{"paper_id":"1f0575fa-2ee4-483d-b8ac-73bedb84f7de","body_text":"SUMMARY\nEmerging studies suggest that antibiotics can disrupt the gut microbiome and alter vaccine-induced immune responses, but the specific consequences of early-life exposure on neonatal immune development remains poorly understood. Here, we examined how two antibiotics frequently used in perinatal care, broad-spectrum ampicillin (AMP) and the extended-spectrum combination amoxicillin/clavulanate (AMOX/CLAV), administered during gestation and lactation, influence neonatal gut microbiome composition, fecal metabolome profiles, and responses to the 20-valent pneumococcal conjugate vaccine (PCV20). Maternal treatment with AMOX/CLAV, but not AMP, significantly reduced PCV-specific IgG titers at 4-and 6-weeks post-prime immunization compared to untreated controls. Exclusive exposure to AMOX/CLAV also impaired neutrophil-mediated opsonophagocytic killing, indicating diminished antibody functionality. These effects were transient, with immune parameters normalizing by week 8 post-prime immunization. Metabolomic and microbiome profiling revealed that maternal AMP and AMOX/CLAV differentially perturbed specific metabolite classes including bile acids, N-acyl lipids, and indole-derivatives, as well as key commensal taxa including Bacteroidales and Coriobacteriales within the gut microbiota. Together, these findings reveal a previously underappreciated maternal-offspring route of antibiotic influence that transiently disrupts neonatal vaccine responsiveness through microbiome and metabolome alterations. These results highlight maternal antibiotic exposure as a modifiable factor shaping early-life immunity.\nCompeting Interest Statement\nV.N. is an advisor and holds equity in Cellics, I2Pure, and Clarametyx with prior approval from UC San Diego. P.C.D. is a scientific advisor and holds equity in Cybele, Sirenas and bileOmix, and is a Scientific Co-founder, and advisor, received income and/or holds equity in Ometa, Arome, and Enveda with prior approval by UC-San Diego. P.C.D. consulted for DSM Animal Health in 2023. SMT receives grant funding from Veloxis Pharmaceuticals.The other authors declare no competing interests.","source_license":"CC-BY-4.0","license_restricted":false}