Maternal-prenatal gut microbiome-systemic metabolome perturbations and T_H2-skewed immunity link to offspring gut microbiome disruption and atopic dermatitis susceptibility

Background
Emerging evidence suggests that maternal-prenatal gut microbiome disturbances shape offspring allergic outcomes through modulation of the in utero immune environment. Yet, no comprehensive clinical studies in human mother–offspring dyads have deconvoluted the maternal-prenatal gut microbiome and systemic immune-metabolome signatures underlying offspring allergic predisposition.

Methods
We performed a longitudinal nested case–control study involving 128 well-characterized mother–offspring dyads from defined cases (offspring with atopic dermatitis (AD); n = 64) and controls (offspring without AD; n = 64). Maternal stool and blood samples were collected at multiple time points during gestation for multi-omic profiling. Structural and functional gut microbiome composition was characterized via metagenomic sequencing, while systemic metabolome and serum immune milieu were profiled using targeted plasma metabolomics and Olink proximity extension assays, respectively. In offspring early-life, stool samples were collected longitudinally up to 6 months of age for gut microbiome and metabolome analyses.

Results
Mothers of AD infants exhibited longitudinal enrichments of gut Klebsiella pneumoniae, Roseburia intestinalis, Clostridioides difficile and Bilophila sp. 4_1_30, alongside depletions in gut Clostridium sp. CAG:678, Romboutsia timonensis, Akkermansia muciniphila, Blautia hansenii and Alistipes ihumii during pregnancy. These taxonomic shifts were associated with systemic metabolomic alterations, including elevated branched-chain amino acids and immune-related metabolites (e.g., creatine, ornithine), and a concurrent pro-inflammatory TH2-skewed immunological milieu marked by increased interleukin-4 (IL-4) and IL-5 and decreased CXCL11. In early life, AD infants harbored a dysbiotic gut microbiome characterized by persistent enrichments of potentially pathogenic Escherichia coli and K. pneumoniae, along with depletion of short chain fatty acid-producing Bacteroides species and beneficial colonizers. Integrated multi-omic analyses across the prenatal-postnatal axis indicated that the impaired establishment of gut microbiome in AD infants may, in part, be attributed to the (1) potential transmission of maternally originated Klebsiella and (2) immunomodulatory effects of a maternal-prenatal pro-inflammatory, TH2-skewed milieu during gestation.

Conclusions
Our study uncovers a distinct maternal-prenatal gut microbiome and systemic metabolome–immune signature that predisposes offspring to AD by disrupting early-life gut microbial establishment. These findings highlight the gestational period as a critical window for preventive strategies targeting the maternal microbiome or systemic immune-metabolic axes to mitigate allergic disease susceptibility in offspring.