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. 2020 Nov 24;4(22):5797-5809.
doi: 10.1182/bloodadvances.2020002677.

Associations of the gut microbiome and clinical factors with acute GVHD in allogeneic HSCT recipients

Emma E Ilett  1 , Mette Jørgensen  1 , Marc Noguera-Julian  2   3 , Jens Christian Nørgaard  1 , Gedske Daugaard  4 , Marie Helleberg  1 , Roger Paredes  2   5 , Daniel D Murray  1 , Jens Lundgren  1 , Cameron MacPherson  1 , Joanne Reekie  1 , Henrik Sengeløv  6
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Associations of the gut microbiome and clinical factors with acute GVHD in allogeneic HSCT recipients

Emma E Ilett et al. Blood Adv. .

Erratum in

"V体育ios版" Abstract

Acute graft-versus-host disease (aGVHD) is a leading cause of transplantation-related mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). 16S ribosomal RNA (16S rRNA) gene-based studies have reported that lower gut bacterial diversity and the relative abundance of certain bacteria after aHSCT are associated with aGVHD. Using shotgun metagenomic sequencing and a large cohort, we aimed to confirm and extend these observations. Adult aHSCT recipients with stool samples collected from day -30 to day 100 relative to aHSCT were included. One sample was selected per patient per period (pre-aHSCT (day -30 to day 0), early post-aHSCT (day 1 to day 28), and late post-aHSCT (day 29 to day 100)), resulting in 150 aHSCT recipients and 259 samples. Microbial and clinical factors were tested for differences between time periods and an association with subsequent aGVHD. Patients showed a decline in gut bacterial diversity posttransplant, with several patients developing a dominance of Enterococcus. A total of 36 recipients developed aGVHD at a median of 34 days (interquartile range, 26-50 days) post-aHSCT. Lower microbial gene richness (P = . 02), a lower abundance of the genus Blautia (P = . 05), and a lower abundance of Akkermansia muciniphila (P = . 01) early post-aHSCT was observed in those who developed aGVHD. Myeloablative conditioning was associated with aGVHD along with a reduction in gene richness and abundance of Blautia and A muciniphila. These results confirm low diversity and Blautia being associated with aGVHD. Crucially, we add that pretransplant conditioning is associated with changes in gut microbiota VSports手机版. Investigations are warranted to determine the interplay of gut microbiota and conditioning in the development of aGVHD. .

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures (V体育2025版)

None
Graphical abstract
Figure 1.
Figure 1.
Dynamics of gut diversity relative to aHSCT. Diversity measures (the inverse Simpson index on a –log10 scale [A]), gene richness [B], and metabolic richness [C]) of samples for each period (pre-aHSCT, early post-aHSCT, and late post-aHSCT). Overall Kruskal-Wallis analysis was performed on the 3 periods within each diversity measure; thereafter, pairwise Wilcoxon tests were performed for differences in diversity between each period (ie, pre-aHSCT and early post-aHSCT; pre-aHSCT and late post-aHSCT; and early post-aHSCT and late post-aHSCT). ymin lower whisker is smallest observation greater than or equal to lower hinge − 1.5 * IQR; ymax upper whisker is largest observation less than or equal to upper hinge + 1.5 * IQR.
Figure 2.
Figure 2.
Significant changes in bacterial abundance relative to aHSCT. Heatmap of bacterial abundance in each period (pre-aHSCT, early post-aHSCT, and late post-aHSCT). The bacterial genera and species shown are only those found to be significantly different in abundance between the pre-aHSCT and early post-aHSCT periods and/or the pre-aHSCT and late post-aHSCT periods and those present in ≥10% of samples tested, at a minimum of 0.01% relative abundance. Clustering by row (ie, by bacteria) is based on Pearson clustering distances and has been performed separately for genera and species. Clustering by column (ie, by sample) is based on Euclidean distances and has been performed separately for each time period.
Figure 3.
Figure 3.
Gut diversity and associations with aGVHD. Gut microbial diversity in inverse Simpson index (A), gene richness (B), and metabolic richness (C) in those who developed vs those who did not develop aGVHD pre-aHSCT and early post-aHSCT samples. Kruskal-Wallis tests were performed per diversity measure and period. ymin lower whisker is smallest observation greater than or equal to lower hinge − 1.5 * IQR; ymax upper whisker is largest observation less than or equal to upper hinge + 1.5 * IQR.
Figure 4.
Figure 4.
Gut microbial gene abundance and metabolic pathways associations with aGVHD. (A) Log2 fold-changes of genes found in significantly higher amounts among those who do not develop aGVHD both pre-aHSCT and early post-aHSCT. (B) Discovery analysis of metabolic pathways found in at least 10% of samples tested at an abundance of 1000 copies per 1 million reads in pre-aHSCT and early post-aHSCT samples.
Figure 5.
Figure 5.
Bacterial species and genera associated with subsequent development of aGVHD. (A-B) The relative abundance (% on a –log10 scale) of the significant predefined bacteria, Blautia and A muciniphila, respectively, among those who do not develop aGVHD vs those who do develop aGVHD early post-aHSCT. (C-D) Our discovery method for bacterial genera and species (present in ≥10% of samples tested at a minimum of 0.01% relative abundance, colored by bacterial order) in early post-aHSCT samples. Those under the dotted line have not passed the DESeq2 threshold of an FDR of P < .01. Those depicted by a larger dot have a lower P value from the Wilcoxon test taking into account compositionality. Those with the largest dot (P ≤ .05) and above the dotted line are the significant bacteria based on our discovery model. The only bacterial genera that have passed this are Blautia, Campylobacter, and Akkermansia, which are shown as the labeled dot on the top of the graph and for species A muciniphila. To see all bacteria passing either threshold (DESeq or Wilcoxon), see supplemental Figure 4.
Figure 6.
Figure 6.
Clinical factors associated with aGVHD. Multivariable logistic regression model of clinical factors associated with the development of aGVHD. aOR, adjusted odds ratio; Ref, reference.
Figure 7.
Figure 7.
Conditioning type and associations with microbial factors early post-aHSCT. (A) The gene richness (number of unique genes) for those who underwent nonmyeloablative conditioning vs those who underwent nonmyeloablative conditioning early post-aHSCT. (B) Relative abundance (% shown on a –log10 scale) of the bacterial genus Blautia early post-aHSCT in those who underwent nonmyeloablative vs those who underwent myeloablative conditioning. (C) Relative abundance (% shown on a –log10 scale) of the bacterial species A muciniphila early post-aHSCT in those who underwent nonmyeloablative vs those who underwent myeloablative conditioning. ymin lower whisker is smallest observation greater than or equal to lower hinge − 1.5 * IQR; ymax upper whisker is largest observation less than or equal to upper hinge + 1.5 * IQR.
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