut microbiome, which is the community of microbes that colonizes the gastrointestinal tract immediately following birth. The gut microbiome communicates with the brain through the production of metabolites and microbially derived signals, which are essential to human stress response network development. Ecological perturbations to the gut microbiome during early life may result in the alteration of signals implicated in developmental programming during this critical window, predisposing individuals to numerous diseases later in life. The vulnerability of stress response networks to maladaptive development has been exemplified through animal models determining a causal role for gut microbial ecosystems in HPA axis activity, stress reactivity, and brain development. In this review, we explore the evolutionary significance of the stress-axis system for health maintenance and review recent findings that connect early-life microbiome disturbances to alterations in the development of stress response networks.

Keywords: HPA axis; cortisol; gut-brain axes; immunity; inflammation; pediatrics; physiology; vertebrate evolution.

FIGURE 1

Shifts in the gut microbiome and stress response activity with industrialization and urbanization. Urbanization and industrialization have transformed environmental and microbial communities in modern environments. This has resulted in shifts to gut microbial composition, decreased alpha diversity, and loss of key microbial taxa (e.g., Prevotellaceae, Spirochaetaceae and Succinovibrioaceae families). These changes may correlate with divergence from ancestral environments and lifestyles, which includes rural habitation, whole food diets, and increased exposure to environmental microbes and antigens. Modern industrialization provides increased environmental and personal sanitization, pharmaceutical and antibiotic use, exposure to psychological stressors, and consumption of processed foods. These lifestyle changes have had significant impacts on the microbiome and on stress physiology, which can result in stress and immune-related diseases. The parallels between environmental, microbiome and disease incidence shifts are likely not coincidental. Rather, an evolutionary mismatch has led to adaptive responses becoming maladaptive, resulting in adverse shifts in lifelong health trajectories.

FIGURE 2

Evolutionary emergence and biological integration of key cellular and molecular features of the immune (humoral and cell-mediated) and stress axis (neuroendocrine and monoamine) systems in chordate animals. Converging timescale lines depict increasing complexity and integration between the two physiological systems as new classes of vertebrates arose over millions of years before present (mybp). Gut microbial communities also influence host physiology by directly producing biomolecules (e.g., monoamines) encoded in microbial genomes (★), or by influencing the production of host stress and immune molecules. The complex interaction between the microbiome and host plays an important role in regulating many host physiological processes, like metabolism, immunity and stress responses. Features of humoral immunity include: antimicrobial peptides (AMP), lysozymes, complement proteins, cytokines, and variable lymphocyte receptors (VLR), which function as antigen-binding antibodies in basal fish like jawless hagfish, and are precursors to immunoglobulins (Igs) (e.g., IgM, IgD, IgA, IgG, IgE). Cell-mediated immune features depicted are: phagocytic cells which provided early immune protection in invertebrates, T and B cells, toll-like receptors (TLR), major histocompatibility complex (MHC), T-cell receptor (TCR) and dendritic cells. Monoamine features of the stress axis include epinephrine (EPI), norepinephrine (NE), dopamine (DA) and serotonin (5-HT), while neuroendocrine stress axis molecules include adrenocorticotropin hormone (ACTH) homologs in invertebrates and diuretic hormones (DH), which were likely precursors to the corticotropin releasing hormone (CRH) family of peptides, including urotensin 1 (UI) in fish, sauvagine (SVG) in amphibians and urocortin (Ucn) in mammals. Corticosteroids (CS) and aldosterone (ALDO) are terminal hormones of the stress axis, which bind to glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), respectively, found in various tissues in the body to regulate stress reactivity and immunity.

FIGURE 3

Mechanisms of stress axis and immune system interactions and biological integration. Activation of the hypothalamic-pituitary-adrenal (HPA) axis terminates with the release of glucocorticoids (GCs), epinephrine (EPI) and norepinephrine (NE) at peripheral tissues, like the adrenal gland, or directly from nerve endings. These stress-related molecules bind to receptors located in various tissues in the body to manage physiological responses to stress, and to receptors on immune cells and tissues to regulate immune and inflammatory processes, including the release of various cytokines. Released cytokines, in turn, travel via circulation and afferent fibers of the vagus nerve to the central nervous system to interact with various brain regions like the hypothalamus (HYP), the nucleus tractus solitarii (NTS), paraventricular nucleus (PVN), ventral tegmental area (VTA), and the amygdala, to regulate the activity of the stress axis. Acetylcholine (ACh) and corticotropin releasing hormone (CRH), released from efferent nerve fibers, also interact with immune cells to regulate functions. Finally, gut microbial communities (i.e., the microbiome) release various metabolic products (e.g., short chain fatty acids (SCFA), monoamines, neurotransmitters and other features, like peptidoglycans) that are utilized, incorporated and recognized by the host and its immune cells to regulate both stress and immune systems via afferent vagal nerve terminals.

FIGURE 4

The maternal-fetal-placental endocrine unit. The maternal and fetal HPA axes share a common signal integration site, the placenta, forming the maternal-fetal-placental endocrine unit. This unit represents a complex endocrine network, with the placenta regulating steroidogenic crosstalk between the mother and fetus. In contrast to the negative feedback mechanisms of the maternal and fetal HPA axes, a positive feedback relationship exists between the maternal and fetal HPA axes and placental CRH production. Placental CRH is produced in response to maternal or fetal cortisol and acts on the maternal or fetal anterior pituitary in an allocrine fashion to activate each respective HPA axis. Maternal cortisol and placental CRH aid in regulating the development of the fetal HPA axis through several mechanisms, highlighting the importance of this endocrine network. First, placental CRH is thought to act on the fetal HPA axis via two key mechanisms, by (a) increasing the responsivity of the fetal adrenal cortex to ACTH, and (b) directly stimulating the fetal adrenal cortex to produce cortisol. Second, maternal cortisol may cross the placenta and directly act on the fetal anterior pituitary in an inhibitory fashion, preventing ACTH and cortisol release. However, the influence of maternal cortisol on the fetal compartment is dampened by the actions of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), which renders maternal cortisol inactive through oxidation to cortisone. Under the influence of maternal stress, the regulatory actions of the maternal-fetal-placental unit may break down, causing shifts in hormone levels such as increased placental CRH or decreased 11β-HSD2 resulting in higher levels of cortisol in the fetal compartment via fetal production or transfer of maternal cortisol across the placenta, respectively. This may have important implications on fetal HPA axis ontogeny and increase the risk of disease development later in life.