Abstract
Preterm birth (PTB) remains a major pregnancy complication, yet the role of the maternal gut virome in its etiology is largely unknown. Here we show that the maternal gut virome undergoes ecological destabilization prior to PTB, coupled with distinct host metabolic remodeling. Nested within the Tongji-Huaxi-Shuangliu Birth Cohort, we integrate longitudinal gut virome and bacteriome profiles from 300 stool samples, alongside matched serum metabolomes and clinical profiles, from 100 pregnant women (50 with PTB and 50 with term birth) across early, middle, and late pregnancy. We reveal that although the maternal gut virome is highly personalized and longitudinally stable within individuals, PTB is characterized by reduced virome convergence and specific alterations in viral populations emerging during mid-to-late pregnancy. Host-phage analyses identify remodeling of Klebsiella- and Prevotella-associated viral communities linked to PTB risk. PTB-associated virome alterations are further associated with amino acid metabolic remodeling, particularly glutamate- and aspartate-related pathways, supported by reproducible virus-metabolite associations and enriched viral auxiliary metabolic genes. In addition, L-aspartate partly mediates associations between monocyte-related inflammatory indices and PTB. Multi-omics modeling demonstrates that virome-metabolome signatures achieve strong predictive performance for both PTB and imminent delivery, with viral features contributing substantially to prediction accuracy and retaining predictive value in external validation. Collectively, these findings highlight the maternal virome and its metabolic signatures as key determinants of PTB susceptibility.