System-level metabolic effects of trematode infections in rodent models

Background: Trematode infections impose a great burden on the developing world by impairing life quality, productivity and life span of an individual. The prerequisite for efficient treatment and control of the diseases is the use of a quick and sensitive diagnostic tool which could replace the multi-diagnostic approach that is still used. The metabolic profiling approach implies the use of spectroscopic tools such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) on potentially interesting biofluids and tissues, and is coupled with multivariate mathematical data modelling. It has been applied to many different field of research, such as biochemistry, medical sciences, drug pathway discovery, non-communicable diseases, nutrition and psychological disorders, and has been established as an efficient method for biomarker recovery and pathway deciphering. There is growing interest in metabolic profiling in systems biology. The first attempt to bring together metabolic profiling with the epidemiology of neglected tropical diseases was in mid-2002, when urine samples were obtained from more than 500 individuals in a rural Western part of Côte d’Ivoire. However, it was impossible to extract any meaningful information with regard to specific parasitic infection. The high degree of metabolic variation of the studied population in terms of age, genetic and nutritional background and the fact that the majority of individuals harboured three or more parasites concurrently might explain this observation.
My thesis outline was put forward once the metabolic profiles of selected parasitic infections in suitable rodent models, namely Schistosoma mansoni and Trypanosoma brucei brucei in the mouse, and Schistosoma japonicum in the hamster, were established as an alternative to directly exploring human populations in order to ascertain if characteristic biomarkers of infection could be found for single host-parasite scenarios. The success of these experimental investigations encouraged further studies, including the extension of metabolic profiling to other host-parasite models, in order to gain insight into specificity of biomarkers and to reveal the diagnostic potential of this metabolic profiling approach.
Goal and objectives: The overarching goal of this Ph.D. project was to deepen our understanding of trematode-induced metabolic changes in selected rodent models, and to critically assess the potential of a metabolic profiling approach applied to biofluids and tissue samples for biomarker recovery that may contain diagnostic and prognostic properties.
The specific objectives were (i) to optimise faecal sample preparation for subsequent 1H NMR spectroscopy, and to assess metabolic variation in faecal samples with regard to species (i.e. human, rat and mouse), gender and age, (ii) to assess longitudinally the biochemical changes
in urine, plasma and faecal water of E. caproni-infected mice, and to compare the diagnostic capacity of different biofluids collected from infected and uninfected control mice, (iii) to gain information about E. caproni-induced changes in selected tissue samples e.g. (liver, kidney, spleen, ileum, jejunum and colon) of infected mice and correlate identified biomarkers with the previously extracted markers in the biofluids, which might reveal infection-related systems level changes (iv) to evaluate the remote and direct impact of three different trematodes (E. caproni, F. hepatica, S. mansoni) on the rodent host neural metabolic composition.
Findings: Comparing the diagnostic templates, all three biofluids showed interesting deviations between uninfected control and E. caproni-infected mice. Urine and plasma were considered as most suitable biofluids due to the large number of potential biomarkers
identified and because faecal water showed high fluctuations in the metabolic concentrations over time and a high degree of variation from one animal to another which was significantly higher than in urine and plasma. More detailed metabonomic investigations were performed
with E. caproni to assess systems impact on the mouse host. Resulting changes in the metabolic profiles of biofluids and tissue samples were correlated with each other, and revealed new insights into the biological pathomechanisms of this trematode, e.g. impact on gut microbial species and a trematode-induced imbalance of the transporter system in the gut. Whereas E. caproni did not induce any biochemical changes in the neural profile, rats infected with F. hepatica, and mice infected with S. mansoni showed strong deviations from uninfected control animals. F. hepatica-induced changes in the rat brain nucleotide metabolism was correlated to certain cytokine levels, e.g. IFN-γ, IL-5 and IL-13, and was consistent with modulation of the immune mechanisms.This finding provides a rationale for deeper analysis into the interaction of parasitic worms with the central nervous system of the host organism.