Butyrate-producing bacteria in pregnancy maintenance: mitigating dysbiosis-induced preterm birth

BACKGROUND: Preterm birth (PTB) is a major contributor to neonatal morbidity, mortality, and long-term health complications. Despite advances in perinatal care, PTB rates remain high, and its multifactorial etiology is not fully understood. Increasing evidence suggests that maternal gut microbiota plays a critical role in pregnancy maintenance, potentially through modulation of immune responses. However, the underlying causal mechanisms remain unclear. We hypothesized that dysbiosis disrupts immune tolerance and promotes PTB, and that butyrate (short-chain fatty acid produced by specific gut bacteria) may counteract this effect by enhancing regulatory T cell (Treg)-mediated immune regulation. METHODS: We established a dysbiosis-induced PTB mouse model using vancomycin treatment combined with subclinical immune activation via anti-CD3ε antibody. Pregnant mice were fed either a standard or butyrate-enriched diet. Outcomes included gestational length, PTB incidence, live pup rates, and Treg cell levels assessed by flow cytometry. Parallelly, 16S rRNA gene sequencing was performed on fecal samples from 32 pregnant women to compare gut microbial composition between spontaneous PTB and term birth groups. Multivariate logistic regression and correlation analyses were conducted to assess associations with gestational outcomes. RESULTS: Vancomycin-induced dysbiosis in mice significantly reduced Treg cell populations and increased PTB rates (43.3% in dysbiosis vs. 0% in controls; p < 0.05), while butyrate supplementation reduced PTB incidence (p = 0.03), prolonged gestation (p = 0.01), and restored Treg counts (p < 0.001). In human samples, significant reductions in Lachnospiraceae and Ruminococcaceae, representative butyrate-producing bacteria, were seen in PTB cases. Their combined abundance was independently associated with sPTB risk (p = 0.019) and positively correlated with gestational age (r = 0.59, p < 0.001). CONCLUSIONS: Our findings demonstrate that maternal dysbiosis increases PTB risk via impaired immune tolerance, and that butyrate supplementation effectively reverses this effect in vivo. Human data support the translational relevance of butyrate-producing microbiota in pregnancy maintenance. These results highlight butyrate as a promising target for dietary interventions aimed at reducing PTB incidence by restoring immune homeostasis. Trial registration Not applicable.