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Impact of investigational microbiota therapeutic RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial.

ABSTRACT: BACKGROUND: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. RESULTS: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. CONCLUSIONS: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. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02299570 . Registered 19 November 2014 Video Abstract.

SUBMITTER: Kwak S

PROVIDER: S-EPMC7457799 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Impact of investigational microbiota therapeutic RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial.

Kwak Suryang S Choi JooHee J Hink Tiffany T Reske Kimberly A KA Blount Kenneth K Jones Courtney C Bost Margaret H MH Sun Xiaoqing X Burnham Carey-Ann D CD Dubberke Erik R ER Dantas Gautam G

Microbiome 20200831 1

<h4>Background</h4>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 i ...[more]

PMID: 32862830

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Project description:BackgroundRBX2660 is an investigational microbiota restoration therapy in phase 3 clinical development for preventing recurrent Clostridioides difficile infections (CDIs). In a randomized, double-blinded placebo-controlled phase 2B trial, RBX2660 was effective at preventing CDI recurrence. The current study was performed to characterize the fecal bacterial microbiome before and after treatment among RBX2660- or placebo-treated responders in that trial.MethodsSamples were sequenced using 16S methods, and the resulting relative abundance data were fit to a Dirichlet-multinomial distribution to determine group mean relative taxonomic abundance and overdispersion at the class level. Alpha diversity was determined for all samples. Biostatistical tools, including effect size and repeated-measures analysis, were applied to evaluate the statistical significance of observed changes.ResultsAt study entry, subjects' microbiomes were dominated by Gammaproteobacteria and Bacilli, with low abundance of Bacteroidia and Clostridia. After treatment, Bacteroidia, Clostridia, and alpha diversity increased among RBX2660 responders, concomitant with a decrease of Gammaproteobacteria and Bacilli. The resulting compositions differed significantly from baseline compositions, and the changes among RBX2660 responders differed significantly from those in placebo responders, in whom Bacteroidia or Gammaproteobacteria abundance did not change as much. Repeated-measures analyses indicated more rapid and extensive microbiome remodeling among RBX2660 responders compared with placebo responders, and effect size analyses revealed that RBX2660 responders' microbiomes became more similar to the RBX2660 composition, also compared with placebo responders.ConclusionsPrevention of recurrent CDI with RBX2660 was associated with restorative microbiome changes that may help resist C. difficile colonization and recurrence. RBX2660 was more effective than placebo at restoring participant microbiomes.

Project description:Microbiota transplant is becoming a popular process to restore or initiate "healthy" gut microbiota and immunity. But, the potential risks of the related practices need to be carefully evaluated. This study retrospectively examined the resistomes of donated fecal microbiota for treating intestinal disorders, vaginal microbiota of pregnant women, and infant fecal microbiota from rural and urban communities, as well as the impact of transplants on the fecal resistome of human and animal recipients. Antibiotic resistance (AR) genes were found to be abundant in all donor microbiota. An overall surge of resistomes with higher prevalence and abundance of AR genes was observed in the feces of all transplanted gnotobiotic pigs as well as in the feces of infant subjects, compared to those in donor fecal and maternal vaginal microbiota. Surprisingly, transplants using rural Amish microbiota led to more instead of less AR genes in the fecal microbiota of gnotobiotic pigs than did transplants using urban microbiota. New AR gene subtypes undetected originally also appeared in gnotobiotic pigs, in Crohn's Disease (CD) patients after transplant, and in feces of infant subjects. The data illustrated the key role of the host gastrointestinal tract system in amplifying the ever-increasing AR gene pool, even without antibiotic exposure. The data further suggest that the current approaches of microbiota transplant can introduce significant health risk factor(s) to the recipients, and newborn human and animal hosts with naïve gut microbiota were especially susceptible. Given the illustrated public health risks of microbiota transplant, minimizing massive and unnecessary damages to gut microbiota by oral antibiotics and other gut impacting drugs becomes important. Since eliminating risk factors including AR bacteria and opportunistic pathogens directly from donor microbiota is still difficult to achieve, developing microbial cocktails with defined organisms and functions has further become an urgent need, should microbiota transplantation become necessary.

Project description:BackgroundThe selection pressure exercised by antibiotic drugs is an important consideration for the wise stewardship of antimicrobial treatment programs. Treatment decisions are currently based on crude assumptions, and there is an urgent need to develop a more quantitative knowledge base that can enable predictions of the impact of individual antibiotics on the human gut microbiome and resistome.ResultsUsing shotgun metagenomics, we quantified changes in the gut microbiome in two cohorts of hematological patients receiving prophylactic antibiotics; one cohort was treated with ciprofloxacin in a hospital in Tübingen and the other with cotrimoxazole in a hospital in Cologne. Analyzing this rich longitudinal dataset, we found that gut microbiome diversity was reduced in both treatment cohorts to a similar extent, while effects on the gut resistome differed. We observed a sharp increase in the relative abundance of sulfonamide antibiotic resistance genes (ARGs) by 148.1% per cumulative defined daily dose of cotrimoxazole in the Cologne cohort, but not in the Tübingen cohort treated with ciprofloxacin. Through multivariate modeling, we found that factors such as individual baseline microbiome, resistome, and plasmid diversity; liver/kidney function; and concurrent medication, especially virostatic agents, influence resistome alterations. Strikingly, we observed different effects on the plasmidome in the two treatment groups. There was a substantial increase in the abundance of ARG-carrying plasmids in the cohort treated with cotrimoxazole, but not in the cohort treated with ciprofloxacin, indicating that cotrimoxazole might contribute more efficiently to the spread of resistance.ConclusionsOur study represents a step forward in developing the capability to predict the effect of individual antimicrobials on the human microbiome and resistome. Our results indicate that to achieve this, integration of the individual baseline microbiome, resistome, and mobilome status as well as additional individual patient factors will be required. Such personalized predictions may in the future increase patient safety and reduce the spread of resistance.Trial registrationClinicalTrials.gov, NCT02058888 . Registered February 10 2014.

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Impact of investigational microbiota therapeutic RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial.

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Impact of investigational microbiota therapeutic RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial.

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