This prospective, birth cohort multi-omic study investigates the relationship between infant gut microbiome and metabolites, early-life risk factors, and the development of neurodevelopmental disorders (NDs) in later childhood. The study followed 16,440 Swedish children over 20 years, identifying biomarkers and risk factors associated with NDs, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disabilities, and speech disorders. Key findings include: 1. **Microbial and Metabolomic Changes**: Infants with future NDs showed significant differences in their gut microbiota and metabolome, particularly in the presence of *Coprococcus* and *Citrobacter*. 2. **Early-Life Risk Factors**: Infections, antibiotic use, preterm birth, parental smoking, and HLA genetics were associated with increased risk of NDs. 3. **Gastrointestinal and Mood Issues**: Early gastrointestinal problems and mood issues, such as irritability and gastrointestinal symptoms, were more common in infants who later developed NDs. 4. **Cord Serum Metabolome**: Linolenic acid was inversely associated with future ASD, while perfluorodecanoic acid (PFDA) was positively associated. 5. **HLA Genotype**: DR4-DQ8 homozygosity was more prevalent in future NDs, especially ASD. 6. **Microbial Differences by ND Subtype**: The gut microbiome varied significantly among different ND subtypes, with distinct microbial communities for ASD, ADHD, speech disorders, and multiple NDs. 7. **Stool Metabolome**: Future ASD was associated with higher levels of certain metabolites, such as 3-isopropylmalate and quinate, while controls showed higher levels of 2-hydroxyphenylacetic acid and L-lysine. The study highlights the importance of early-life gut health and microbial balance in the development of NDs, suggesting potential early-life interventions to mitigate these disorders.This prospective, birth cohort multi-omic study investigates the relationship between infant gut microbiome and metabolites, early-life risk factors, and the development of neurodevelopmental disorders (NDs) in later childhood. The study followed 16,440 Swedish children over 20 years, identifying biomarkers and risk factors associated with NDs, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disabilities, and speech disorders. Key findings include: 1. **Microbial and Metabolomic Changes**: Infants with future NDs showed significant differences in their gut microbiota and metabolome, particularly in the presence of *Coprococcus* and *Citrobacter*. 2. **Early-Life Risk Factors**: Infections, antibiotic use, preterm birth, parental smoking, and HLA genetics were associated with increased risk of NDs. 3. **Gastrointestinal and Mood Issues**: Early gastrointestinal problems and mood issues, such as irritability and gastrointestinal symptoms, were more common in infants who later developed NDs. 4. **Cord Serum Metabolome**: Linolenic acid was inversely associated with future ASD, while perfluorodecanoic acid (PFDA) was positively associated. 5. **HLA Genotype**: DR4-DQ8 homozygosity was more prevalent in future NDs, especially ASD. 6. **Microbial Differences by ND Subtype**: The gut microbiome varied significantly among different ND subtypes, with distinct microbial communities for ASD, ADHD, speech disorders, and multiple NDs. 7. **Stool Metabolome**: Future ASD was associated with higher levels of certain metabolites, such as 3-isopropylmalate and quinate, while controls showed higher levels of 2-hydroxyphenylacetic acid and L-lysine. The study highlights the importance of early-life gut health and microbial balance in the development of NDs, suggesting potential early-life interventions to mitigate these disorders.