Disease Biomarker Profiling: Focus on Bladder Cancer and Dietary Fructose Intolerance

Abstract

Robust biomarkers are essential for disease surveillance and intervention. In this thesis, we profiled metabolic perturbations of bladder cancer and dietary fructose intolerance, both persistent diseases with limited current understanding and few surveillance biomarkers. Urinary metabolomics of clinical bladder cancer yielded tryptophan-kynurenine ratio (KYN/TRP) as a potential biomarker. KYN/TRP correlated positively with tumor load (R2=0.67) in orthotopic cancer murine models. These findings were supported by expression of the mediating enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in tissue biopsies. An IDO1 inhibitor was further explored as therapy in orthotopic cancer mice, displaying marginal treatment efficacy. In our investigation of dietary fructose intolerance, a randomized crossover study on fructose or placebo ingestion yielded symptomatic fructose-intolerant and tolerant subjects. Hydrogen and methane breath gases were higher in the fructose-intolerant, but systemic exposure of fructose was similar between intolerant and tolerant phenotypes. Further plasma untargeted metabolomics and targeted short-chain fatty acids analyses did not reveal prominent differences between tolerant and intolerant phenotypes, although valerate was moderately correlated to hydrogen (r=0.34), methane (r=0.45), and fructose (r=−0.41). We postulate a bigger role of niche intestinal microbes in mediating gases production and visceral hypersensitivity, and a lesser role of fructose intestinal malabsorption in dietary fructose intolerance.