An Artificial Microbiome Consortium Prevents Recurrence of Clostridioidesdifficile Infection: Paving the Way for Fecal Microbiota Transplantation 2.0

Abstract

Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N Engl J Med 2022;386:220–229. Increasing evidence suggests that fecal microbiota transplantation (FMT) is more effective than antibiotics in treating and preventing recurrent Clostridioides difficile infection (rCDI). However, FMT carries a risk of transmission of burdensome pathogens. Feuerstadt et al assessed the efficacy of SER-109, an experimental microbiome therapeutic made of live purified Firmicutes bacterial spores, in reducing the risk of rCDI. One hundred eighty-two patients with rCDI were randomized 1:1 to receive SER-109 or placebo (4 capsules daily for 3 days). They were subsequently followed up over the next 8 weeks to assess recurrence of CDI. Rates of CDI recurrence were significantly lower in the SER-109 group than in the placebo group (12% vs 40%; relative risk, 0.32; 95% CI, 0.18–0.58); these findings were seen regardless of age stratification (younger than 65 years or older than 65 years) or type of antibiotic used in previous episodes of CDI (vancomycin or fidaxomicin). There were no serious adverse events related to SER-109. Engraftment of SER-109 dose species started by week 1 and gradually increased and persisted through to week 8. Microbiome changes in the treatment group showed declines in proinflammatory Enterobacteriaceae and increases in favorable Firmicutes (eg, Lachnospiraceae), the latter known to produce secondary bile acids that inhibit C difficile spore germination. The main study limitations include the low representation of minority patients, as nearly 90% of enrolled patients were White, and the absence of pre-antibiotic microbiome samples, which prevents assessment of the effect of SER-109 in patients without recent history of antibiotic treatment. However, this randomized controlled trial provides further evidence that artificial microbial consortia may be a promising approach to treating rCDI. Targeted manipulation of the gut microbiome with microbial consortia may overcome issues related to donor safety and shortages associated with classical FMT. Given that these approaches are likely to be more expensive, it would be important for future studies to compare synthetic microbial consortia with standard FMT. If these are better or equivalent to classical FMT, then this will herald the era of FMT 2.0.