Disentangle beneficial effects of strain engraftment after fecal microbiota transplantation in subjects with MetSyn

Abstract

Fecal Microbiota Transplantation (FMT) has emerged as a potential modality for mitigating microbiome-associated diseases. Despite this potential, the precise causal pathways by which specific gut microbiota strains induce remission remain inadequately elucidated. In this study, we aimed to discern the impact of engraftment of donor-infused strains on alterations in plasma metabolites, subsequently contributing to the amelioration of clinical parameters involved in subjects with metabolic syndrome (MetSyn) receiving an FMT. We observed that a higher fraction of donor strains engrafted in the recipient is correlated to a reduction in diastolic blood pressure and found specific strain associations through canonical correlation analysis. Integrating the metabolomics profile shows that engraftment of Collinsella aerofaciens and Fusocatenibacter saccharovorans was related to a reduction in 2-oxoarginine in plasma, which was subsequently correlated to a reduction in diastolic blood pressure. In conclusion, we applied a novel framework to elucidate on the complex and heterogenous FMT intervention, establishing a connection between engrafted microbiota and clinical outcome parameters. Our findings underscore the potential therapeutic efficacy of FMT in ameliorating MetSyn, demonstrating a potential contribution of microbial strain engraftment to the improvement of MetSyn via modulation of circulating metabolites.

Keywords: CCA; FMT; gut microbiota; metabolites; microbiome; strain engraftment.

Figure 1.

A simplified schematic representation of the process of pitting the donor gut microbiome against the recipient (MetSyn patients) their gut microbiome is presented. This process involves the introduction of many different strains from many different FMT donors, resulting in either engraftment or no engraftment in the recipient after FMT.

Figure 2.

Strain-sharing networks of the different studies. The letters correspond to the specific donor. Subjects receiving FMT from the same donor have the same letter. Additionally, to distinguish between FMT recipients, these subjects received an additional number.Number.The letter and number combinations correspond to specific FMT triads belonging to the specific donor, with the color of the node distinguishing the sample types (orange = pre-fmt; green = post-fmt; blue = donor). The edges represent the percentage of strain-sharing between the different samples.

Figure 3.

Fraction of donor strains that are shared with the post-fmt sample against the fraction of pre-fmt strains that are shared with the post-fmt within each of the FMT triads. The fraction is defined by the number of shared strains (either between pre- and post-fmt samples or between donor and post-fmt samples) divided by the total number of strains in the post-fmt sample characterized by StrainPhlAn. The larger triangles represent the mean position for each sub-study. The diagonal dashed line represents a cutoff in which post-fmt samples above this line share a larger fraction of strains with its donor and below this line share a larger fraction of strains with its pre-fmt sample.

Figure 4.

(a) Heatmap depicting the engraftment status of the top 30 most engrafting donor strains (rows) in relation to the subjects separate post-fmt (columns). The subjects were grouped per sub-study depicted by the sidebar on top of the heatmap. Engraftment of the corresponding donor SGB is indicated by the threshold output of StrainPhlAn. (b) Relative abundance of the most engrafting SGBs in post-fmt samples colored by phylum taxonomic level.

Figure 5.

Correlation circle plot depicting the first two canonical variates with coordinates of the different variables of the strain engraftment- and clinical data modalities in the same dimensional space. The coordinates of each feature were obtained via the correlation between each original (centered and scaled) feature and each of the canonical variate. Note that this analysis included a total of 19 subjects rather than 29 as 10 subjects from the Fatmed study had missing data in diastolic blood pressure values.