Integrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation

Abstract

In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), treatment-induced changes to the gastrointestinal tract (GIT) microbiome have been linked to adverse outcomes, most notably graft-versus-host disease (GvHD). However, it is presently unknown whether this relationship is causal or consequential. Here, we performed an integrated meta-omic analysis to probe deeper into the GIT microbiome changes during allo-HSCT and its accompanying treatments. We used 16S and 18S rRNA gene amplicon sequencing to resolve archaea, bacteria, and eukaryotes within the GIT microbiomes of 16 patients undergoing allo-HSCT for the treatment of hematologic malignancies. These results revealed a major shift in the GIT microbiome after allo-HSCT including a marked reduction in bacterial diversity, accompanied by only limited changes in eukaryotes and archaea. An integrated analysis of metagenomic and metatranscriptomic data was performed on samples collected from a patient before and after allo-HSCT for acute myeloid leukemia. This patient developed severe GvHD, leading to death 9 months after allo-HSCT. In addition to drastically decreased bacterial diversity, the post-treatment microbiome showed a higher overall number and higher expression levels of antibiotic resistance genes (ARGs). One specific Escherichia coli strain causing a paravertebral abscess was linked to GIT dysbiosis, suggesting loss of intestinal barrier integrity. The apparent selection for bacteria expressing ARGs suggests that prophylactic antibiotic administration may adversely affect the overall treatment outcome. We therefore assert that such analyses including information about the selection of pathogenic bacteria expressing ARGs may assist clinicians in "personalizing" regimens for individual patients to improve overall outcomes.

Continuous pre- and post-transplant exposure to a disease-associated gut microbiome promotes hyper-acute graft-versus-host disease in wild-type mice

“…The bloom of E. coli we observed associated with the development of acute GVHD is consistent with previous observations both in mice and humans. 14 , 30 Expansion of E. hormaechei subsp. steigerwaltii has not been described previously, although unclassified Enterobacter spp.…”

“…We additionally recovered four E. coli MAGs from publicly available datasets from patients undergoing hematopoietic stem cell transplantation; one adult that developed acute GVHD and three pediatric patients that did not. 30,31 A further E. hormaechei subsp. steigerwaltii MAG was also obtained from a pediatric patient that developed acute GVHD.…”

The Gut Microbiota and Hematopoietic Stem Cell Transplantation: Challenges and Potentials

“…Both mortality as well as incidence of acute GvHD were higher in allo-HSCT recipients who were colonized by antibiotic-resistant bacteria [11, 12]. An integrated meta-omics analysis determined a higher number and expression of antibiotic-resistant genes (ARGs) in the gut microbiome of a patient after allo-HSCT who died due to GvHD [13]. Another retrospective study indicated that the treatment of neutropenic fever with antibiotics such as imipenem-cilastatin and piperacillin-tazobactam was linked to increased GvHD-related mortality within 5 years [14].…”

Precision identification of diverse bloodstream pathogens in the gut microbiome

“…Yet, microbial pathogenicity and transmission depend in part on strain-level variability, as different strains of the same species can vary widely in their ability to cause disease 11,12 . Whole genome sequencing (WGS) has facilitated the exploration of strain-level determinants of virulence and has enabled precise tracking of pathogens 11,13,14 .…”