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.

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Gut microbiome maturation in infants born prematurely is uniquely influenced by the physiological, clinical, and environmental factors surrounding preterm birth and early life, leading to altered patterns of microbial succession relative to term infants during the first months of life. These differences in microbiome composition are implicated in acute clinical conditions that disproportionately affect preterm infants, including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS). Probiotic supplementation initiated early in life is an effective prophylactic measure for preventing NEC, LOS, and other clinical concerns relevant to preterm infants. In parallel, reported benefits of probiotics on the preterm gut microbiome, metabolome, and immune function are beginning to emerge. This review summarizes the current literature on the influence of probiotics on the gut microbiome of preterm infants, outlines potential mechanisms by which these effects are exerted, and highlights important clinical considerations for determining the best practices for probiotic use in premature infants.

Background Early life has been identified as a critical window, during which time deviations from typical patterns of gut microbiome maturation have been associated with adverse health outcomes later in life. In the first 2-3 years of life, the infant gut microbiome undergoes ecological shifts characterized by increasing bacterial alpha diversity and variable changes in fungal alpha diversity. Research has shown not all infants follow these maturational trends, but our understandings of the factors linked to atypical microbiome maturation patterns are limited. Purpose We assessed bacterial and fungal gut microbiome maturation in early life to determine if atypical maturational patterns were observed in otherwise healthy infants and identify factors associated with these patterns. Method In 100 infants from the CHILD Cohort Study, we assessed the bacterial and fungal gut microbiome in stool samples collected at 3 and 12 months of age using 16S and ITS2 Illumina sequencing, respectively. We performed untargeted metabolomics on urine samples collected at 3 and 12 months using liquid chromatography-mass spectrometry/mass spectrometry. Microbiome and metabolomic measures were evaluated by ecological and multivariate analyses using RStudio. Result(s) Gut microbiome analyses revealed 24% and 20% of infants displayed atypical alpha diversity trajectories in the first year of life for bacteria or fungi, respectively. Atypical patterns were linked to reduced abundance of Bacteroides and increased Candida at 3 months. Functional analysis revealed an atypical bacterial alpha diversity trend was associated with elevated urinary trimethylamine N-oxide, creatine, indole acetic acid, and 2-furoylglycine, and an atypical fungal trend was associated with elevated urinary lactate. Using decision trees, the strongest predictors of atypical alpha diversity trends were interkingdom dynamics, breastfeeding duration, and maternal diet during pregnancy. Logistic regression revealed an atypical bacterial trend was positively associated with delivery via C-section and inversely associated with exclusive breastfeeding at 3 months, and an atypical fungal trend was positively associated with gestational consumption of artificially sweetened beverages and inversely associated with prenatal antibiotics. Interkingdom network analyses revealed the gut microbiome of infants with an atypical bacterial or fungal alpha diversity trend displayed a greater number of interkingdom interactions reflective of a less stable or immature gut microbiome. Conclusion(s) Our findings reveal a substantial proportion of infants display atypical patterns of gut microbiome maturation in the first year of life. While known microbiome-modifying factors were important determinants of maturational patterns, these factors were generally less influential than interkingdom influences. Together, this highlights the importance of interkingdom analyses at the individual level to generate more nuanced understandings of maturational trajectories in early life. Please acknowledge all funding agencies by checking the applicable boxes below CIHR, Other Please indicate your source of funding; Alberta Children's Hospital Research Institute Disclosure of Interest None Declared