Gastrointestinal toxicity during induction treatment for childhood acute lymphoblastic leukemia: The impact of the gut microbiota

Study information

Reviewed Marked as Reviewed by Claregrieve1 on 2022/11/18

study design

time series / longitudinal observational

Citation

PMID PubMed identifier for scientific articles.

32115690

DOI Digital object identifier for electronic documents.

10.1002/ijc.32942

URI

Authors

De Pietri S, Ingham AC, Frandsen TL, Rathe M, Krych L, Castro-Mejía JL, Nielsen DS, Nersting J, Wehner PS, Schmiegelow K, Hasle H, Pamp SJ, Müller K

Journal

International journal of cancer

Year

2020

Keywords:

C-reactive protein, acute lymphoblastic leukemia, citrulline, gastrointestinal toxicity, microbiota, mucositis

Intestinal mucositis is a common side effect of chemotherapy leading to diarrhea, abdominal pain and increased risk of infections. The intestinal microbiota has been recognized as a key regulator of mucosal immune responses. Therefore, we hypothesized that intestinal microbial changes would be associated with enterocyte loss and systemic inflammation during induction treatment for childhood acute lymphoblastic leukemia (ALL). We prospectively included 51 children newly-diagnosed with ALL treated in Denmark in 2015-2018. Plasma C-reactive protein (CRP), plasma citrulline (marker of functional enterocytes mass) measurements and fecal samplings were performed on treatment Days 1, 8, 15, 22 and 29. Moreover, intestinal mucositis was scored by a trained nurse/physician. Fecal samples in patients and 19 healthy siblings were analyzed by 16S rRNA gene sequencing (V3-V4 region). Bacterial alpha diversity was lower in patients compared to siblings. It decreased from Day 1 to Days 8-22 and increased on Day 29. Shannon alpha diversity index was correlated with CRP on Days 15-29 (rho = -0.33-0.49; p < 0.05) and with citrulline on Days 15 and 29 (although with p values <0.06, rho = 0.32-0.34). The abundance of unclassified Enterococcus species (spp.) was correlated with CRP on Days 22-29 (rho = 0.42-0.49; p < 0.009), while the abundance of unclassified Lachnospiraceae spp. was correlated with citrulline on days 8-15 (rho = 0.48-0.62, p < 0.001). Systemic inflammation, enterocyte loss and relative abundance of unclassified Enterococcus spp. reached a peak around Day 15. In conclusion, specific changes in the microbiota were associated with the severity of enterocyte loss and systemic inflammation during chemotherapy.

Experiment 1

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Reviewed Marked as Reviewed by Claregrieve1 on 2022/11/18

Curated date: 2021/01/10

Curator: WikiWorks

Revision editor(s): Claregrieve1, WikiWorks, Victoria

Subjects

Location of subjects: Denmark

Host species Species from which microbiome was sampled. Contact us to have more species added.: Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Acute lymphoblastic leukemia acute lymphoblastic leukemia,acute lymphoblastic leukemia (ALL),acute lymphoblastic leukemia (disease),acute lymphoblastic leukemia/lymphoma,acute lymphocytic leukaemia,acute lymphocytic leukemia,acute lymphocytic leukemias,acute lymphogenous leukemia,acute lymphoid leukemia,ALL,ALL - acute lymphocytic leukemia,leukemia, lymphoblastic, malignant,lymphoblastic leukemia,lymphoblastic leukemia, acute,precursor cell lymphoblastic leukemia,precursor Lymphoblasic leukemia,precursor lymphoblastic leukemia,Acute lymphoblastic leukemia

Group 0 name Corresponds to the control (unexposed) group for case-control studies: baseline

Group 1 name Corresponds to the case (exposed) group for case-control studies: induction chemotherapy

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: children (ages 1-18 years old) newly diagnosed with Acute Lymphoblastic Leukemia and undergoing induction chemotherapy according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) post initiation of induction chemotherapy

Group 0 sample size Number of subjects in the control (unexposed) group: 32

Group 1 sample size Number of subjects in the case (exposed) group: 51

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V3-V4

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: Mann-Whitney (Wilcoxon)

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: Yes

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: decreased

Signature 1

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Reviewed Marked as Reviewed by Claregrieve1 on 2022/11/18

Curated date: 2021/01/10

Curator: William Lam

Revision editor(s): Claregrieve1, WikiWorks

Source: Figure 4

Description: Differential microbial abundance between baseline and Day 15 of induction chemotherapy

Abundance in Group 1: increased abundance in induction chemotherapy

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Enterococcus sp.

Revision editor(s): Claregrieve1, WikiWorks