An engineered Clostridial mini consortium modulates intestinal inflammation

Abstract

Modern lifestyle factors have altered gut microbiota composition and function. Bacteria in the Clostridia class modulate mucosal immune responses through various mechanisms including production of secondary bile acids (SBA). Here, we present a novel system to study how the SBA isodeoxycholic acid (isoDCA) regulates host immunity. Through targeted mutagenesis of bile acid epimerization genes, we engineered Ruminococcus gnavus to ablate isoDCA production. Combining R. gnavus (WT or KO) with Peptacetobacter hiranonis created a two-member consortium that toggles isoDCA production on or off while keeping all other variables constant. Using this system, we demonstrate that isoDCA induces colonic lamina propria RORγt⁺Foxp3⁺ regulatory T cells (pTregs) through a mechanism requiring both the Takeda G protein-coupled receptor 5 (TGR5) and the Farnesoid X receptor (FXR). Engraftment of this isoDCA+ consortium protected against colitis in an adoptive T cell transfer model by reshaping the microbiota and suppressing host inflammation.