Engineering commensal Lachnospiraceae for programmable therapeutic delivery in the gut [Host RNA-seq]

Lachnospiraceae are a prevalent and abundant family in the human gut microbiome that produce metabolites linked to intestinal and metabolic health1. Despite their promise as engineered live biotherapeutics, genetic manipulation of Lachnospiraceae remains challenging.

Here, we develop a modular toolkit for Lachnospiraceae engineering, including constitutive and inducible expression and chromosomal integration systems. Applying this toolkit to the native commensal Coprococcus comes, we program secretion of the mammalian cytokine interleukin-22 (IL-22) in the mouse intestinal tract, where it induces epithelial defense transcriptional programs. In a mouse model of metabolic dysfunction-associated steatotic liver disease, IL-22–secreting C. comes improves glucose homeostasis, reduces systemic endotoxemia and attenuates hepatic steatosis.