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. 2017 Nov 29;65(12):1984-1991.
doi: 10.1093/cid/cix699.

Stool Microbiota at Neutrophil Recovery Is Predictive for Severe Acute Graft vs Host Disease After Hematopoietic Cell Transplantation

Jonathan L Golob  1   2 , Steven A Pergam  1   2 , Sujatha Srinivasan  1 , Tina L Fiedler  1 , Congzhou Liu  1 , Kristina Garcia  1 , Marco Mielcarek  3   4 , Daisy Ko  1 , Sarah Aker  1 , Sara Marquis  1 , Tillie Loeffelholz  1 , Anna Plantinga  5 , Michael C Wu  6 , Kevin Celustka  1 , Alex Morrison  1 , Maresa Woodfield  1 , David N Fredricks  1   2   7
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Stool Microbiota at Neutrophil Recovery Is Predictive for Severe Acute Graft vs Host Disease After Hematopoietic Cell Transplantation (VSports在线直播)

Jonathan L Golob et al. Clin Infect Dis. .

Abstract

Background: Graft-versus-host disease (GVHD) is common after allogeneic hematopoietic cell transplantation (HCT) VSports手机版. Risk for death from GVHD has been associated with low bacterial diversity in the stool microbiota early after transplant; however, the specific species associated with GVHD risk remain poorly defined. .

Methods: We prospectively collected serial weekly stool samples from 66 patients who underwent HCT, starting pre-transplantation and continuing weekly until 100 days post-transplant, a total of 694 observations in HCT recipients. We used 16S rRNA gene polymerase chain reaction with degenerate primers, followed by high-throughput sequencing to assess the relative abundance of sequence reads from bacterial taxa in stool samples over time V体育安卓版. .

Results: The gut microbiota was highly dynamic in HCT recipients, with loss and appearance of taxa common on short time scales. As in prior studies, GVHD was associated with lower alpha diversity of the stool microbiota. At neutrophil recovery post-HCT, the presence of oral Actinobacteria and oral Firmicutes in stool was positively correlated with subsequent GVHD; Lachnospiraceae were negatively correlated. A gradient of bacterial species (difference of the sum of the relative abundance of positive correlates minus the sum of the relative abundance of negative correlates) was most predictive (receiver operator characteristic area under the curve of 0 V体育ios版. 83) of subsequent severe acute GVHD. .

Conclusions: The stool microbiota around the time of neutrophil recovery post-HCT is predictive of subsequent development of severe acute GVHD in this study. VSports最新版本.

Keywords: GVHD; gut; hematopoietic; microbiome; transplant. V体育平台登录.

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Figures

Figure 1.
Figure 1.
The stool microbiome of hematopoietic cell transplantation (HCT) donors and HCT recipients over time. The height of each colored bar or strip is proportionate to the relative abundance of 1 specific organism identified to the species or genus level. The legend is simplified to the family level for legibility. The coloration is related to the phylum of the organism: Firmicutes, purple/blue (Lachnospiraceae in purple); Proteobacteria, tan; Bacteroides, orange; and Actinobacteria, teal. A. The stool microbiome of 36 healthy HCT donors, demonstrating a typical dominance of Lachnospiracea or Bacteroides, with occasional codominance with Enterobacteraceae. B–E, HCT recipients’ microbiota over time. The x-axis is days relative to transplant. The vertical dashed line depicts the date of neutrophil recovery. For those with severe acute graft-versus-host disease (GVHD) (D and E), the date of GVHD onset is depicted with a black dot on the timeline. C, A patient who underwent a partial colectomy prior to transplant. E, Three HCT recipients who developed both severe and steroid-refractory acute GVHD. The HCT recipients with the most samples were included in this figure; those with fewer samples were omitted in consideration of space. Abbreviations: GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation.
Figure 2.
Figure 2.
Alpha diversity and graft-versus-host disease (GVHD). A, Balanced weighted phylogenetic diversity (BWPD) and inverse Shannon (InvSh) species diversity. The top row is for all observed time points; the bottom row is only for samples closest to neutrophil recovery. Alpha diversity was statistically significantly lower in those with severe GVHD (P < 0.05) as calculated by general estimating equations with independence as a correlation structure when all time points are considered. B, A receiver operator characteristic for BWPD (dashed blue) and InvSh (solid orange) at neutrophil engraftment as a test for subsequent development of severe (grade 3–4) acute GVHD. Abbreviations: AUC, area under the curve; BWPD, balanced weighted phylogenetic diversity; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; InvSh, inverse Shannon; ROC, receiver operator characteristic.
Figure 3.
Figure 3.
Positively and negatively correlated organisms at neutrophil recovery and graft-versus-host disease (GVHD). A gradient was calculated by taking the sum of the relative abundance of positive correlated organism (with GVHD) minus the sum of the relative abundance of the negative correlates. The value for this gradient is shown for all time points in panel A and for the time point closest to engraftment in panel B for hematopoietic cell transplant (HCT) recipients. C, The receiver operator characteristic for this gradient at neutrophil recovery as a predictor for development of severe (grade 3–4) acute GVHD. D, Sensitivity or specificity at various cutoff values for the gradient, allowing one to select a cutoff optimized for either specificity (ie, for a higher-risk intervention) or sensitivity (ie, for inclusion in a GVHD prophylaxis trial). Abbreviations: AUC, area under the curve; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation.
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