The Gut-Brain Axis as a Mediator of Environmental Endocrine Disruptors in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Mechanistic Synthesis

The rising global prevalence of Attention-Deficit/Hyperactivity Disorder (ADHD) underscores the importance of environmental factors, particularly endocrine-disrupting chemicals (EEDs), whose mechanistic links to ADHD remain unclear. The gut-brain axis, a key modulator of neurodevelopment, is susceptible to EEDs and is altered in ADHD, suggesting a potential mediating pathway. Following PRISMA guidelines and PROSPERO registration (CRD1152480), we systematically searched PubMed, Web of Science, and Embase (Jan 2014–Jul 2025) for studies on EEDs, gut microbiota, and ADHD. Data from 127 included studies (observational, experimental, interventional) were narratively synthesized to evaluate the gut-brain axis as a mediator. We found: 1) consistent epidemiological associations between prenatal/childhood EED exposure (e.g., phthalates, BPA, pesticides) and increased ADHD risk; 2) a distinct gut microbial signature in ADHD featuring reduced alpha-diversity, elevated Firmicutes/Bacteroidetes ratio, depletion of beneficial taxa ( Lactobacillus, Bifidobacterium ), and impaired short-chain fatty acid (SCFA) production; 3) evidence that EED exposure induces convergent gut dysbiosis; and 4) interventional studies indicating that modulating the microbiota (via probiotics, synbiotics, FMT) can ameliorate ADHD-related behaviors. These findings support a novel mechanistic model wherein EEDs disrupt gut microbiota homeostasis, contributing to ADHD pathogenesis via immune-inflammatory, microbial-metabolite (e.g., SCFA), and neuroendocrine pathways along the gut-brain axis. This review synthesizes evidence positioning the gut-brain axis as a critical mediator linking environmental EED exposure to ADHD. It proposes a unifying etiological framework and highlights the microbiome as a promising target for preventive and therapeutic strategies. Future longitudinal and intervention studies are needed to establish causality.