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.
Highlights
The contribution of the gut-brain-microbiome axis to health and disease states is a relatively new field of research (Figure 1) with increasing interest from both public and scientific spheres (Drossman and Hasler, 2016)
While autism spectrum disorder (ASD) is still diagnosed by deficits in social communication, repetitive behaviors, and/or restrictive interests, comorbidities like seizures, epilepsy, sleep disturbance, hypotonia, and GI distress are common with significant negative impacts on quality of life (Christensen et al, 2018; “IACC, 2019 Strategic Plan For Autism Spectrum Disorder 2018–2019 Update,” 2019; Leader et al, 2020)
We found that while there was no difference in enteric neuron count, there was a significant decrease in the expression of serotonin-positive enteroendocrine cells in shank3ab mutants
Summary
The contribution of the gut-brain-microbiome axis to health and disease states is a relatively new field of research (Figure 1) with increasing interest from both public and scientific spheres (Drossman and Hasler, 2016). An understanding of this axis draws on a range of disciplines including neurobiology, gastroenterology, microbiology, endocrinology, and psychology (Liang et al, 2018; Neuhaus et al, 2018). This breadth of subjects relevant to the gut-brain-microbiome field speaks to the diversity of its potential applications. We review how recent studies of the gut-brain-microbiome axis have changed our understanding of ASD related symptoms and highlight the important role the zebrafish model can play in future research
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