Emerging evidence suggests that the gut microbiota play an important role in the development of many diseases including diabetes, cardiovascular disease and cancer. Despite tremendous advances in characterizing microbial diversity within the gastrointestinal tract, very little is known about their function and role of even the most dominant bacterial species within the human host. It is becoming widely accepted that the metabolic products formed by gut bacteria directly impact on human health and disease, particularly regarding immune response and inflammation. In most cases, the products of metabolism are uncharacterized and their mechanism of action unknown. To advance this area of research, this information is vital. This proposal will establish the link between microbial diversity and metabolic functionality by 1) identifying the microbial metabolites and their in vivo concentrations, 2) establishing their mechanism of formation and 3) characterizing the bacterial species responsible. It will deliver these results through a series of acute human interventions with well characterized substrates (macro-, micro- and non-nutrients quantitatively determined) and both the microbial population and metabolites produced identified. The mechanism of transformation and the bacteria responsible will be determined by in vitro incubations, again with well characterized substrates, key metabolites and a unique and comprehensive collection of microbial isolates. Finally, the inflammatory activity of the quantitatively identified metabolites will be established ex vivo. This investigation will deliver several important outcomes including: Identifying microbial metabolites which exhibit inflammatory activity at relevant in vivo concentrations. This will provide essential information (not currently available) informing wider studies looking at the action of microbial metabolites on particular receptors and biomarkers of health. Determining the bacterial species responsible, elucidating their potential function in the gut. Identification of keystone species with unique function will be a major focus and will allow us to identify extent of redundancy of certain species with regard to metabolite production. Established is the role of major macronutrients to drive microbial metabolism, both in the production of phytochemical metabolites and provision of carbohydrate/protein by-products. Only once the complex interplay between diet, the gut microbiota and human health is firmly established, will the role by which the gut microbiota contributes to maintenance of health or disease development be elucidated.
Identifying the important microbial metabolites that exhibit inflammatory activity at relevant in vivo concentrations is essential information, not currently available and will inform wider studies looking at the action of microbial metabolites on particula receptors and biomarkers of health. Determining the species responsible for their transformation will elucidate their potential function and extent of functional redundancy of the gut microbiota. Additionally, this work will establish the effect of the major macronutrients in driving microbial metabolism. Overall, this work will deliver an understanding of the complex interplay between diet, the gut microbiota and human health. Only once this link is firmly established, will the role by which the gut microbiota contributes to disease development be elucidated.
