Suryang Kwak1,2,† , JooHee Choi1,†, Tiffany Hink3, Kimberly A. Reske3, Kenneth Blount4, Courtney Jones4, Margaret H. Bost3, Xiaoqing Sun1,2, Carey-Ann D. Burnham2,3,6, Erik R. Dubberke3,*, Gautam Dantas1,2,5,6,* and for the CDC Prevention Epicenter Program
1The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA. 2Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine in St. Louis, St.
Louis, MO 63110, USA. 3Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA. 4Rebiotix Inc. a Ferring Company, Minneapolis, MN 55113, USA. 5Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, USA. 6Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
†Suryang Kwak and JooHee Choi contributed equally to this work
Intestinal microbiota restoration can be achieved by complementing a subject’s perturbed microbiota with that of a healthy donor. Recurrent Clostridioides difficile infection (rCDI) is one key application of such treatment. Another emerging application of interest is reducing 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 a decrease of ARG relative abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts toward average configurations from unperturbed individuals were more significant and longer-lasting in RBX2660 recipients compared to placebo. We quantified microbiome and resistome modification by RBX2660 using a novel “transplantation index” metric. We identified taxonomic and metabolic features distinguishing the baseline microbiome of non-transplanted patients and taxa specifically enriched during the process of transplantation. We elucidated the correlation between resistome and taxonomic transplantations and post-treatment dynamics of patient-specific and RBX2660-specific ARGs. 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.
Through shotgun metagenomic sequencing, we elucidated the effects of RBX2660 in the microbiome and resistome. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG relative 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.
ClinicalTrials.gov, NCT02299570. Registered 19 November 2014