Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics

Abstract

BackgroundFecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection and shows promise for treating other medical conditions associated with intestinal dysbioses. However, we lack a sufficient understanding of which microbial populations successfully colonize the recipient gut, and the widely used approaches to study the microbial ecology of FMT experiments fail to provide enough resolution to identify populations that are likely responsible for FMT-derived benefits.MethodsWe used shotgun metagenomics together with assembly and binning strategies to reconstruct metagenome-assembled genomes (MAGs) from fecal samples of a single FMT donor. We then used metagenomic mapping to track the occurrence and distribution patterns of donor MAGs in two FMT recipients.ResultsOur analyses revealed that 22% of the 92 highly complete bacterial MAGs that we identified from the donor successfully colonized and remained abundant in two recipients for at least 8 weeks. Most MAGs with a high colonization rate belonged to the order Bacteroidales. The vast majority of those that lacked evidence of colonization belonged to the order Clostridiales, and colonization success was negatively correlated with the number of genes related to sporulation. Our analysis of 151 publicly available gut metagenomes showed that the donor MAGs that colonized both recipients were prevalent, and the ones that colonized neither were rare across the participants of the Human Microbiome Project. Although our dataset showed a link between taxonomy and the colonization ability of a given MAG, we also identified MAGs that belong to the same taxon with different colonization properties, highlighting the importance of an appropriate level of resolution to explore the functional basis of colonization and to identify targets for cultivation, hypothesis generation, and testing in model systems.ConclusionsThe analytical strategy adopted in our study can provide genomic insights into bacterial populations that may be critical to the efficacy of FMT due to their success in gut colonization and metabolic properties, and guide cultivation efforts to investigate mechanistic underpinnings of this procedure beyond associations.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0270-x) contains supplementary material, which is available to authorized users.

Restoration of short chain fatty acid and bile acid metabolism following fecal microbiota transplantation in patients with recurrent Clostridium difficile infection

“…Studies using genome assembly from metagenomic data to track transplantation of microbes during FMT, which provides more discrete taxonomic resolution than 16S rRNA gene-based surveys, have made similar observations (52, 53). A recent study in two patients with CDI treated with FMT demonstrated that Bacteroidales, but not Clostridiales, were more likely to colonize individuals (52).…”

“…A recent study in two patients with CDI treated with FMT demonstrated that Bacteroidales, but not Clostridiales, were more likely to colonize individuals (52). Following FMT in obese individuals, Li et al identified that the dominance and resilience of transplanted species such as Roseburia hominis , Ruminococcus lactaris , and Akkermansia muciniphila were not consistently observed across individuals (53).…”

High-throughput isolation and sorting of gut microbes reduce biases of traditional cultivation strategies

“…In this study, we used a single stool sample collected previously from a fecal microbiota transplant donor [52]. Sample collection was approved by University of Chicago Ethics Committee and by the University of Chicago Institutional Review Board (IRB 132-0212) and written and informed consent was obtained for the stool donor.…”

Control of Clostridium difficile Infection by Defined Microbial Communities

“…This suppression of Proteobacteria populations may play an important role in resetting intestinal immune homeostasis, as several species of Proteobacteria are capable of thriving in the inflamed intestine and perpetuating continued inflammation (reviewed in (162)) The stability and similarity of recipients’ microbiota following transplant when compared to donor can vary, suggesting that some microbiota compositions may be more stable (160). In a recent study utilizing shotgun metagenomic sequencing to examine microbial colonization following FMT, Lee et al (163) observed a significant increase in Bacteroidetes post-transplant and, interestingly, a negative correlation between genes involved in sporulation and successful colonization of the FMT recipient. This suggests that alternative treatments that rely heavily or solely on spore forming bacteria (such as Seres Therapeutics SER-109, described in detail below) may suffer from limited colonization efficiency.…”

“…(Although there is some support for diagnosis based solely upon a positive NAAT in the presence of symptoms, other experts recommend use of a multi-step approach to distinguish asymptomatic from symptomatic colonization (reviewed in (45)). The analysis also suggested that the 1 × 10 8 spores received by patients in the Phase II trial (Phase I recipients received doses from 3 × 10 7 to 2 × 10 9 spores) may have been suboptimal – possibly due to the limited colonization efficiency of spore forming bacteria (163). Despite the setback, Seres Health recently announced (June 12, 2017) the initiation of a Phase 3 SER-109 clinical study (ECOSPOR III) in patients with multiply recurrent C. difficile infection.…”