A specific bacterial consortium restores resistance against Clostridioides difficile through gut metabolites.

The gut microbiota is a major factor underlying Clostridioides difficile infection (CDI) that determines vulnerability to the infection. Restoration of gut microbiota balance using a bacterial consortium represents a promising therapeutic approach. Here, we identified a CDI-resistant consortium (CDRC) comprising Blautia producta, Blautia faecis, Enterococcus faecium, and Clostridium scindens through stepwise microbiome analysis and in vivo evaluation. We adopted a progressive reductionist approach to elucidate the interplay among these bacterial constituents, their functions, and their impact on CDI resistance. Through ex vivo experiments, bacterial genome analysis, and metabolite profiling, we confirmed the synergistic effect of the CDRC, derived from interbacterial interactions, and the effect of associated metabolites (deoxycholic acid, lactic acid, succinic acid, and inositol). Additionally, the clinical scalability of the CDRC was confirmed using a humanized microbiota mouse model. Our study offers valuable insight into consortium research, serving as a guide for the rational design of microbiome-derived therapeutics.