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Yet, no comprehensive clinical studies in human mother\u2013offspring dyads have deconvoluted the maternal-prenatal gut microbiome and systemic immune-metabolome signatures underlying offspring allergic predisposition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a longitudinal nested case\u2013control study involving 128 well-characterized mother\u2013offspring dyads from defined cases (offspring with atopic dermatitis (AD);\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200964) and controls (offspring without AD;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200964). 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\u00a0months of age for gut microbiome and metabolome analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mothers of AD infants exhibited longitudinal enrichments of gut\n                      <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                      ,\n                      <jats:italic>Roseburia intestinalis<\/jats:italic>\n                      ,\n                      <jats:italic>Clostridioides difficile<\/jats:italic>\n                      and\n                      <jats:italic>Bilophila<\/jats:italic>\n                      sp. 4_1_30, alongside depletions in gut\n                      <jats:italic>Clostridium<\/jats:italic>\n                      sp. CAG:678\n                      <jats:italic>, Romboutsia timonensis<\/jats:italic>\n                      ,\n                      <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                      ,\n                      <jats:italic>Blautia hansenii<\/jats:italic>\n                      and\n                      <jats:italic>Alistipes ihumii<\/jats:italic>\n                      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\n                      <jats:sub>H<\/jats:sub>\n                      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\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      and\n                      <jats:italic>K. pneumoniae<\/jats:italic>\n                      , along with depletion of short chain fatty acid-producing\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      species and beneficial colonizers\n                      <jats:italic>.<\/jats:italic>\n                      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\n                      <jats:italic>Klebsiella<\/jats:italic>\n                      and (2) immunomodulatory effects of a maternal-prenatal pro-inflammatory, T\n                      <jats:sub>H<\/jats:sub>\n                      2-skewed milieu during gestation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study uncovers a distinct maternal-prenatal gut microbiome and systemic metabolome\u2013immune 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>This study is registered at ClinicalTrials.gov (NCT 03531658).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-026-01655-5","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:26:21Z","timestamp":1776399981000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Maternal-prenatal gut microbiome-systemic metabolome perturbations and TH2-skewed immunity link to offspring gut microbiome disruption and atopic dermatitis susceptibility"],"prefix":"10.1186","volume":"18","author":[{"given":"Daniel Zhi Wei","family":"Ng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaik Chin","family":"Yap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina Jing Xuan","family":"Tay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiung-Hui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Low","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth Huiwen","family":"Tham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn Xiu Ling","family":"Loo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynette P.","family":"Shek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Goh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kok Wee","family":"Chong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si Hui","family":"Goh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zai Ru","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo P. 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