Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy

Abstract

Autism spectrum disorder (ASD) has become a common neurodevelopmental disorder. The heterogeneity of ASD poses great challenges for its research and clinical translation. On the basis of reviewing the heterogeneity of ASD, this review systematically summarized the current status and progress of pathogenesis, diagnostic markers, and interventions for ASD. We provided an overview of the ASD molecular mechanisms identified by multi-omics studies and convergent mechanism in different genetic backgrounds. The comorbidities, mechanisms associated with important physiological and metabolic abnormalities (i.e., inflammation, immunity, oxidative stress, and mitochondrial dysfunction), and gut microbial disorder in ASD were reviewed. The non-targeted omics and targeting studies of diagnostic markers for ASD were also reviewed. Moreover, we summarized the progress and methods of behavioral and educational interventions, intervention methods related to technological devices, and research on medical interventions and potential drug targets. This review highlighted the application of high-throughput omics methods in ASD research and emphasized the importance of seeking homogeneity from heterogeneity and exploring the convergence of disease mechanisms, biomarkers, and intervention approaches, and proposes that taking into account individuality and commonality may be the key to achieve accurate diagnosis and treatment of ASD.

Keywords: autism spectrum disorder; biomarker; intervention therapy; molecular mechanisms; multi‐omics.

FIGURE 1

Potential influences of autism spectrum disorder (ASD). ASD is a heterogenous group of neurodevelopmental disorders characterized by social communication impairments, repetitive behaviors, restricted range of interest, and other clinical considerations. ASD is a multifactorial disease that involves the interactions of genetic and environmental factors. The genetic factors include genetics (single gene disorder, copy number variations and single‐nucleotide polymorphism), epigenetic (DNA methylation, chromatin modification and noncoding RNA), and sex differences factors (female protective effect and sex chromosome gene dose sex hormone levels). In contrast, the environmental factors comprise prenatal exposure (microbiota–gut–brain axis, environmental toxin, immune dysfunction, medications, and diet) and postnatal exposure (lifestyle and impairment/dysfunction). These factors lead to abnormal neuron development, changes in the structure and function of the brain, resulting in ASD.

FIGURE 2

The graphical abstract of potential pathology of autism spectrum disorder (ASD) investigated by multi‐omics methods. The dysregulation of signaling pathways in neuron lead to abnormal balance between excitatory and inhibition. Many genes mutation influenced the postsynaptic density including the cytoskeleton organization, glutamate neurotransmission, cell–cell signaling, and mitochondrional function. The accumulation of negative effect further impacts the downstream of synapse. The maternal immune activation and mitochondrial dysregulation are associated with oxidation and inflammation. The red labels indicates that the genes are associated with the process in the studies. E/I, excitation and inhibition.

FIGURE 3

Potential mechanisms of gut microbiota imbalance and autism spectrum disorder (ASD) occurrence. The gut flora and brain can interact through immune, metabolic, and gut nervous system pathways and ultimately leading to abnormalities in gut brain axis and neural development. Gut flora alternation causes metabolism changes and its dysbiosis linked to greater intestinal mucosa and blood–brain barrier (BBB) permeability. Feedback regulation exists in gene expression, dietary preference, and gut flora. ANC, autonomic nervous system; CNS, central nervous system; FMT, fecal microbiota transplantation; HPA, hypothalamic–pituitary–adrenal; MTT, microbiota transfer therapy.

FIGURE 4

The summary of intervention therapy in autism spectrum disorder (ASD). Interventions for ASD mainly include behavioral and educational interventions, and we provide an overview of recent meta‐analyses, reviews, and consensus on them, as well as other important and emerging interventions. In terms of pharmacologic interventions, there are still no medications that target the core symptoms, and drug treatment is mainly for other abnormal symptoms or neuropsychiatric comorbidities of ASD. Treatments for common pathophysiology and gut flora are under investigation. Overall, early intervention has a significant effect, with community and family support being important. Given the characteristics of ASD, intervention and treatment need to take into account both commonalities and individuality. Finding common disease mechanisms and identifying well‐characterized subgroups will provide the basis for disease diagnosis and treatment, and disease markers and drug targets can influence and inform each other.