THE LINK BETWEEN GUT MICROBIOME AND AUTISM SPECTRUM DISORDER
ALA, OLUWAPELUMI ADEBAYO
DOKITA EDITORIAL BOARD MEMBER
Introduction
Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental impairment that manifests in early childhood and affects speech and motor activities. Before the understanding of human genetics and its role in health and diseases improved, it was believed that this disease was caused by ill environmental factors. Effective treatment has however evaded man and victims have had to cope with this disorder for the entire period of their lives.
This paper elucidates the genetic basis of ASD and pathological changes that it causes. It also brings to light the relationship between ASD and gut microbiome and how this relationship can be explored to make a breakthrough in the treatment of this lifelong ailment.
AUTISM SPECTRUM DISORDER
Autism Spectrum Disorder (ASD) is a group of complex developmental disorders that affects language, speech, social interaction, neurodevelopment and sensory perception [1]. The disability in ASD affects verbal and non-verbal communication, information processing, response and behaviour. It is characterised by limited and repetitive behavioural pattern. The symptoms and severity of the disorder vary among the people affected by it such that their learning and thinking processes can range from highly gifted to severely problematic. The characteristics of ASD are observed in early childhood but diagnosis by clinical observation is not made until late childhood.
Kanner (1943) first described a case of autism following his management of 11 children who shared symptoms of obsessive interests in objects, difficulty in speech and indifference to people [2]. The first epidemiological study of autism that was conducted 23 years later revealed a prevalence of 4.5 per 10,000 people. A rapid increase has however been noted as it has been found that 1 in 59 individuals are autistic and the male-to-female ratio is 3:1 [3]. This increase has been attributed to improved awareness and clarity on the criteria for diagnosis based on Diagnostic and Statistical Manual of Mental Disorders (DSM). In the latest review of DSM, DSM-5 defined autism spectrum disorder to include Asperger Syndrome, childhood disintegrative disorder, pervasive developmental disorder – not otherwise specified (PDD-NOS), and autistic disorder. Prior to the review, they used to be independently considered [4].
Genetics has been identified as a primary basis for the disease. Several associated factors are directly involved in the pathogenesis of ASD, some of which are genetic modifiers that produce even worse effects on the genes. This suggests that ASD is a product of complex interaction between genes and environmental, immunological, and inflammatory factors. More recently, the gut microbiota has entered the fold. Among the myriads of systemic problems in people with ASD are gastrointestinal tract (GIT) problems. They include abdominal pain, diarrhea, constipation, gastroesophageal reflux, and intestinal infections. Studies of the GIT of these patients have not been conclusive. It has however been noted that in ASD children, there is a direct link between their imbalanced immune response and the state of their GIT [5].
GENETIC BASIS OF ASD
Following Kanner’s initial description of ASD, it was largely assumed that environmental factors were the cause of the disease. Our orientation about it began to change as the knowledge and understanding of human genetics grew. Folstein and Rutter in 1977, through their studies, discovered that incidence among siblings was high and even higher in dizygotic twins than in monozygotic twins [6]. The advent of genetic sequencing technology revealed that ASD has a multigenic and heterogenous root with a broad range of pathogenic variations among the afflicted population. The risk genes identified to be susceptible to mutation fall under 2 broad classes of proteins involved in synapse formation and transcription regulation.
Synapse-related risk genes include genes encoding for adhesion proteins such as cadherins and neurexins; ion-transport proteins such as sodium voltage-gated channel and calcium voltage-gated channels and more. The susceptible genes involved in transcription include chromodomain helicase DNA binding protein 8 (CHD8), Methyl-CPG Binding Protein 2 (MeCP2), RNA binding forkhead box (RBFOX) genes and more [7]. Diverse phenotypes that occur from the mutation of any of these genes give reason to the variation in the severity of ASD in the affected population.
SYSTEMIC PATHOLOGICAL CHANGES IN ASD
Autopsy and radiological findings using magnetic resonance imaging (MRI) technique have revealed structural and functional differences in the brains of ASD-affected individuals. These differences in a way explain the neurological problems of sensory perception, social interaction, obsessiveness and speech barrier seen in ASD. The neurological differences are classified as follows:
a. Structural differences [8,9]
i. Large brain with increased neurons in the cerebral cortex
ii. Altered hippocampus size and cell number
iii. Altered number of Purkinje cells
iv. Decreased size of the cerebellum
b. Functional differences [8]
i. Decreased activity in the temporal lobe
ii. Functional impairment of the basal ganglia
iii. Reduced neuron recruitment for tasks
c. Neurotransmitter differences [8]
i. Raised serotonin level in 40% of ASD-affected populace
ii. Dopamine insufficiency
Other co-morbidities associated with ASD include GIT infection, diarrhea, constipation, neurological inflammation and increased inflammatory cytokines in the brain causing a compromise in the effectiveness of the blood-brain barrier [5].
ASD AND THE GUT MICROBIOME
The human gut is home to millions of microorganisms by virtue of a complex ecological relationship. These microorganisms include bacteria, fungi and some viruses. The 5 major bacterial phyla in the human gut include Actinobacteria, Proteobacteria, Verrucomicrobia, Firmicutes and Bacteroidetes. Their distribution within the GIT varies based on factors such as pH, gas composition, and water activity. Their composition within the gut also varies over an individual’s life span. The initial colonization of the human gut begins at birth following vaginal delivery or through breast feeding for babies born through C-section. There is evidence that the composition of this microbiota changes towards senescence. This might be related to the malnutrition and cognitive impairment experienced in this age [10].
The gut microbiota has been identified to play key roles in conditions such as colorectal cancer, obesity, Parkinson’s disease, and Alzheimer’s disease. The GIT symptoms initially highlighted are linked to the severity of ASD symptoms. It is worthy to note that a cause-effect link between the GIT symptoms and ASD has not yet been established [10].
The gut-brain axis theory states that the brain and gut influence and communicate with each other. This is evidenced by studies that show that behavioural patterns were influenced by infusion of specific strains of bacteria in animal and human studies [11]. Another influence of the gut microbiota on cerebral processes was revealed in a study in which there was reduced production of brain-derived neurotrophic factor (BDNF), a protein that is essential for learning and behavioural processes involving the hippocampus and the cerebral cortex [11]. Pathways available for communication between the gut and the brain include the autonomic nervous system, neuroendocrine, and neuro-immune pathways [10].
Several factors connect ASD symptoms with gut microbiota. Early life events like mode of delivery contribute to the composition of the gut microbiome. Curran et el (2015) found out that infants born through C-section had higher chances of developing ASD compared to those born through vaginal delivery [12]. Antibiotics used to kill pathogens also kill commensal bacteria thereby compromising the gut homeostasis. There is in fact an association between antibiotics used in pregnancy and higher risk factor for ASD to develop in the child. A reduction in Clostridium groups also produced positive effects on ASD symptoms in children [12].There is no effective therapy for ASD. However, interventions such as probiotics, prebiotics, fecal microbiota transplantation and diet can be employed to modulate the gut microbiota as an effective treatment modality [10].
CONCLUSION
Genetics and environmental factors play primary roles in the aetiology of ASD. The high prevalence of ASD calls for an urgent intervention in form of effective treatment. The understanding of the microbiota-gut-brain axis can prove very useful in treatment of ASD symptoms with the aim of improving the life quality of the patient and their families.
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