Advances in synthetic biology toolboxes paving the way for mechanistic understanding and strain engineering of gut commensal Bacteroides spp. and Clostridium spp.

The gut microbiota plays a significant role in influencing human immunity, metabolism, development, and behavior by producing a wide range of metabolites. While there is accumulating data on several microbiota-derived small molecules that contribute to host health and disease, our knowledge regarding the molecular mechanisms underlying metabolite-mediated microbe-host interactions remains limited. This is primarily due to the lack of efficient genetic tools for most commensal bacteria, especially those belonging to the dominant phyla Bacteroides spp. and Clostridium spp., which hinders the application of synthetic biology to these gut commensal bacteria. In this review, we provide an overview of recent advances in synthetic biology tools developed for the two dominant genera, as well as their applications in deciphering the mechanisms of microbe-host interactions mediated by microbiota-derived small molecules. We also discuss the potential biomedical applications of engineering commensal bacteria using these toolboxes. Finally, we share our perspective on the future development of synthetic biology tools for a better understanding of small molecule-mediated microbe-host interactions and their engineering for biomedical purposes.