Faecalibacterium prausnitzii EXL01 Strain for the prevention of multiple-recurrent Clostridioides difficile Infection.

BACKGROUND AND AIMS: Recurrent Clostridioides difficile infection (rCDI) results from persistent microbiome dysfunction and impaired colonization resistance. Although fecal microbiota transplantation (FMT) is effective, defined and scalable alternatives are needed. We evaluated whether a single commensal strain could restore key microbiome functions and prevent recurrence.

METHODS

We assessed Faecalibacterium prausnitzii EXL01 in a murine CDI model and a multicenter, open-label single-arm phase I trial including adults with ≥3 CDI episodes. Following vancomycin preconditioning, patients received oral EXL01 for 8 weeks with 8-week follow-up. Primary endpoint was safety. Secondary endpoints included recurrence at week 8. Longitudinal stool samples underwent shotgun metagenomics and metabolomics. Outcomes were benchmarked against matched FMT cohorts. Additional in vitro and murine studies of EXL01 were performed.

RESULTS

In mice, EXL01 reduced C. difficile burden and intestinal inflammation in an antibiotic-disrupted murine model. Six patients were treated; no treatment-related serious adverse events occurred. Five of six patients (83.3%) remained recurrence-free at week 8, comparable to matched FMT cohorts. EXL01 was detectable in stool up to 8 weeks post-treatment. Multi-omics analyses showed that EXL01 engraftment was correlated with restoration of bile acid metabolism, including reduced primary bile acids and increased secondary bile acids, and increased short-chain fatty acid production, particularly butyrate, despite limited taxonomic recovery. EXL01 selectively deconjugated bile acids in vitro.

CONCLUSIONS

A single, well-characterized bacterial strain was associated with restoration of key microbiome functions and low recurrence rates in high-risk rCDI. These findings support precision microbiome therapeutics targeting ecosystem function rather than taxonomic complexity. Controlled trials are ongoing. (clinicaltrials.gov; NCT06306014).