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Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders - PubMed

  • ️Tue Jan 01 2019

Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders

Elena Biagi et al. BMC Med Genomics. 2019.

Abstract

Background: The onset of acute Graft-versus-Host Disease (aGvHD) has been correlated with the gut microbiota (GM) composition, but experimental observations are still few, mainly involving cohorts of adult patients. In the current scenario where fecal microbiota transplantation has been used as a pioneer therapeutic approach to treat steroid-refractory aGvHD, there is an urgent need to expand existing observational studies of the GM dynamics in Hematopoietic Stem Cell Transplantation (HSCT). Aim of the present study is to explore the GM trajectory in 36 pediatric HSCT recipients in relation to aGvHD onset.

Methods: Thirty-six pediatric patients, from four transplantation centers, undergoing HSCT were enrolled in the study. Stools were collected at three time points: before HSCT, at time of engraftment and > 30 days following HSCT. Changes in the GM phylogenetic structure were studied by 16S rRNA gene Illumina sequencing and phylogenetic assignation.

Results: Children developing gut aGvHD had a dysbiotic GM layout before HSCT occurred. This putative aGvHD-predisposing ecosystem state was characterized by (i) reduced diversity, (ii) lower Blautia content, (iii) increase in Fusobacterium abundance. At time of engraftment, the GM structure underwent a deep rearrangement in all patients but, regardless of the occurrence of aGvHD and its treatment, it reacquired a eubiotic configuration from day 30.

Conclusions: We found a specific GM signature before HSCT predictive of subsequent gut aGvHD occurrence. Our data may open the way to a GM-based stratification of the risk of developing aGvHD in children undergoing HSCT, potentially useful also to identify patients benefiting from prophylactic fecal transplantation.

Keywords: 16S rRNA gene sequencing; Acute graft-versus-host disease; Alloreactivity; Gut microbiota; Hematopoietic stem cell transplantation; Pediatric patients.

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Conflict of interest statement

Ethics approval and consent to participate

Study protocol was approved by the University of Bologna Ethics Committee (ref. number 19/2013/U/Tess). Written informed consent was obtained, in accordance with the Declaration of Helsinki, from each enrolled patient or parent/legal guardian.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1

Schematic overview of the sampling time for each enrolled subject. Subjects are indicated with a progressive number preceded by a letter associated with the enrolling center (B, Bologna; P, Pavia; R, Rome; V, Verona). HSCT (green dots), skin grade I-III aGvHD diagnosis (yellow dots), gastrointestinal grade II-IV aGvHD diagnosis (red dots), and fecal sample collection (black dots) are plotted on timelines with distance from HSCT expressed in days

Fig. 2
Fig. 2

Gut microbiota variability before HSCT, in relation to aGvHD development. a PCoA based on Bray-Curtis distances of genus-level relative abundance profiles of samples collected before HSCT from patients who did not develop aGvHD (green), who developed aGvHD (I-II grade) only involving the skin (gold), and who developed gastrointestinal aGvHD (II-IV grade) (dark red). Samples are identified by filled circles. First and second principal components (MDS1 and MDS2) are plotted, accounting for 22.1 and 13.3% of variance in the dataset, respectively. Box and whiskers distribution of the relative abundance (%) of OTUs assigned to the genera Fusobacterium (b) and Blautia (c) in samples collected before HSCT from subjects who did not develop aGvHD (green), who developed aGvHD (I-II grade) only involving the skin (gold), and who developed gastrointestinal aGvHD (II-IV grade) (dark red)

Fig. 3
Fig. 3

Gut microbiota variability at engraftment, in relation to aGvHD development. a PCoA based on Bray-Curtis distances of genus-level relative abundance profiles of samples collected at the engraftment from patients who did not develop aGvHD (green), who developed aGvHD (I-II grade) only involving the skin (gold), and who developed gastrointestinal aGvHD (II-IV grade) (dark red). Samples are identified by filled circles. First and second principal components (MDS1 and MDS2) are plotted, accounting for 26.2 and 10.4% of variance in the dataset, respectively. The biplot of the average bacterial coordinates weighted by the corresponding bacterial relative abundance per sample was superimposed on the PCoA plot for two of the bacterial genera contributing to the ordination space (arrows). b Box and whiskers distribution of the relative abundance (%) of OTUs assigned to the genus Bacteroides in samples collected before HSCT from subjects who did not develop aGvHD (green), who developed aGvHD (I-II grade) only involving the skin (gold), and who developed gastrointestinal aGvHD (II-IV grade) (dark red). Log2 fold changes of the main discriminant genera between pre-HSCT and engraftment samples in subjects who did not develop aGvHD (c), who developed aGvHD (I-II grade) only involving the skin (d), and who developed gastrointestinal aGvHD (II-IV grade) (e). Genera for which P ≤ 0.05 was obtained for at least one of the three groups of subjects are shown (please see Additional file 2: Table S1) (O., Oscillospira; F., Faecalibacterium; [Ru.], [Ruminococcus]; Ro., Roseburia; L., Lachnospira; D., Dorea; C., Coprococcus; Bl., Blautia; Bi., Bifidobacterium). Average values of log2 ratios are reported as bar plot, whereas dots identify the single values obtained for each subject included in each group. Filled black dots and bacterial names in bold are used when the abundance of the OTUs assigned to that genus was significantly different between pre-HSCT and engraftment samples (paired Wilcoxon test, P < 0.05), whereas empty circles are used when the difference was not significant

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