Neonatal gut microbiota associates with childhood multi–sensitized atopy and T–cell differentiation

Abstract

Altered infant human gut microbiome composition and metabolic activity are implicated in childhood atopy and asthma ¹ . We hypothesized that compositionally distinct neonatal human gut microbiota exist and are differentially related to relative–risk ( RR) of childhood atopy and asthma. Using stool samples ( n = 298; aged 1–11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age 35 days) were divisible into three microbiota–composition states (NGM1–3). Each incurred significantly different RR for multi–sensitized atopy at age–two years and doctor–diagnosed asthma at age–four years. The highest risk group, NGM3, showed lower relative abundance of certain bacteria (e.g. Bifidobacterium, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi ( Candida and Rhodotorula), and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of adult human peripheral T–cells with sterile fecal water from NGM3 subjects increased the proportion of CD4 ⁺ cells producing interleukin–4 and reduced the relative abundance of Foxp3 ⁺CD25 ⁺CD4 ⁺ cells. 12,13 DiHOME which discriminated NGM3 from lower–risk NGMs, recapitulated the effect of NGM3 fecal water on Foxp3 ⁺CD25 ⁺CD4 ⁺ cell relative abundance. These findings suggest that neonatal gut microbiome dysbiosis drives CD4 ⁺ T–cell dysfunction associated with childhood atopy.