NMR-based Metabonomic Studies On Ulcerative Colitis And Bacteremia

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease, are of significant public burden. The interplay between genetic mutation and environmental factors is believed to contribute to etiology of IBD. While focused attention has been paid to the aforementioned research, time-specific and organ-specific metabolic changes associated with IBD is still lacking. Animal models have always been important part of our advance in biomedical research, simply due to advantages in easy manipulation and readily accessible to multiple sampling points and organ tissues. It is widely accepted that UC is associated to defects in the epithelial barrier integrity, whereby causing the intestinal bacteria invasion into blood of host. In order to seek for responses of host to bacteria invasion into blood, we also investigate the changes of Klebsiella pneumoniae (K. pneumoniae)-induced bacteremia at the metabolic level. Bacteremia is caused by bacterial infection in the blood and can rapidly spread to other pats of the body, causing multiple organ failure. Bacteremia is expected to generate measurable changes in metabolic levels. Therefore it is possible to monitor dynamic metabolic changes associated with bacteremia and identify metabolites related to the event. Developing an in-depth and systematic study of changes associated with bacteremia could provide a comprehensive view on the host metabolic response to bacteremia and open a window for nutritional intervention against the disease.For these reasons, this thesis investigated the metabolic signatures of dextran sulfate sodium (DSS)-induced colitis at the systems level, and employed a rat model to investigate metabolic modification induced by K. pneumoniae infection, using a metabonomic strategy.First, we investigated metabolic consequences of DSS-induced acute ulcerative colitis in murine employing’H nuclear magnetic resonance (NMR)-based metabonomics approach with complementary information of serum clinical chemistry and histopathology. We found that acute ulcerative colitis led to significant elevations in the levels of amino acids in plasma, and decreases in the membrane related metabolites and a range of nucleotides, nucleobase and nucleoside in colon. In addition, colitis induced elevations in the levels of nucleotides in liver accompanied with declined levels of glucose. DSS-induced colitis also caused increase in the levels of oxidized glutathione and decreases in the levels of taurine in spleen. Furthermore, colitis resulted in depletion in the levels of gut microbial cometabolites in urine together with increase of citric acid cycle intermediates. These findings suggested that DSS-induced colitis caused disturbance of lipid and energy metabolism, damage to colon and liver, promoted anti-oxidative and anti-inflammatory response, and perturbed gut microbiotal community. The information obtained here provided details of the time-dependent and holistic metabolic changes in the development of the DSS-induced acute ulcerative colitis, which could be useful in discovery of novel therapeutic targets for management of IBD.Second, we investigated the metabolic consequences of a K. pneumoniae bacteremia in vivo by employing a combination of1H NMR spectroscopy and multivariate data analysis. We found that K. pneumoniae-induced bacteremia caused stimulated glycolysis and tricarboxylic acid cycle and promoted oxidation of fatty acids and creatine phosphate to facilitate the high energy expenditure that is required to fight the infectious process. In addition, K. pneumoniae bacteremia also induced anti-bacterial endotoxin, anti-inflammatory and anti-oxidization host responses. Furthermore, bacteremia disturbed gut microbiotal functions via alterations of a range of amines and bacteria-host co-metabolites. Our results suggest that supplementation of glucose together with a high-fat and choline-rich diet could ameliorate the damage associated with bacteremia.To sum up, this thesis provided important information on time-dependent and organ-specific metabolic alterations associated with DSS-induced ulcerative colitis in a mouse model. In addition, we have characterized time dependence of plasma and urinary metabolic alterations in response to K. pneumoniae infection using the metabonomic strategy, indicative of global changes in metabolic regulation.