Sporadic colorectal cancer (CRC) remains a major cause of worldwide mortality. It is a disease whose aetiology is defined primarily by interactions between the host and his environment. The gut microbiota, which sits at the interface between the host’s physiology and exposome, is now recognised as a critical modulator in CRC aetiology. However, our understanding of this immensely complex, highly individualised and multi-faceted relationship is incomplete and not easily amenable to traditional reductive scientific investigation. In this work, I have therefore employed systems medicine approaches in a large, prospective, cross-sectional case-control study of patients at all stages of colorectal neoplastic progression. Using 16S rRNA gene sequencing, I show that gut microbiota composition is indicative of CRC disease stage and molecular phenotype, and define two anti-correlated community sub-types, which could explain this association. Utilising liquid-chromatography mass spectrometry, I further define metabolomic changes in the developing tumour micro-environment, including the over-representation of phospholipid species, long chain fatty acids and amino acids, and, for the first time, relate these changes to microbial composition and function. Finally, Rapid Evaporative Ionisation Mass Spectrometry is developed as a tool for sampling the metabolic changes of dysplasia and cancer, both at the mucosa via colonoscopy, and in faeces, raising the spectre of an entirely novel approach for tumour chemical phenotyping and non-invasive CRC screening.