Microbial and host factors contribute to bloodstream infection in a pediatric acute lymphocytic leukemia mouse model

Abstract

Background: Hematological malignancies are the most common cancers in the pediatric population, and T-cell acute lymphocytic leukemia (T-ALL) is the most common hematological malignancy in children. Bloodstream infection (BSI) is a commonly occurring complication in leukemia due to underlying conditions and therapy-induced neutropenia. Several studies identified the gut microbiome as a major source of BSI due to bacterial translocation. This study aimed to investigate changes in the intestinal and fecal microbiome, and their roles in the pathophysiology of BSI in a pediatric T-ALL mouse model using high-throughput shotgun metagenomics sequencing, and metabolomics. Results: Our results show that BSI in ALL is characterized by an increase of a mucin degrading bacterium (Akkermansia muciniphila) and a decrease of butyrate producer Clostridia spp., along with a decrease in short-chain fatty acid (SCFA) concentrations and differential expression of tight junction proteins in the small intestine. Functional analysis of the small intestinal microbiome indicated a reduced capability of SCFA synthesis, while SCFA supplementation ameliorated the development of BSI in ALL. Conclusions: Our data indicates that changes in the microbiome, and the resulting changes in levels of SCFAs contribute significantly to the pathogenesis of bloodstream infection in ALL. Our study provides tailored preventive or therapeutic approaches to reduce BSI-associated mortality in ALL.

Keywords

• Bacterial translocation
• Leukemia
• Microbiome
• Host-pathogen interactions