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See detailDynamic change of the human gastrointestinal microbiome in relation to mucosal barrier effects during chemotherapy and immune ablative intervention
Kaysen, Anne UL

Doctoral thesis (2017)

Numerous studies have demonstrated that the gastrointestinal tract (GIT) microbiota plays important roles for the human host. Since the GIT microbiota interfaces with the immune system and represents a ... [more ▼]

Numerous studies have demonstrated that the gastrointestinal tract (GIT) microbiota plays important roles for the human host. Since the GIT microbiota interfaces with the immune system and represents a first line of defense against infectious agents, interest has grown in whether the GIT microbiota may influence the outcome of different anticancer treatments. In this study, the GIT of pediatric patients with different cancer types as well as adult patients with hematologic malignancies undergoing an allogeneic hematopoietic stem cell transplantation were sampled throughout their treatment. In order to deeply profile not only the composition of the community, but also the functional capacity and expression, recently developed wet- and dry-lab methodologies for integrated multi-omic analyses were applied. The trajectories of the prokaryotic and microeukaryotic GIT communities of the patients were described in detail using 16S, 18S rRNA gene amplicon sequencing, as well as metagenomic and metatranscriptomic shotgun sequencing. Indeed, changes in the GIT microbiome in response to treatment were detected. Some changes that are generally thought to be detrimental for human health were detected during treatment, such as a decrease in alpha-diversity, a decrease in relative abundance of bacteria associated with health-promoting properties (such as Blautia spp., Roseburia spp. and Faecalibacterium spp.), as well as an increase in the relative abundance of antibiotic resistance genes. These changes were more pronounced in the adult hematology patients than in the pediatric patients, which is likely due to the more intensive treatment. Some observations need further investigation in order to explain their implication in human health. For example, in the pediatric patients, lower relative abundance of Akkermansia muciniphila was associated with mucositis and functional gene categories that are linked to bacteriophages or the bacterial defense mechanism against bacteriophages were associated with the overall status of the patient and mucositis development. Importantly, in both cohorts, high inter-individual but also high intra-individual variation in the prokaryotic communities were detected while the microeukaryotic community did not exhibit drastic changes. In conclusion, the employed integrated multi-omics analysis allowed detailed profiling of the GIT community including archaea, bacteria, eukaryotes and viruses as well as the functional potential including antibiotic resistance genes. In the future, analysis of the individual-specific processes within the GIT microbial community of patients throughout treatment might allow to adjust therapy regimens accordingly and improve the overall outcome of the therapy. [less ▲]

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See detailIntegrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation.
Kaysen, Anne UL; Heintz-Buschart, Anna UL; Muller, Emilie UL et al

in Translational Research: the Journal of Laboratory and Clinical Medicine (2017)

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 ... [more ▼]

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. [less ▲]

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