An engineered Clostridial mini-consortium modulates intestinal inflammation
Modern lifestyle factors have altered gut microbiota composition and function. Clostridia are known to modulate intestinal immunity through various mechanisms including unique production of secondary bile acids. Here, we present a novel system to study how the metabolite isodeoxycholic acid (isoDCA) modulates 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 RORgt+FoxP3+ regulatory T cells (pTregs) through a mechanism requiring both the Takeda G protein-coupled receptor 5 (TGR5) and the Farnesoid X receptor (FXR). Lastly, this isoDCA+ consortium protected against colitis in an adoptive T cell transfer model by reshaping the microbiota and suppressing host inflammation.