A Synthetic Probiotic Engineered for Colorectal Cancer Therapy Modulates Gut Microbiota

Abstract

Background: Successful chemoprevention or chemotherapy is achieved through targeted delivery of prophylactic agents during initial phases of carcinogenesis or therapeutic agents to malignant tumors. Bacteria can be used as anticancer agents, but efforts to utilize attenuated pathogenic bacteria suffer from the risk of toxicity or infection. Lactic acid bacteria are safe to eat and often confer health benefits, making them ideal candidates for live vehicles engineered to deliver anticancer drugs.Results: In this study, we developed an effective bacterial drug delivery system for colorectal cancer (CRC) therapy using the lactic acid bacterium Pediococcus pentosaceus. It is equipped with dual gene cassettes driven by a strong inducible promoter that encode the therapeutic protein P8 fused to a secretion signal peptide and a complementation system. In an inducible CRC cell-derived xenograft mouse model, our synthetic probiotic significantly reduced tumor volume and inhibited tumor growth relative to the control. Mice with colitis-associated CRC induced by azoxymethane and dextran sodium sulfate exhibited polyp regression and recovered taxonomic diversity when the engineered bacterium was orally administered. Further, the synthetic probiotic modulated gut microbiota and alleviated the chemically induced dysbiosis. Correlation analysis demonstrated that specific bacterial taxa potentially associated with eubiosis or dysbiosis, such as Akkermansia or Turicibacter, have positive or negative relationships with other microbial members.Conclusions: Taken together, our work illustrates that an effective and stable synthetic probiotic composed of P. pentosaceus and the P8 therapeutic protein can reduce CRC and contribute to rebiosis, and the validity and feasibility of cell-based designer biopharmaceuticals for both treating CRC and ameliorating impaired microbiota.

Gut Microbiota: A Potential Target for Cancer Interventions

“…130 More recently, Chung et al synthesized stable synthetic probiotics using Pediococcus pentosaceus and P8 therapy protein that ameliorated azoxyMethane and Dextran sodium sulfate-induced colitis-associated CRC impaired flora, while tumor growth and tumor volume were significantly inhibited. 131 Furthermore, Lactobacillus kefiri LKF01 is safe and effective in preventing severe diarrhea in cancer patients receiving 5-FU or capecitabine-based treatment. 132 Prebiotics are usually fibers or polyphenols that cannot be digested by the host and are selectively used by gut microbes to produce health benefits.…”