Engineering commensal Lachnospiraceae for programmable therapeutic delivery in the mouse gut

Abstract Engineered native gut bacteria could offer persistent, programmable therapeutic delivery in the gut, but many dominant taxa remain genetically intractable. Members of one such family of obligate anaerobic Clostridia, Lachnospiraceae, are prevalent in the human gut microbiome and produce metabolites linked to intestinal and metabolic health. Here we report a modular toolkit for engineering Lachnospiraceae, including constitutive and inducible expression, chromosomal integration and secretion systems. Applying this toolkit to gut native Coprococcus comes , we programmed the secretion of cytokine interleukin-22 (IL-22) in the mouse intestinal tract, where it induces epithelial defence transcriptional programmes. In a mouse model of metabolic dysfunction-associated steatotic liver disease, IL-22-secreting C. comes improved glucose homeostasis, reduced systemic endotoxemia and attenuated hepatic steatosis. This work demonstrates that native Lachnospiraceae can be genetically programmed to modulate host metabolic and immune physiology. The toolkit provides a foundation for the development of Lachnospiraceae-derived engineered therapeutics and for dissecting causal relationships between commensal gene programmes and host physiology.