A designed synthetic microbiota provides insight to community function in Clostridioides difficile resistance

Abstract

Clostridioides difficile , a major cause of antibiotic-associated diarrhea, is suppressed by the gut microbiome, but the precise mechanisms are not fully described. Through a meta-analysis of 12 human studies, we designed a synthetic fecal microbiota transplant (sFMT1) by reconstructing microbial networks negatively associated with C. difficile colonization. This lab-built 37-strain consortium formed a functional community suppressing C. difficile in vitro and in animal models. Using sFMT1 as a tractable model system, we find that bile acid 7α-dehydroxylation is not a determinant of sFMT1 efficacy while one strain performing Stickland fermentation—a pathway of competitive nutrient utilization—is both necessary and sufficient for the suppression of C. difficile , replicating the efficacy of a human fecal transplant in a gnotobiotic mouse model. Our data illustrate the significance of nutrient competition in suppression of C. difficile and a generalizable approach to interrogating complex community function through robust methods to leverage publicly available sequencing data. • Machine learning designs microbial communities through robust cross-cohort signals • Synthetic consortia form stable communities in vivo suppressing C. difficile • Proline-fermenting strains are necessary and sufficient for C. difficile repression • P. anaerobius is as efficacious as a human fecal transplant in a gnotobiotic model Tian et al. leverage meta-analysis of human studies to design a synthetic fecal transplant as an alternative approach for managing C. difficile infection. Through multi-omics characterization and iterative reduction of community complexity, they identify a single proline-fermenting strain as necessary and sufficient for suppressing C. difficile infection in mice.

Topics & Concepts