The study investigates the association between neonatal gut microbiota composition and the risk of childhood atopy and asthma. Using 16S rRNA sequencing of stool samples from 298 infants aged 1-11 months, the researchers identified three distinct microbiota states (NGM1-3) based on bacterial community composition. Each state was associated with different risks for multi-sensitized atopy at age two and doctor-diagnosed asthma at age four. The highest-risk group, NGM3, showed lower relative abundance of certain beneficial bacteria (e.g., Bifidobacterium, Akkermansia, and Faecalibacterium) and higher relative abundance of particular fungi (e.g., Candida and Rhodotorula). NGM3 also exhibited a distinct fecal metabolome enriched in pro-inflammatory metabolites. Ex vivo experiments showed that sterile fecal water from NGM3 subjects increased the proportion of CD4+ cells producing interleukin-4 and reduced the relative abundance of regulatory T cells (Foxp3+CD25+CD4+). The study suggests that neonatal gut microbiome dysbiosis drives CD4+ T-cell dysfunction, which is associated with childhood atopy and asthma.The study investigates the association between neonatal gut microbiota composition and the risk of childhood atopy and asthma. Using 16S rRNA sequencing of stool samples from 298 infants aged 1-11 months, the researchers identified three distinct microbiota states (NGM1-3) based on bacterial community composition. Each state was associated with different risks for multi-sensitized atopy at age two and doctor-diagnosed asthma at age four. The highest-risk group, NGM3, showed lower relative abundance of certain beneficial bacteria (e.g., Bifidobacterium, Akkermansia, and Faecalibacterium) and higher relative abundance of particular fungi (e.g., Candida and Rhodotorula). NGM3 also exhibited a distinct fecal metabolome enriched in pro-inflammatory metabolites. Ex vivo experiments showed that sterile fecal water from NGM3 subjects increased the proportion of CD4+ cells producing interleukin-4 and reduced the relative abundance of regulatory T cells (Foxp3+CD25+CD4+). The study suggests that neonatal gut microbiome dysbiosis drives CD4+ T-cell dysfunction, which is associated with childhood atopy and asthma.