Despite decades of research, the etiological origins of Autism Spectrum Disorder (ASD) remain elusive. Recently, the mechanisms of ASD have encompassed emerging theories involving the gastrointestinal, immune, and nervous systems. While each of these perspectives presents its own set of supporting evidence, the field requires an integration of these modular concepts and an overarching view of how these subsystems intersect. In this systematic review, we have synthesized relevant evidences from the existing literature, evaluating them in an interdependent manner and in doing so, outlining their possible connections. Specifically, we first discussed gastrointestinal and immuno‐inflammation pathways in‐depth, exploring the relationships between microbial composition, bacterial metabolites, gut mucosa, and immune system constituents. Accounting for temporal differences in the mechanisms involved in neurodevelopment, prenatal and postnatal phases were further elucidated, where the former focused on maternal immune activation (MIA) and fetal development, while the latter addressed the role of immune dysregulation in contributing to atypical neurodevelopment. As autism remains, foremost, a neurodevelopmental disorder, this review presents an integration of disparate modules into a “Gut‐Immune‐Brain” paradigm. Existing gaps in the literature have been highlighted, and possible avenues for future research with an integrated physiological perspective underlying ASD have also been suggested.

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Hooks et al. posit that gastrointestinal microbes alter the end state of development indirectly. Here, we present the immune system as the link that facilitates communication between the gut and the brain. Illustrating the case of autism spectrum disorder, we explicate the role of the immune system in responding to microbial dysbiosis by inducing an inflammatory state that affects neurodevelopment. We propose two models: directly, within the infant, and indirectly, via maternal and infant systems.

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