The study explores the association between neonatal gut microbiota composition and the development of childhood atopy and asthma. Using stool samples from 298 infants aged 1–11 months, researchers identified three distinct neonatal gut microbiota states (NGM1–3) through 16S rRNA sequencing. NGM3, the highest-risk group, was characterized by lower relative abundance of certain bacteria (e.g., Bifidobacterium, Akkermansia, Faecalibacterium) and higher relative abundance of fungi (e.g., Candida, Rhodotorula), along with a distinct fecal metabolome enriched in pro-inflammatory metabolites. Ex vivo experiments showed that NGM3 fecal water increased CD4+ T-cells producing interleukin-4 and reduced Foxp3+ CD25+ CD4+ T-cells, indicating immune dysfunction. The metabolite 12,13 DiHOME, which distinguished NGM3 from lower-risk groups, replicated the effect of NGM3 fecal water on T-cell populations. These findings suggest that neonatal gut microbiota dysbiosis drives CD4+ T-cell dysfunction linked to childhood atopy and asthma. The study also highlights the importance of early-life microbiota composition in influencing immune development and allergic disease risk. The results indicate that interventions targeting the neonatal gut microbiome may offer a strategy for preventing allergic diseases.The study explores the association between neonatal gut microbiota composition and the development of childhood atopy and asthma. Using stool samples from 298 infants aged 1–11 months, researchers identified three distinct neonatal gut microbiota states (NGM1–3) through 16S rRNA sequencing. NGM3, the highest-risk group, was characterized by lower relative abundance of certain bacteria (e.g., Bifidobacterium, Akkermansia, Faecalibacterium) and higher relative abundance of fungi (e.g., Candida, Rhodotorula), along with a distinct fecal metabolome enriched in pro-inflammatory metabolites. Ex vivo experiments showed that NGM3 fecal water increased CD4+ T-cells producing interleukin-4 and reduced Foxp3+ CD25+ CD4+ T-cells, indicating immune dysfunction. The metabolite 12,13 DiHOME, which distinguished NGM3 from lower-risk groups, replicated the effect of NGM3 fecal water on T-cell populations. These findings suggest that neonatal gut microbiota dysbiosis drives CD4+ T-cell dysfunction linked to childhood atopy and asthma. The study also highlights the importance of early-life microbiota composition in influencing immune development and allergic disease risk. The results indicate that interventions targeting the neonatal gut microbiome may offer a strategy for preventing allergic diseases.