Bacteria-based therapeutics are engineered live microbial cells that produce a drug or perform a metabolic function while inhabiting a specific physiological niche on or within the host. This targeted therapeutic approach can help minimize negative side effects associated with many drugs (e.g., off-target toxicity from intravenous chemotherapy distributed throughout the entire body). Antibody therapies are also traditionally administered intravenously, but do not accumulate to high levels in the gut and thus have limited impact on gut disease. On the other hand, bacterial therapeutics allow production of antibodies directly within the gut. Current bacterial therapies utilize transient colonizers of the human body (e.g., Escherichia coli, Lactococcus lactis, Salmonella typhimurium), limiting applications in long-term disease treatment and monitoring. Bacteroides species, are long-term stable colonizers of the human gut and are thus a promising for developing long-term bacterial therapeutics and diagnostics. Bacteroides also benefit from already being highly abundant and prevalent in the human gut microbiota. However, more work is required in identifying and optimizing protein secretion machinery for Bacteroides species.

This technology is a molecular toolkit for engineering of the stable gut colonizing bacteria Bacteroides thetaiotaomicron. The system allows expression and secretion of protein cargos from multiple Bacteroides species. In contrast to transient colonizers such as E. coli, Bacteroides can be better leveraged for long-term therapeutic and diagnostic applications, providing a platform for targeted approaches to the treatment of ailments such as cancer and gut-related diseases.

Benefits

Effective secretion achieved in multiple Bacterioides speices. Preserved function for the secreted cargo.

Application

Bacterial-based therapeutics, Gut microbiome

Publication

Yeh, YH., Kelly, V.W., Rahman Pour, R. et al. A molecular toolkit for heterologous protein secretion across Bacteroides species. Nat Commun 15, 9741 (2024). https://doi.org/10.1038/s41467-024-53845-7 [2]