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Background <p>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.</p> Methods <p>We performed a longitudinal nested case–control study involving 128 well-characterized mother–offspring dyads from defined cases (offspring with atopic dermatitis (AD); <i>n</i> = 64) and controls (offspring without AD; <i>n</i> = 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&#xa0;months of age for gut microbiome and metabolome analyses.</p> Results <p>Mothers of AD infants exhibited longitudinal enrichments of gut <i>Klebsiella pneumoniae</i>, <i>Roseburia intestinalis</i>, <i>Clostridioides difficile</i> and <i>Bilophila</i> sp. 4_1_30, alongside depletions in gut <i>Clostridium</i> sp. CAG:678<i>, Romboutsia timonensis</i>, <i>Akkermansia muciniphila</i>, <i>Blautia hansenii</i> and <i>Alistipes ihumii</i> 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 T<sub>H</sub>2-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 <i>Escherichia coli</i> and <i>K. pneumoniae</i>, along with depletion of short chain fatty acid-producing <i>Bacteroides</i> species and beneficial colonizers<i>.</i> 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 <i>Klebsiella</i> and (2) immunomodulatory effects of a maternal-prenatal pro-inflammatory, T<sub>H</sub>2-skewed milieu during gestation.</p> Conclusions <p>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.</p> Trial registration <p>This study is registered at ClinicalTrials.gov (NCT 03531658).</p>

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Maternal-prenatal gut microbiome-systemic metabolome perturbations and TH2-skewed immunity link to offspring gut microbiome disruption and atopic dermatitis susceptibility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月17日

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  • Daniel Zhi Wei Ng,
  • Gaik Chin Yap,
  • Carina Jing Xuan Tay,
  • Chiung-Hui Huang,
  • Siyan Zhao,
  • Adrian Low,
  • Elizabeth Huiwen Tham,
  • Evelyn Xiu Ling Loo,
  • Lynette P. Shek,
  • Anne Goh,
  • Kok Wee Chong,
  • Si Hui Goh,
  • Zai Ru Cheng,
  • Hugo P. S. Van Bever,
  • Oon Hoe Teoh,
  • Yung Seng Lee,
  • Fabian Yap,
  • Kok Hian Tan,
  • Yap-Seng Chong,
  • Shiao-Yng Chan,
  • Johan Gunnar Eriksson,
  • Keith M. Godfrey,
  • Christophe Lay,
  • Jan Knol,
  • Stephan C. Schuster,
  • Jun Shi Lai,
  • Mary Foong-Fong Chong,
  • Jonathan Wei Jie Lee,
  • Bee Wah Lee,
  • Eric Chun Yong Chan,
  • Le Duc Huy Ta

摘要

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.

Trial registration

This study is registered at ClinicalTrials.gov (NCT 03531658).