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

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  • Silvia De Pietri, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • ,
  • Anna C Ingham, Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark ysan@ssi.dk.
  • ,
  • Thomas L Frandsen, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • ,
  • Mathias Rathe, Department of Cardiology and OPEN-Odense Patient Data Explorative Network, Odense University Hospital, Odense, Denmark.
  • ,
  • Lukasz Krych, Københavns Universitet
  • ,
  • Josue L Castro-Mejía, Københavns Universitet
  • ,
  • Dennis S Nielsen, Københavns Universitet
  • ,
  • Jacob Nersting, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • ,
  • Peder S Wehner, Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
  • ,
  • Kjeld Schmiegelow, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., c University Hospital Rigshospitalet, Institute of Clinical Medicine, Medical Faculty, University of Copenhagen , Copenhagen , Denmark.
  • ,
  • Henrik Hasle
  • Sünje J Pamp, Research Group for Genomic Epidemiology, Technical University of Denmark, Kongens Lyngby, Denmark.
  • ,
  • Klaus Müller, Institute for Inflammation Research, Copenhagen University Hospital, Rigshospitalet, Denmark.

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.

OriginalsprogEngelsk
TidsskriftInternational Journal of Cancer
Vol/bind147
Nummer7
Sider (fra-til)1953-1962
Antal sider10
ISSN0020-7136
DOI
StatusUdgivet - 2020

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