Gut microbiota-derived 1H-Indole-3-propanoic acid deficiency mediates BPB-induced decidualization impairment via TLR4/NF-κB pathway

As an important alternative to bisphenol A (BPA), the reproductive toxicity of bisphenol B (BPB) has drawn increasing concern, but the mechanism by which BPB impairs uterine decidualization remains unclear. This study investigated whether early pregnancy BPB exposure impairs decidualization via the "gut microbiota-1H-Indole-3-propanoic acid (IPA)-Toll-like receptor 4/nuclear factor kappa-B (TLR4/NF-κB)" axis. Results showed that BPB inhibited embryo implantation, decidual cell proliferation, angiogenesis, and disrupted intestinal barrier integrity. 16S rRNA sequencing and metabolomics revealed that BPB induced gut dysbiosis (reduction in Lactobacillus) and decreased serum IPA, with IPA positively correlated with Lactobacillus abundance. Network pharmacology predicted that IPA targets were enriched in the TLR4/NF-κB pathway. Fecal microbiota transplantation confirmed that transferring BPB-exposed microbiota replicated decidualization impairment and IPA reduction. Exogenous IPA supplementation inhibited BPB-induced TLR4/NF-κB activation and inflammatory cytokine release, and rescued decidualization. The TLR4 inhibitor TAK-242 partially restored decidualization function. In summary, early pregnancy BPB exposure reduces IPA-producing bacteria such as Lactobacillus, leading to decreased IPA, which subsequently activates the uterine TLR4/NF-κB pathway and impairs decidualization. Supplementation of IPA or TLR4 inhibition effectively rescues this impairment, providing a potential target for intervention in environmentally related reproductive disorders.