Drivers and Determinants of Strain Dynamics Following Faecal Microbiota Transplantation

Abstract

Faecal microbiota transplantation (FMT) is an efficacious therapeutic intervention, but its clinical mode of action and underlying microbiome dynamics remain poorly understood. Here, we analysed the metagenomes associated with 142 FMTs, in a time series-based meta-study across five disease indications. We quantified strain-level dynamics of 1,089 microbial species based on their pangenome, complemented with 47,548 newly constructed metagenome-assembled genomes. Using subsets of procedural-, host- and microbiome-based variables, LASSO-regularised regression models accurately predicted the colonisation and resilience of donor and recipient microbes, as well as turnover of individual species. Linking this to putative ecological mechanisms, we found these sets of variables to be informative of the underlying processes that shape the post-FMT gut microbiome. Recipient factors and complementarity of donor and recipient microbiomes, encompassing entire communities to individual strains, were the main determinants of individual strain population dynamics, and mostly independent of clinical outcomes. Recipient community state and the degree of residual strain depletion provided a neutral baseline for donor strain colonisation success, in addition to inhibitive priority effects between species and conspecific strains, as well as putatively adaptive processes. Our results suggest promising tunable parameters to enhance donor flora colonisation or recipient flora displacement in clinical practice, towards the development of more targeted and personalised therapies.

Identification of clinical and ecological determinants of strain engraftment after fecal microbiota transplantation using metagenomics

“…While these findings are in agreement with those from a strain-level microbiota analysis of FMT-treated rCDI patients, 14 they contrast the 20%-53% reported for a metabolic syndrome patient cohort. 13 A recent preprint from the authors of the latter study described a reduced frequency of 22% conspecific coexisting strain observations in a more diverse post-FMT patient cohort, after detection of the same species in recipients and donors before FMT, 15 which is still considerably higher than the 2% conspecific coexistence rate observed in our analysis. However, microbial strains have been defined based on different biological, genomic, and bioinformatic concepts, 44 and while our strain profiling relies on the mapping of metagenomic reads to species-specific marker gene combinations to detect strain-specific single nucleotide variant (SNV) profiles, 22 Schmidt et al used a combination of strain population-specific gene content and SNV profiles that demanded substantially fewer alignment sites for pairwise comparisons, 15 which may lead our method to underestimate and the latter to overestimate shared strain numbers.…”

“… 12 The concept of propagule pressure is used in invasion ecology to explain the successful colonization of a newly introduced population as determined by the quality, quantity, and frequency of invading organisms 39 identified as an important neutral or stochastic factor that shapes the post-FMT microbiome assembly process. 15 However, our finding that strains from predicted oral, oxygen-tolerant, and gram-positive species had a reduced chance of engraftment indicates that microbial adaptation to the gut environment is another relevant determinant of engraftment success. Microbiome assembly after FMT might thus be governed by resource competition and niche processes, which are deterministic and not neutral, and have recently been reported to control microbial colonization and resilience in post-FMT rCDI patients.…”

“…However, microbial strains have been defined based on different biological, genomic, and bioinformatic concepts, 44 and while our strain profiling relies on the mapping of metagenomic reads to species-specific marker gene combinations to detect strain-specific single nucleotide variant (SNV) profiles, 22 Schmidt et al. used a combination of strain population-specific gene content and SNV profiles that demanded substantially fewer alignment sites for pairwise comparisons, 15 which may lead our method to underestimate and the latter to overestimate shared strain numbers.…”

“… 12 However, previous strain-level microbiota analyses came to differing conclusions about conspecific strain populations after FMT, reporting “durable coexistence of donor and recipient strains” after FMT in metabolic syndrome patients, 13 or engraftment of multi-strain donor species populations in an “all-or-nothing manner” without substantial and lasting coexistence of recipient and donor strains. 14 Furthermore, frequent coexistence of donor and recipient strains has been justified with the importance of neutral and stochastic ecological determinants, 15 whereas another study identified competition and adaptation that would favor fitness as a main ecological driver for microbiome organization after FMT. 16 These ambiguous conclusions reflect our limited understanding of the ecological principles that govern the post-FMT microbiome assembly process and its relationship to the clinical conditions in which FMT is applied.…”

Using the microbiome in clinical practice

“…To that end, a number of recommendations have been developed towards ensuring safe FMT, including patient and sample screening, labelling methods, and storage conditions (Saha and Khanna, 2021). Once banked, samples could theoretically be characterized and classified to highlight which would most likely improve certain disease states, improve treatment responsiveness and help with weight loss and ageing, even taking into account recipient characteristics (Schmidt et al ., 2021). Down the line, we could even envision a world in which FMT from “star” donors would be used as probiotics are today to improve general well‐being and gut functionality, though as a one time or annual supplement rather than a daily one.…”