Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders

Abstract

The gut microbiome has a tremendous influence on human physiology, including the nervous system. During fetal development, the initial colonization of the microbiome coincides with the development of the nervous system in a timely, coordinated manner. Emerging studies suggest an active involvement of the microbiome and its metabolic by-products in regulating early brain development. However, any disruption during this early developmental process can negatively impact brain functionality, leading to a range of neurodevelopment and neuropsychiatric disorders (NPD). In this review, we summarize recent evidence as to how the gut microbiome can influence the process of early human brain development and its association with major neurodevelopmental psychiatric disorders such as autism spectrum disorders, attention-deficit hyperactivity disorder, and schizophrenia. Further, we discuss how gut microbiome alterations can also play a role in inducing drug resistance in the affected individuals. We propose a model that establishes a direct link of microbiome dysbiosis with the exacerbated inflammatory state, leading to functional brain deficits associated with NPD. Based on the existing research, we discuss a framework whereby early diet intervention can boost mental wellness in the affected subjects and call for further research for a better understanding of mechanisms that govern the gut-brain axis may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.

Keywords: attention-deficit/hyperactivity disorder; autism spectrum disorder; drug resistance; gut microbiome; inflammation; neurodevelopmental psychiatric disorder; probiotics; schizophrenia.

FIGURE 1

Significant risk factors affecting events with in human developmental window could bring on neurodevelopmental psychiatric disorders. The critical developmental window spans from the fetal stage until childhood, which consists of early colonization and development of the microbiome, development of the brain and nervous system, and development and maturation of the immune system. Within this period, the composition and diversity of the gut microbiome, genetics, maternal, and other reverent factors can alter the overall developmental homeostasis by causing disturbances in the immune system. Gut dysbiosis, immune alteration, and other factors induce microglial activation via inflammatory response, which leads to systemic and neuroinflammation. This negatively affects the brain development process and leads to abnormal brain development and functionality, including anxiety, depression, intellectual disability, and behavioral abnormality that can be seen in neurodevelopmental and psychotic disorders.

FIGURE 2

Role of the gut microbiome in healthy brain development. The gut microbiome plays an essential role in various processes of brain development such as neurogenesis, myelination, microglial maturation, development and maintenance of blood-brain barrier integrity, development of HPA-axis, and HPA-axis stress response. Any alterations in this developmental process can significantly increase the risk for neurodevelopmental disorders.

FIGURE 3

Gut-brain homeostasis and inflammatory mechanisms in neurodevelopmental psychiatric disorders due to gut brain dysbiosis. In infancy, the dysbiotic gut is characterized by less diverse microbiota with an abundance of pathogenic microbes, less beneficial microbes, and disrupted gut epithelial barrier with consequent GI tract-related disorders. When severe, the pathogenic microbes may cross through and enter the blood, which holds a massive immune response and releases inflammatory cytokines that lead to inflammation. Cytokine imbalance can induce microglial activation in the brain, which again causes neuroinflammation. This is associated with a disruption in brain development, and delay in neurodevelopmental subsequently may lead to NDD and NPDs.

FIGURE 4

The gut microbes regulate the development and maturation of the immune system and play a crucial role in brain development (Green: normal interaction; Red: aberrant interaction). Gut dysbiosis and the immune system in brain development led to neurodevelopmental disorders. A gut dysbiosis alters the immune system homeostasis and leads to the activation of inflammatory response. Such aberration during brain development can disrupt the developmental pathways, leading to developmental delays and neurodevelopmental disorders.

FIGURE 5

Probiotic therapy to overcome adverse effects NDDs at developmental time points. Probiotic treatment at specific time points such as in-utero, after immediate birth, infancy and childhood may help and support the establishment of stable and healthy gut microbiota, prevent the dysregulation in the developmental process, and play the role of a crucial preventive measure for the onset of neurodevelopmental and psychotic disorders via neutralizing the effects of inducing factors.