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Title: Influence of gene-environment interaction on the gut microflora-mammalian contribution to metabolism and toxicity
Author: Swann, Jonathan Richard
ISNI:       0000 0001 3493 3851
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Gut microbial composition and activity exert a strong influence on the metabolic phenotype of the host, and variation in the metabolic phenotype is a major factor underlying inter-individual variation in drug responses. In this thesis, the role of gut microflora on the mammalian metabolic system was explored with specific focus on the influence on xenobiotic metabolism and toxicity. Systems biology approaches were utilised to examine microfloral-mammalian interactions and mechanisms of drug toxicity. Multi-omic techniques, namely transcriptomics and metabonomics, were employed to characterise animal models used for investigating microfloral-mammalian interactions. These included germ-free, antibiotic-treated, and 'conve-ntional' rats. The utility of applying systems biology approaches to elucidate mechanisms of toxicity was demonstrated in conventional animals administered methapyrilene using metabonomic and protein-analysis techniques. Finally, the influence of the gut microbiota on the metabolism and toxicity of hydrazine was explored using an integrated transcriptomic and metabonomic approach. Microfloral absence modulated host metabolism directly and indirectly at the transcriptome and metabonome level, specifically drug, lipid and energy metabolism. Temporary suppression of the microbiota through antibiotic treatment did not disrupt the biological system greatly but minor disruption was observed upon re-colonisation. Methapyrilene dosing modified the structure and activity of a urea cycle enzyme and by integrating metabonomics and focused assays the potential for these protein modifications to be a mechanism of toxicity were investigated. In germ-free anitn~ls the effect of hrdrazine was variable, \A{ith toxicity enhanced in two of the three members compared to conventional animals. This highlights the potential for microbiota to influence host susceptibility towards drug toxicity and shows that toxic responses can be diverse in the absence of a functional microbiome. These studies demonstrate the use of applying systems biology approaches to investigate complex biological systems and indicate that gut microorganisms can modulate host metabolism and potentially be a factor in idiosyncratic drug responses.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available