Human brain development begins in the third week of gestation.
At the time of birth, about 86 billion neurons with up to 100 trillion connections are produced. This development requires precise regulation from molecular signaling pathways. Hormones like oxytocin, neurotransmitters like serotonin, and the immune system all play important roles in forming the neural circuitry underlying social cognition, emotion, and behavior.
The gut microbiota in the initial days of life is unstable and of low diversity. By age three, by which verbal communication and the ability to infer and reason about the intentions, emotions, and thoughts of others develops, the gut microbial composition stabilizes into a pattern that more resembles an adult-like profile.
Autism Spectrum Disorders (ASD)
ASD affects about 1 in 68 children and is characterized by deficits in social communication, social interaction, and restricted/repetitive behavioral patterns. The processing of emotional stimuli is impaired in individuals with ASD. Taken together, this can result in language delay and many at the severe end of the spectrum will not develop language abilities.
The origins of ASD are likely to occur during the prenatal timeframe. Maternal infections during pregnancy are associated with development of neurodevelopmental disorders. Risk factors such as advanced parental age, low birth weight, and multiple births have been identified, while others such as mode of birth have been advanced. However, data suggests that C-section birth – known to alter microbiome signatures – is associated only with a slightly increased risk of ASD.
Schizophrenia Spectrum Disorders (SSD)
Schizophrenia has a general population lifetime prevalence of ~0.9% with a slightly greater risk for males and psychotic symptoms usually manifest clinically during the adolescent years.
Schizophrenia is classically characterized by delusions, hallucinations, affective flattening, alogia (lack of speech), avolition (lack of motivation to complete tasks), and cognitive symptoms. Social interaction and communication deficiencies can be prominent even in early stages.
Although psychotic symptoms usually manifest in adolescence, it has been established that schizophrenia is associated with poor premorbid functioning, cognitive impairment, and social deficits prior to onset of symptoms.
The immune system is an important player in the pathophysiology of schizophrenia. and neuro-immune signaling changes during the adolescent period. There is some suggestion that schizophrenia is associated with altered intestinal and blood brain barrier function. Infections at different stages of brain development result in varying degrees of lifelong changes in behavior and cognition.
ASD and Microbiota
GI symptoms are a common comorbidity in ASD, however the underlying mechanism is not fully known. The vast majority of human studies show that ASD is associated with altered microbial profiles. ASD is also highly associated with atypical eating patterns.
SSD and the Microbiota
Data from pre-clinical studies indicate that certain domains related to schizophrenia, such as social cognition, are under partial influence of the gut microbiota.
Communication Pathways of Brain-Gut-Microbiota Axis
Although the functional significance of the gut microbiota has yet to be fully determined, it is clear that an intricate and interlinked symbiotic relationship exists between host and microbe, and there are a number of bidirectional signaling pathways by which the gut microbiota can impact the brain via the brain-gut axis.
A key signaling pathway involves modulation of the immune system, though other pathways include the hypothalamic-pituitary-adrenal (HPA) axis, tryptophan metabolism, production of bacterial metabolites (such as short-chain fatty acids), and via the vagus nerve.
Microbiota and the Immune System
A bidirectional communication system exists between the immune system and the central nervous system.
A critical function of the gut microbiota is to prime the development of the neuroimmune system. Alterations in the gut microbiota signature early in life can predispose to immune disorders and the surface of the gut is a key interface in this process.
Mechanistic Influences of Microbiota on Brain Function and Development
Structural components of bacteria interact with the immune system via toll-like receptors (TLRs). Activation of TLRs trigger the induction of pro- and anti-inflammatory cytokines. Dysregulation of this process, or excessive TLR activation, can result in chronic inflammatory and over-exuberant repair responses. Consequently, TLRs may serve as molecular communication channels between gut microbiota alterations and immune system homeostasis. A clinical study in subjects diagnosed with psychotic disorders showed specific alterations in TLR agonist-mediated cytokine release compared to healthy controls.
Microglia, central to the inflammatory process, are emerging as playing key roles in brain development, plasticity, and cognition. Pre-clinical studies have shown that acute stress results in microglia activation and increased levels of proinflammatory cytokines in areas such as the hippocampus and hypothalamus. Most studies show increases in activated microglia in response to chronic stress. Preliminary changes in the microenvironment of the microglia may result in a susceptibility to a secondary inflammatory stimulus which may be of relevance to neurodevelopmental disorders. In human studies, microglial dysregulation has been demonstrated in several psychiatric disorders. The gut microbiota is emerging as an important neuroimmunomodulator and is also involved in the maturation and activation of microglia.
Microbiota and Neurochemistry
Both ASH and schizophrenia are associated with dysregulation of synaptic function and structure. The gut microbiota plays a role in developmental programming of the brain, specifically synapse maturation and synaptogenesis.
A key regulator of synaptic plasticity and neurogenesis in the brain is brain-derived neurotrophic factor (BDNF). Maintaining appropriate levels of BDNF and other neurotrophins, especially during critical neurodevelopmental windows, is vital for both ASD and schizophrenia. Children with ASD have been shown to have increased levels of blood BDNF and individuals diagnosed with schizophrenia have shown to have reduced blood levels. Prebiotics can alter BDNF levels and increase BDNF gene expression in the hippocampus.
At the neurotransmitter level, several signaling pathways have been shown to be dysfunctional in ASD and schizophrenia. Glutamatergic (relating to glutamate) and GABA-ergic dysfunction and the consequences on excitatory to inhibitory cortical activity is one hypothesis to account for the similarities in the social and cognitive disturbances in ASD and schizophrenia. GABA is an important inhibitory neurotransmitter in the brain and GABA dysfunction has been implicated in ASD and schizophrenia. Interestingly, certain bacteria can produce GABA by metabolizing dietary glutamate.
Serotonin has a wide range of physiological functions and is involved in the modulation of anxiety, conditioned fear, stress responses, reward, and social behavior. Serotonin and its precursor tryptophan are critical signaling molecules in the grain-gut-microbiota axis. In the GI tract, serotonin plays an important role in secretion, sensing, and signaling and the gut microbiota itself is also an important regulator of serotonin synthesis and secretion.
The essential micronutrient zinc plays an important role in immune function an GI development and function. Diet, prenatal and early life stress, immune system dysregulation, and impaired GI function can affect zinc status. Zinc deficiency has been proposed as an environmental risk factor for ASD.
Dietary factors can result in epigenetic alterations that lead to disease susceptibility. Prenatal malnutrition increases the risk of schizophrenia. It has also been suggested that the microbiota is an important mediator of gene-environment interactions. Short-chain fatty acids produced by certain classes of bacteria and can cross the blood-brain barrier where it can subsequently alter gene expression in the brain.
The brain interprets perceived stressors to determine physiological and behavioral responses. This process can promote adaptation (allostasis) but when responses are exaggerated or overused (allostatic overload), pathology can result. The immune system and HPA axis are important to the stress response and act as mediators to alter neural circuitry and function. Stressful life events can precipitate psychotic symptoms. Also, early life stressors such as childhood trauma or social adversity/defeat stressors such as minority status can increase risk of psychosis. Schizophrenia is commonly comorbid with anxiety and depressive disorders and about 40% of young people with ASD have at least one anxiety disorder and higher levels of depression. Stress can reshape gut microbiota composition.
In pre0clinical studies, both prebiotic and probiotic treatment can reduce stress-related behaviors. “Psychobiotics”, originally defined as live bacteria that when ingested in adequate amounts could produce a positive mental health benefit in terms of anxiety, mood, and cognition, has more recently been expanded to include “any substance that exerts a microbiome-mediated psychological effect”.