Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by core features of social communication deficits and high prevalence of gastrointestinal comorbidities. With its continuously rising global prevalence, current therapeutic modalities remain unable to target and ameliorate the core symptoms of ASD. The microbiota-gut-brain axis (MGBA), a critical pathway mediating crosstalk between the gut microbiota and the brain, has been extensively documented to be deeply involved in the pathological progression of ASD in recent years. However, prior studies have predominantly focused on the unidirectional regulation of the brain by gut microbiota, lacking an integrated account of the bidirectional regulation across immune, metabolic, and endocrine systems. Centered on the immune-metabolic-endocrine interactive network, this review systematically delineates the bidirectional regulatory mechanisms of the MGBA in ASD by integrating recent evidence from microbiota sequencing, animal models, and clinical intervention studies, with the aim of clarifying the bidirectional causal controversy between intestinal microecological disturbance and ASD behavioral abnormalities. This review proposes that in children with ASD, decreased abundance of beneficial intestinal bacteria and disrupted metabolic profiles of short-chain fatty acids synergistically impair intestinal barrier integrity, triggering peripheral chronic inflammation that further drives excessive microglial activation-mediated central neuroinflammation. Subsequently, disturbances in the homeostasis of multiple neurotransmitters including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), histamine, and dopamine occur via the vagus nerve and hypothalamic-pituitary-adrenal (HPA) axis, ultimately driving ASD behavioral abnormalities. Conversely, chronic stress and behavioral characteristics associated with ASD reshape the intestinal microecology through neuroendocrine pathways, forming a vicious cycle of "microbiota dysbiosis-immune inflammation-HPA axis hyperactivity-further intestinal microecological imbalance". This review summarizes the therapeutic efficacy and translational bottlenecks of three types of microecological interventions: fecal microbiota transplantation (FMT), probiotics, and ketogenic diet, and analyzes the current limitations in the field, including pronounced population heterogeneity, unclear cross-talk mechanisms among multiple pathways, and the scarcity of large-sample clinical evidence. Collectively, this review preliminarily elucidates the complete multi-system interactive framework of MGBA regulation in ASD, providing theoretical support for mechanistic research and gut-targeted individualized interventions for ASD.
