A prospective, birth cohort multi-omic study reveals disruptions in the infant gut microbiome associated with later-diagnosed neurodevelopmental disorders (NDs). Microbial and metabolomic changes, correlating with risk factors, HLA genetics, and mood/gastrointestinal issues, support the hypothesis of early-life origins of NDs, underscoring an important role of gut microbiota. The study followed 16,440 Swedish children for over 20 years, identifying 1,197 children who developed NDs. Significant associations were found between early-life factors and future ND diagnoses, including intellectual disability, speech disorder, ADHD, and ASD. The study found that microbiome connections to future diagnosis, as well as early emerging mood and gastrointestinal problems, suggest links to immunodysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment. The study highlights the importance of gut microbiota in neurodevelopmental disorders, with findings indicating that early-life factors such as infections, antibiotic use, parental smoking, and HLA genetics play a significant role in ND risk. The study also found that certain metabolites, such as linolenic acid and PFDA toxins, were lower and higher, respectively, in the cord serum of future ASD cases. The study's findings suggest that early-life gut microbiome changes may be a key factor in the development of neurodevelopmental disorders.A prospective, birth cohort multi-omic study reveals disruptions in the infant gut microbiome associated with later-diagnosed neurodevelopmental disorders (NDs). Microbial and metabolomic changes, correlating with risk factors, HLA genetics, and mood/gastrointestinal issues, support the hypothesis of early-life origins of NDs, underscoring an important role of gut microbiota. The study followed 16,440 Swedish children for over 20 years, identifying 1,197 children who developed NDs. Significant associations were found between early-life factors and future ND diagnoses, including intellectual disability, speech disorder, ADHD, and ASD. The study found that microbiome connections to future diagnosis, as well as early emerging mood and gastrointestinal problems, suggest links to immunodysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment. The study highlights the importance of gut microbiota in neurodevelopmental disorders, with findings indicating that early-life factors such as infections, antibiotic use, parental smoking, and HLA genetics play a significant role in ND risk. The study also found that certain metabolites, such as linolenic acid and PFDA toxins, were lower and higher, respectively, in the cord serum of future ASD cases. The study's findings suggest that early-life gut microbiome changes may be a key factor in the development of neurodevelopmental disorders.