Framework for rational donor selection in fecal microbiota transplant clinical trials

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.

From Donor to Patient: Collection, Preparation and Cryopreservation of Fecal Samples for Fecal Microbiota Transplantation

“…A rationalization of the classification of donors in addition to their selection should optimize targeting and increase the probability of success of FMT clinical trials. A classification of genome-and microbiome-associated and metagenomic analysis (e.g., short-chain fatty acid concentration) of the host phenotype is a starting framework for rational donor classification by FMT banks [37]. The effectiveness of FMT probably depends on the ability of the donor to provide the necessary taxa capable of restoring metabolic deficits in recipients who contribute to the disease.…”

In Situ Profiling of the Three Dominant Phyla Within the Human Gut Using TaqMan PCR for Pre-Hospital Diagnosis of Gut Dysbiosis

“…Fecal microbiota transplantation (FMT) is a novel therapy for UC that restores the composition and function of the bacterial flora in the gut [31,32]. For FMT to be successful, it is crucial to characterize the presence and absence of individual taxa in the samples of potential fecal donors and UC patients [33]. For decades, next-generation sequencing (NGS) has been used to analyze gut microbiota [34].…”

“…For decades, next-generation sequencing (NGS) has been used to analyze gut microbiota [34]. Despite the popularity of NGS, the cost and time constraints make it difficult for emergency services to employ it [33][34][35]. In addition, and of concern because the number of UC patients is rapidly increasing [36], it is more costly to monitor the clinical efficacy of FMT (i.e., analyzing the gut microbiota) of numerous people with NGS.…”

Re-Evaluating the Evidence for Faecal Microbiota Transplantation ‘Super-Donors’ in Inflammatory Bowel Disease

“…When 16S rRNA gut microbiota composition data were available, we tested for associations between donor material α-diversity and patient outcomes, 23,24,28 since part of the motivation for using pools of stool from multiple donors is the hypothesis that high bacterial diversity in FMT material is beneficial. 13,19,29,37 When possible, we also . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

“…6,[9][10][11][12] If FMT's efficacy varied widely across stools or donors, then rational selection of FMT material based on biomarkers predictive of efficacy could improve the clinical practice of FMT. 6,11,13,14 Differences in FMT efficacy between stool donors or specific stools could be also an important starting point for scientific investigations into the "active ingredient"…”