Suryang Kwak1, JooHee Choi1, Tiffany Hink1, Kimberly A. Reske1, Kenneth Blount2, Courtney Jones2, Margaret H. Bost1, Xiaoqing Sun1, Carey-Ann D. Burnham1, Erik R. Dubberke1, Gautam Dantas1
1Washington University in Saint Louis School of Medicine, 2Rebiotix Inc
Intestinal microbiota restoration can be achieved by replacing a subject’s perturbed microbiota with that of a healthy donor. Recurrent Clostridioides diffcile infection (rCDI) is one key application of such treatment. Another application of interest is depletion of antibiotic resistant genes (ARGs) and organisms (AROs). In this study, we investigated fecal specimens from a multicenter, randomized, double-blind, placebo-controlled phase 2b study of microbiota-based investigational drug RBX2660. Patients were administered either placebo, 1 dose of RBX2660 and 1 placebo, or 2 doses of RBX2660 via enema and longitudinally tracked for changes in their microbiome and antibiotic resistome.
All patients exhibited significant recovery of gut microbiome diversity and decrease of ARG abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts towards healthier configurations were more significant and longer lasting in RBX2660 recipients compared to placebo. We identified 18 taxa and 21 metabolic functions distinguishing the baseline microbiome of non-transplanted patients, and the majority of features were correlated to intrinsic vancomycin resistance. We also identified 7 patient-specific and 3 RBX2660-specific ARGs and tracked their dynamics post treatment. Whole genome sequencing of AROs cultured from RBX2660 product and patient samples indicate ARO eradication in patients via RBX2660 administration, but also, to a lesser extent, introduction of RBX2660-derived AROs.
By including a placebo group, we distinguished the effects of RBX2660 from baseline postantibiotic microbiome dynamics. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG abundance, but RBX2660 administration more rapidly and completely changed the composition of patients’ microbiome, resistome, and ARO colonization by transplanting RBX2660 microbiota into the recipients. Although ARGs and AROs were transmitted through RBX2660, the resistome post-RBX2660 more closely resembled that of the administered product —a proxy for the donor—than an antibiotic perturbed state.
Microbiota-based therapy, Placebo, Microbiome, Resistome, Clostridioides diffcile infection, Antibiotic resistant organisms