ReviewEarly-life adversity and brain development: Is the microbiome a missing piece of the puzzle?
Introduction
It is almost 150 years since the neuroanatomist and Nobel price awardee Camillo Golgi stated that “functional scars in the brain” might be the organic cause of mental disorders (Zanobio, 1963). During the intervening period it has become more apparent that during sensitive developmental episodes, the environment exerts a critical impact on the maturation of brain structure and behavioral function (Weinstock, 2008, Korosi and Baram, 2009, Loman and Gunnar, 2010, Lucassen et al., 2013, Lucassen et al., 2014). Indeed, there is substantial evidence that adverse early-life events have significant and long-lasting effects on brain function and may increase the risk of developing psychopathology in adulthood (McCrory et al., 2010). The manifold effects of early-life stress on the development of brain and behavior emerge as a function of the type, intensity, timing and the duration of each particular environmental insult (Lupien et al., 2009a, O’Mahony et al., 2009). Intriguingly, one of the factors that has recently emerged to play a role in how the body deals with early-life stressors is the gut microbiome (Cryan and O’Mahony, 2011). In this review we highlight the influence of undesirable events during early life, incorporating both prenatal and postnatal periods, on the developing brain. We discuss the state of the art, including studies from both clinical and preclinical settings, with an emphasis on different types of insults (see Fig. 1) as well as the varying effects and possible underlying mechanisms. Within this framework, we integrate the gut microbiome as a vital part of this puzzle and a factor with both a broad susceptibility and reach, capable itself of disrupting the developing central nervous system and inducing permanent phenotypic perturbations. The implications of these emerging concepts are wide-ranging and nurturing the gold standard assembly of the gut microbiome may be a viable preventative strategy to tackle the often silent origins of behavioral and emotional problems that first manifest during adolescence and adulthood.
Section snippets
Adverse events and brain development-importance of timing
During the development of the mammalian brain sensitive windows exist during which dynamic and extensive processes are occurring (see Fig. 2). The enduring influence of an insult depends on the maturational stage of the brain and to what extent the normal developmental trajectory is disrupted (Andersen, 2003). Epidemiological data support the concept that the time of exposure may be essential to some types of stressors, as similar adverse events occurring at early or late stages have been
Prenatal stressors and psychopathology
The negative influence exerted by adverse life events during gestation on brain development has received a great deal of attention since the proposal that psychiatric disorders may be developmental in origin (Barker, 2013, Barker et al., 2013, Capra et al., 2013, O’Donnell et al., 2014, Kim et al., 2015). Brain development begins early in embryonic life with neurulation, where the neural plate is transformed into the neural tube at approximately two to three weeks gestation (Rice and Barone,
Postnatal events and the development of brain disorders
The postnatal period is particularly important with regard to brain development as it is open to environmental modulation. During the postnatal period a substantial amount of morphological development, cell differentiation, and acquisition of function takes place (Andersen, 2003, Borre et al., 2014c). In the human brain, formation of synapses begins shortly after birth and synaptic density increases substantially and reach maximum levels by approximately 2 years of age, at which point there are
The gut microbiota as a regulator of the stress response early in life
Just as other mammals, humans harbor enormous quantities of commensal microorganisms on the exposed and internal surfaces of our bodies. Within a particular habitat, for example the gut, the collection of these commensals are referred to microbiota or microflora while the collective genome is termed microbiome (Round and Mazmanian, 2009, Collins et al., 2012, Cryan and Dinan, 2012, Clarke et al., 2014a). Within our gut a unique combination of different populations of organisms exist, mainly
Perspectives and implications
We have considered how the emerging role of the gut microbiome in sculpting multiple aspects of brain and behavior in general should be integrated into the concept of early-life adversity, abnormal brain development and the subsequent expression of psychopathology. Proof-of-principle studies in microbiota-deficient animals have clearly demonstrated a multifaceted impact of growing up germ-free during different neurodevelopmental stages at the level of the CNS. This extends from specific
Conclusions
We argue here that the gut microbiome is a missing piece of the puzzle when attempting to unravel the wide-ranging neurodevelopmental impact of early-life stress on brain and behavior. Our understanding of the implications arising from this important observation may be rudimentary currently but there is now a great momentum behind what has been termed a paradigm shift in neuroscience (Mayer et al., 2014). As our appreciation of brain–gut-microbiome axis signaling grows, the potential for
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