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This study aimed to assess the causal influence of gut microbiota on nervous system malformations and to identify immune cells as potential mediators in this relationship, utilizing a two\u2010step Mendelian randomization (TSMR) approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using genome\u2010wide association studies data on gut microbiota, immune cells, and congenital malformations of the nervous system, we applied TSMR to evaluate the total, direct, and mediating effects. Gut microbiota indicators served as exposures, congenital malformations of the nervous system as outcomes, and immune cell markers as mediators. Statistical analyses included MR Egger, inverse variance weighted, and so forth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our analysis identified 19 gut microbiota indicators causally associated with congenital malformations of the nervous system. Notably,\n                      <jats:italic>Eubacteriaceae<\/jats:italic>\n                      and\n                      <jats:italic>Eubacterium<\/jats:italic>\n                      genera exhibited protective effects, while\n                      <jats:italic>Escherichia<\/jats:italic>\n                      and\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      genera showed positive correlations with malformation risk. Nine immune cell indicators significantly mediated these effects. For example, CD20\n                      <jats:sup>+<\/jats:sup>\n                      B cells were negatively associated with malformation risk, suggesting a protective immune response, whereas CD25\n                      <jats:sup>+<\/jats:sup>\n                      B cells were positively correlated, indicating increased malformation risk.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrated a significant link between gut microbiota composition and congenital nervous system malformations, mediated by specific immune cells. These findings highlighted the potential for gut microbiota modulation and immune\u2010targeted therapies as preventive or therapeutic strategies in reducing malformation risks. Future investigations should aim to replicate these results across diverse populations and further elucidate the underlying biological mechanisms of gut\u2013immune\u2013neural interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>The authors have nothing to report.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/brb3.71150","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T12:45:32Z","timestamp":1767185132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identifying Immune Cells as Mediators in the Impact of Gut Microbiota on Congenital Malformations of the Nervous System"],"prefix":"10.1002","volume":"16","author":[{"given":"Haokun","family":"Tian","sequence":"first","affiliation":[{"name":"Laboratory of Translational Medicine, Beijing 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