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. 2024 Mar 6;14(1):5504.
doi: 10.1038/s41598-024-56242-8.

Gut diversity and the resistome as biomarkers of febrile neutropenia outcome in paediatric oncology patients undergoing hematopoietic stem cell transplantation

Sara Sardzikova  1 , Kristina Andrijkova  1 , Peter Svec  2 , Gabor Beke  3 , Lubos Klucar  3 , Gabriel Minarik  4 , Viktor Bielik  5 , Alexandra Kolenova  2 , Katarina Soltys  6
Affiliations

Gut diversity and the resistome as biomarkers of febrile neutropenia outcome in paediatric oncology patients undergoing hematopoietic stem cell transplantation

Sara Sardzikova et al. Sci Rep. .

Abstract

The gut microbiota of paediatric oncology patients undergoing a conditioning regimen before hematopoietic stem cell transplantation is recently considered to play role in febrile neutropenia. Disruption of commensal microbiota and evolution of opportune pathogens community carrying a plethora of antibiotic-resistance genes play crucial role. However, the impact, predictive role and association of patient´s gut resistome in the course of the therapy is still to be elucidated. We analysed gut microbiota composition and resistome of 18 paediatric oncology patients undergoing hematopoietic stem cell transplantation, including 12 patients developing febrile neutropenia, hospitalized at The Bone Marrow Transplantation Unit of the National Institute of Children´s disease in Slovak Republic and healthy individuals (n = 14). Gut microbiome of stool samples obtained in 3 time points, before hematopoietic stem cell transplantation (n = 16), one week after hematopoietic stem cell transplantation (n = 16) and four weeks after hematopoietic stem cell transplantation (n = 14) was investigated using shotgun metagenome sequencing and bioinformatical analysis. We identified significant decrease in alpha-diversity and nine antibiotic-resistance genes msr(C), dfrG, erm(T), VanHAX, erm(B), aac(6)-aph(2), aph(3)-III, ant(6)-Ia and aac(6)-Ii, one week after hematopoietic stem cell transplantation associated with febrile neutropenia. Multidrug-resistant opportune pathogens of ESKAPE, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli found in the gut carried the significant subset of patient's resistome. Over 50% of patients treated with trimethoprim/sulfamethoxazole, piperacillin/tazobactam and amikacin carried antibiotic-resistance genes to applied treatment. The alpha diversity and the resistome of gut microbiota one week after hematopoietic stem cell transplantation is relevant predictor of febrile neutropenia outcome after hematopoietic stem cell transplantation. Furthermore, the interindividual diversity of multi-drug resistant opportunistic pathogens with variable portfolios of antibiotic-resistance genes indicates necessity of preventive, personalized approach.

Keywords: Alpha-diversity; Gut microbiome; Hematopoietic stem cell transplantation; Multidrug-resistant bacteria; Paediatric oncology; Resistome.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Alpha diversity of gut microbiome of patients without febrile neutropenia (FN-) or developing febrile neutropenia (FN+) before (d-7) and after (d + 7) HSCT represented by Shannon index (A, B) and Simpson index (C, D). The p values were computed using Mann–Whitney test for parametric data and Wilcoxon-rank test for nonparametric data with significance p ≤ 0.05 applied. Significant decrease in alpha diversity was detected in gut microbiome of patients developing febrile neutropenia after HSCT.
Figure 2
Figure 2
Gut microbiome composition at phylum level (I.) calculated as relative abundance visualized as bargraphs. All involved participants including healthy individuals and patients at all time-points of sampling were included. II. – relative abundance of selected bacterial families of gut microbiota of patients before (d-7), one week after (d + 7) and four weeks after (d + 28) compared to healthy individuals (CTRL). Beneficial commensal bacteria (A—Akkermansiaceae, B—Clostridiaceae, C—Lachnospiraceae) and opportunistic pathogens (D—Enterococcaceae, E—Staphylococcaceae, F—Streptococcaceae) visualized as bar charts. Significant decrease (p ≤ 0.05) in relative abundance of Bacteroidota, Akkermansiaceae, Clostridiacea, Lachnospiracea and increase of opportunistic pathogens was observed in gut microbiome of paediatric oncology patients.
Figure 3
Figure 3
The gut bacteriome of the patients undergoing HSCT and healthy individuals visualized using a Krona pie chart. Each chart represents gut composition calculated as average for each bacterial genus detected within the group. CTRL—control group; d-7—before HSCT; d + 7—one week after HSCT; d + 28—one month after HSCT.
Figure 4
Figure 4
Beta diversity of analysed samples represented by the full resistome profile of gut microbiota of paediatric oncology patients before (d-7), one week after (d + 7) and four weeks after (d + 28) HSCT. Resistome was represented by a set of antimicrobial resistance genes identified within the analysed sample. SVD with imputation was used to calculate the principal components. The X and Y axis show principal component 1 and principal component 2 that explain 19.1% and 12.4% of the total variance. Prediction ellipses represent 0.95% probability for new observation to fit the group (n = 47).
Figure 5
Figure 5
Graphical visualization of the absolute number of antimicrobial resistance genes clustered according to their predicted phenotype carried by bacterial genera detected in gut microbiome of healthy individuals and patients.
Figure 6
Figure 6
Graphical visualization of the spread of antimicrobial resistance genes annotated by the predicted antimicrobial group phenotype in paediatric oncology patients before (d-7), one week after (d + 7) and four weeks after (d + 28) HSCT with focus on febrile neutropenia outcome after HSCT (FN – patients with febrile neutropenia, xFN – patients without febrile neutropenia). Rows are centred; unit variance scaling was applied to rows. Both rows and columns were clustered using correlation distance and Ward linkage.
Figure 7
Figure 7
Subset of biomarkers—antimicrobial resistance genes detected in gut microbiome of patients who developed febrile neutropenia, before HSCT (I.a) and after HSCT (I.b) and spearman rank correlation analysis of selected genes (I.b – before HSCT; II.b – one week after HSCT) graphically visualized by a correlation matrix. Correlations ≥ 0.6 (p ≤ 0.05) were considered for further evaluation. (I.b; d-7) who developed febrile neutropenia after HSCT.
Figure 8
Figure 8
The network analysis visualizing the association between opportunistic pathogens Enterococcaceae, Streptococcaceae, Staphylococcaceae, antimicrobial genes of resistance, inflammation biomarkers CRP and procalcitonin and febrile neutropenia.
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