Credit: Kosuke Fujimoto, Seiya Imoto,
and Satoshi Uematsu from The University of Tokyo
Allogenic
hematopoietic cell transplantation (allo-HCT) involves transferring healthy
donor stem cells to recipients with conditions such as blood cancer, bone
marrow failure, or certain genetic blood disorders. Acute graft-versus-host
disease (aGVHD) is a common complication, where the donor's immune cells attack
the recipient's tissues.
Recent studies highlight the significant
role of the microbiome in aGVHD, with dysbiosis contributing to its
pathogenesis. Dysbiosis can lead to the emergence of pathogenic commensal
bacteria including Enterococcus species, particularly E. faecalis and E.
faecium, which are associated with multidrug-resistant infections in allo-HCT
patients. However, there is a lack of effective therapies specifically tailored
to treat dysbiosis in the context of aGVHD.
To address this gap, a multidisciplinary
team led by Associate Professor Kosuke Fujimoto from Osaka Metropolitan
University and The University of Tokyo, alongside Professor Seiya Imoto from
The University of Tokyo, and Satoshi Uematsu from Osaka Metropolitan University
and The University of Tokyo, conducted an in-depth analysis of the intestinal
bacteriome of allo-HCT patients.
The study aimed to investigate the
prevalence and implications of Enterococcus domination in this specific patient
population. Their findings, published on July 10 in the journal Nature, shed light on crucial aspects of gut microbiota dynamics in the context of allo-HCT.
Fujimoto says, "During dysbiosis, some symbiotic commensal bacteria acquire pathogenic characteristics, proliferate, and become directly involved in the onset and progression of the disease. Recognizing the specificity of phage therapy and its ability to spare beneficial bacteria from adverse effects, we focused our research on phage-derived lytic enzymes."
Identification
of bacteriophage-derived enzyme and its antibacterial activity can contribute
to novel therapies that target biofilm-forming bacteria and help in the
treatment against acute graft-versus-host disease. Credit: Kosuke Fujimoto,
Seiya Imoto, and Satoshi Uematsu from The University of Tokyo
The
team initiated their investigation by examining the intestinal microbiome of
allo-HCT patients, where they noted a predominance of Enterococcus species,
particularly E. faecalis. This was notably associated with acute leukemia.
Despite being sensitive to several antibiotics, E. faecalis strains possessed
cytolysin-associated genes, indicating high virulence.
Further exploration through metagenomic
analysis revealed the presence of genetic signatures associated with biofilm
formation. They then proceeded with whole-genome sequencing of E. faecalis.
This unveiled the presence of an intriguing bacteriophage-derived enzyme known
as endolysin, exhibiting potent antibacterial activity specifically targeting
E. faecalis.
Fujimoto and his team conducted rigorous
in-vitro and in-vivo assays to confirm the efficacy of the endolysin. They
found that it exhibited narrow-spectrum activity against E. faecalis and
effectively lysed biofilms. Notably, the endolysin's lytic activity did not
affect other intestinal bacteria species. In mouse models, the efficacy of the
endolysin was assessed in two experiments.
First, mice with induced aGVHD were
treated with the endolysin, resulting in a significant reduction of E. faecalis
colonization in feces and suppression of aGVHD development. In the second
experiment, mice with a gut microbiota resembling that of humans, dominated by
Enterococcus bacteria, were treated with the endolysin, leading to decreased
Enterococcus levels and improved survival rates.
"Bacteriophage research is gaining
momentum, with advancements in phage therapy paving the way for new treatments.
Our discovery of the endolysin enzyme holds promise for future applications in
preventing or treating acute GVHD," says Fujimoto.
Thanks to the research team for the identification of endolysin from bacteriophage, a new class of therapeutic compounds targeting highly-resistant, biofilm-forming bacteria is now possible.
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