Framework for rational donor selection in fecal microbiota transplant clinical trials.

Claire Duvallet,Caroline Zellmer,Pratik Panchal,Shrish Budree,Eric J Alm,Majdi Osman,Franck Carbonero

doi:10.1371/journal.pone.0222881

Claire Duvallet, Caroline Zellmer + Show 5 more

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https://doi.org/10.1371/journal.pone.0222881

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Abstract

Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact.

Highlights

Fecal microbiota transplantation (FMT) is the transfer of gut bacteria through whole stool from a healthy donor to a recipient
This framework represents an approach for optimizing the success of FMT clinical trials given that a clinician is already pursuing a trial, and is not intended to be used for deciding whether or not an FMT trial should be pursued in the first place
In cases where the microbial signature for FMT response is expected to be large, we found that small FMT trials would recover most of the top hits in the majority of cases

Summary

Introduction

Fecal microbiota transplantation (FMT) is the transfer of gut bacteria through whole stool from a healthy donor to a recipient. FMT has demonstrated high cure rates in recurrent C. difficile infection (CDI) across multiple randomized, placebo-controlled trials [1] and has entered standard of care for multiply recurrent CDI in European and North American guidelines [2,3,4]. Beyond CDI, FMT is being explored in range of microbiome-mediated diseases, and has demonstrated promising results in inflammatory bowel diseases [5,6,7,8,9,10]. Despite these early successes, the underlying mechanism of FMT across all disease indications, including CDI, remains unclear.

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