Long-term impact of fecal transplantation in healthy volunteers

Abstract

Background: Fecal microbiota transplantation (FMT) has been recently approved by FDA for the treatment of refractory recurrent clostridial colitis (rCDI). Success of FTM in treatment of rCDI led to a number of studies investigating the effectiveness of its application in the other gastrointestinal diseases. However, in the majority of studies the effects of FMT were evaluated on the patients with initially altered microbiota. The aim of our study was to estimate effects of FMT on the gut microbiota composition in healthy volunteers and to monitor its long-term outcomes.

Results: We have performed a combined analysis of three healthy volunteers before and after capsule FMT by evaluating their general condition, adverse clinical effects, changes of basic laboratory parameters, and several immune markers. Intestinal microbiota samples were evaluated by 16S rRNA gene and shotgun sequencing. The data analysis demonstrated profound shift towards the donor microbiota taxonomic composition in all volunteers. Following FMT, all the volunteers exhibited gut colonization with donor gut bacteria and persistence of this effect for almost ∼1 year of observation. Transient changes of immune parameters were consistent with suppression of T-cell cytotoxicity. FMT was well tolerated with mild gastrointestinal adverse events, however, one volunteer developed a systemic inflammatory response syndrome.

Conclusions: The FMT leads to significant long-term changes of the gut microbiota in healthy volunteers with the shift towards donor microbiota composition and represents a relatively safe procedure to the recipients without long-term adverse events.

Keywords: 16S rRNA gene sequencing; Compositional data analysis; Fecal microbiota transplantation; Healthy volunteers; Metagenome-assembled genome; Metagenomics; Shotgun sequencing.

Fig. 1

Study description. The first line describes sampling points, the second line clinical effect observable caused by taking FMT capsule. The third line describes obtaining sequencing data and bioinformatic analysis. The sampling and sequencing points are presented in Additional file 6: Table S1

Fig. 2

Dynamics of neutrophil counts, lymphocyte counts (a) and lymphocyte sub-populations after FMT (b). The second volunteer (V2) developed SIRS

Fig. 3

Movement of recipient samples to the donor during the observation time based on 16S rRNA gene sequencing taxonomic composition. Bi-dimensional plot obtained by Aitchison distance with the aid of DEICODE. Donor samples: X. Volunteer’s samples: red / blue / green colors (see figure legend). The lines denote the evolution of the volunteer’s samples in time (different time points). The days after FMT procedure (or baseline for donor samples) denoted by color numbers

Fig. 4

Shifts of the taxonomic profile of microbiota in volunteers towards donor values over the observation time. The figure is based on shotgun sequencing data. a on-metric multidimensional scaling bi-dimensional plot of MetaPhlAn2 taxonomic profile (genera level relative abundances), based on the Aitchison distance. The lines denote the evolution of the volunteer’s samples in time (different time points). The days after FMT procedure (or baseline for donor samples) denoted by numbers. b CoDa dendrogram which characterizes association of bacterial families, balances presented as edges. Decomposition of total variance by balances between groups of families is shown by vertical bars. Mean values of balances is shown by anchoring points of vertical bars. Color of vertical bars corresponds to time points. Color rectangles highlighted families belonging to important balances. The arrows direction indicates the predominance of this balance part in the donor. MOTUs with no family information are collapsed into the no-name family

Fig. 5

Comparison of similarity between donor and recipients metagenome-assembled genomes (MAGs). a The AA distance based on 43 marker proteins between all donor MAGs and all MAGs of all recipients. Arrow shows that some MAGs in donor and recipient is present with absolute similarity of marker genes sequence. b The average nucleotide identity (ANI) between similar donor and recipients MAGs. The MAGs with 100% AA similarity of 43 marker proteins were selected. c Anvi’o plot denoted prevalence of donor MAGs across all metagenomic samples. Detection value (proportion of nucleotides in a contig that are covered at least 1x (according to http://merenlab.org/2017/05/08/anvio-views) was used as an abundance metric, which is shown as color brightness. Black color denotes detection value of donor MAGs in the donor samples, red – in the V1 samples, blue – in the V2 samples, green – in the V3 samples. DONOR BIN – clusters of metagenome-assembled genomes similar to the donor bacteria. The days after FMT denoted by numbers. The mapping of recipient metagenomic reads to donor MAGs was performed with 100% similarity