The Gut-Brain-Microbiome Axis and Its Link to Autism: Emerging Insights and the Potential of Zebrafish Models

Abstract

Research involving autism spectrum disorder (ASD) most frequently focuses on its key diagnostic criteria: restricted interests and repetitive behaviors, altered sensory perception, and communication impairments. These core criteria, however, are often accompanied by numerous comorbidities, many of which result in severe negative impacts on quality of life, including seizures, epilepsy, sleep disturbance, hypotonia, and GI distress. While ASD is a clinically heterogeneous disorder, gastrointestinal (GI) distress is among the most prevalent co-occurring symptom complex, manifesting in upward of 70% of all individuals with ASD. Consistent with this high prevalence, over a dozen family foundations that represent genetically distinct, molecularly defined forms of ASD have identified GI symptoms as an understudied area with significant negative impacts on quality of life for both individuals and their caregivers. Moreover, GI symptoms are also correlated with more pronounced irritability, social withdrawal, stereotypy, hyperactivity, and sleep disturbances, suggesting that they may exacerbate the defining behavioral symptoms of ASD. Despite these facts (and to the detriment of the community), GI distress remains largely unaddressed by ASD research and is frequently regarded as a symptomatic outcome rather than a potential contributory factor to the behavioral symptoms. Allowing for examination of both ASD’s impact on the central nervous system (CNS) as well as its impact on the GI tract and the associated microbiome, the zebrafish has recently emerged as a powerful tool to study ASD. This is in no small part due to the advantages zebrafish present as a model system: their precocious development, their small transparent larval form, and their parallels with humans in genetics and physiology. While ASD research centered on the CNS has leveraged these advantages, there has been a critical lack of GI-centric ASD research in zebrafish models, making a holistic view of the gut-brain-microbiome axis incomplete. Similarly, high-throughput ASD drug screens have recently been developed but primarily focus on CNS and behavioral impacts while potential GI impacts have not been investigated. In this review, we aim to explore the great promise of the zebrafish model for elucidating the roles of the gut-brain-microbiome axis in ASD.

Zebrafish Modeling of Autism Spectrum Disorders, Current Status and Future Prospective

“…In recent years, the association between the gastrointestinal tract and the brain has been cited as one of the key mechanisms involved in the pathogenesis of ASD. In this regard, the prominent similar characteristics of zebrafish gastrointestinal tract with those of mammalians, such as having some similar main cells in the gastrointestinal tract, highly conserved gastrointestinal tract function and physiology, innervation by the enteric nervous system, and expression of some similar genes involved in the structure and function of the gastrointestinal system have made the Zebrafish as a suitable animal model for evaluating studies on diseases or disorders related to the gastrointestinal system or gut-brain axis ( 176 ). Since gastrointestinal disorders can be categorized as one of the symptoms of ASD, in 2019 James et al conducted a study based on the effect of a SHANK3 mutated gene on gastrointestinal distress.…”

Can oral microbiome dysbiosis affect the behavior of children with Autism Spectrum Disorders (ASD)? : Narrative review

“…However, due to the inability of ASD children to communicate, most of them cannot tell their parents about it, so they express their feelings in other ways, such as self-harm, tantrums, refusing to eat, etc. (24,34,35).…”

In vivo models to study neurogenesis and associated neurodevelopmental disorders—Microcephaly and autism spectrum disorder

“…The cortical surface area is enlarged in the affected infants and they exhibit macrocephaly. The other co‐morbidities include anxiety, seizures, epilepsy, speech and language delay, and gastrointestinal distress (Figure 3b; James et al, 2021; Patterson, 2011; Sierra‐Arregui et al, 2020; Varghese et al, 2017; Weissberg & Elliott, 2021; Zhao et al, 2018). ASD is a complex genetic disorder which involves genomic abnormalities, de novo mutations, chromatin rearrangements, and genetic variants.…”

“…The zebrafish has become an increasingly popular model to study ASD and its associated co‐morbidities, particularly gastrointestinal issues. Thus, this model is used to determine the effect of ASD on the gut–brain–microbiome axis (James et al, 2021; Sakai et al, 2018; Vaz et al, 2019). Now, a spectrum of transgenic lines labeling different neural cells are also available which are valuable tools to determine the defects which arise during embryogenesis, resulting in NDDs like ASD and epileptic encephalopathy.…”