Live Biotherapeutic Zowell Reprograms Microbiota–Lipid Crosstalk to Enhance Cisplatin Efficacy in Lung Cancer

Background: Lung cancer (LC) remains a leading cause of cancer-related mortality, often compounded by suboptimal chemotherapy efficacy and systemic toxicity. Emerging evidence implicates the gut microbiota in modulating tumor progression, immune function, and treatment outcomes. Methods: We evaluated Zowell, a novel live bacterial therapeutic (LBT) developed via LiveBiom® co-fermentation, as an adjunct to cisplatin in a murine LC model harboring humanized microbiota. Mice were assigned to treatment groups: Zowell alone, cisplatin alone, their combination, and fecal microbiota transplantation (FMT) as a benchmark. Results: Zowell monotherapy significantly reduced tumor burden, and its combination with cisplatin produced synergistic anti-tumor effects. 16S rRNA sequencing revealed enrichment of beneficial taxa (Bifidobacterium, Lactobacillus, and Allobaculum) and suppression of contextual genera (Clostridium and Akkermansia). Treatment rebalanced gut ecology, evidenced by a lowered Firmicutes/Bacteroidetes ratio and increased alpha diversity. Zowell outperformed FMT in reducing tumor volume and inflammatory indices. Lipidomic profiling of tumor tissues identified elevated levels of immunomodulatory lipid mediators, including resolvins and prostanoids, suggesting remodeling of the tumor microenvironment toward inflammation resolution and immune activation. Conclusions: These findings support Zowell as a precision microbiome therapeutic that potentiates chemotherapy through gut microbial reprogramming and tumor lipid signaling modulation, offering translational promise for enhancing immunotherapeutic response and mitigating chemotherapy-induced toxicity.