Vaitkute, Gintare;
(2020)
The gut microbiota throughout paediatric haematopoietic stem cell transplantation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Haematopoietic stem cell transplantation is a curative procedure for a variety of underlying diagnoses including haematological, immunological and metabolic conditions such as acute myeloid leukaemia, Wiskott-Aldrich syndrome and Hurler’s syndrome, respectively. The procedure, which includes conditioning and a period of neutropaenia prior to the transplant engraftment, can lead to significant morbidity including viraemia, bacteraemia and Graft-versus-host disease. Gut microbiota has been extensively studied in adult haematopoietic stem cell transplantation. It is known to affect stem cell reconstitution and has been frequently linked to various clinical outcomes; however, paediatric studies are scarce. This work profiles the gut microbiota of paediatric patients undergoing haematopoietic stem cell transplantation at Great Ormond Street Hospital using both 16S rRNA sequencing and nuclear magnetic resonance spectroscopy. The initial chapter focuses on optimising the 16S rRNA methodology for this project. Subsequent chapters investigate the longitudinal gut microbiota and its dynamics throughout hospitalisation, as well as searches for clinical biomarkers at several time points throughout haematopoietic stem cell transplantation. We find that gut domination with a single taxon, specifically Enterococcus, Enterobacteriaceae, Streptococcus and Staphylococcus is common in this population. Additionally, we observe a loss of diversity around the time of the transplantation and that most patient microbiota profiles are unlike those of healthy individuals, even upon admission. We also identify three clusters within the data, revealing interesting cluster-switching patterns throughout transplantation and find that one cluster is linked to a higher risk of developing viraemia. We also find several biomarkers of viraemia and Graft-versus-host disease at baseline and around the time of engraftment, which may be indicative of overall gut health at that point. The final chapter profiles the faecal metabolome throughout haematopoietic stem cell transplantation and aims to broadly link the metabolome to the 16S data. We observe a loss of short chain fatty acids such as butyrate and acetate and increases in lactate and glucose throughout, which may be indicative of damaged gut epithelium and a loss of beneficial obligate anaerobes. Overall, these findings are indicative of a disruption of the host-microbe cross-talk.
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