Abstract Bioactive materials that sense environmental signals and dynamically regulate metabolic outputs hold great promise for responsive biomanufacturing and therapeutic applications. However, anaerobic microbial bioreactors remain highly vulnerable to oxygen exposure, limiting their robustness and functional stability under normal conditions. Here, we developed an oxygen‐responsive living bioreactor that converts oxygen from an inhibitory factor into a programmable stimulus for sustained anaerobic metabolite production. Using indole‐3‐propionic acid (IPA) as a model output, we established a two‐step strategy combining aerobic‐anaerobic metabolic fusion with interspecies protoplast fusion to genetically embed oxygen tolerance into an anaerobic IPA‐producing chassis, generating the fusion strain (P‐ Cs .HN01/P‐ Bs .168). This engineering system enables robust and high‐level IPA biosynthesis under aerobic conditions without depending on external aerobic partners. Importantly, the enhanced oxygen tolerance and IPA productivity were stably maintained over successive passages, demonstrating that the phenotype is genetically encoded rather than conditionally induced. Functional validation in deoxynivalenol induced intestinal injury models in mice and piglets revealed that fermentation‐derived IPA produced by P‐ Cs .HN01/P‐ Bs .168 engineering bioreactor exerted pronounced protective and detoxifying effects in vivo. Collectively, this work provides a generalizable framework for converting transient microbial interactions into stable, oxygen‐responsive living materials for anaerobic biomanufacturing and biomedical applications.
Ma et al. (2026) studied this question.