I103. Metabolic Fingerprinting of Disease Activity and Response to Therapy

Abstract

Inflammation is a critical component of normal responses to infection and injury, but substantial systemic changes to host organs and cells can result. Energy expenditure can be significant, resulting in widespread modulation of metabolism. Resting nonproliferative tissues have distinctive metabolic activities and requirements, which differ considerably from those in infiltrating immune cells, since these are proliferating and differentiating. Immune responses in tissues may therefore be modulated by the availability of substrates in the inflamed site and host tissue metabolism affected in the inflammatory environment. We have been exploring the potential for metabolomic analysis to identify disease-specific alterations in metabolism to provide novel insights into the inflammatory process. We have used NMR-based metabolomic fingerprinting to identify unique metabolic profiles in the eye in different forms of uveitis, in CSF in neurological conditions, but also in blood and urine in trauma and inflammatory arthritis. This suggests that the site-specific metabolic changes are reflected in systemic metabolic shifts. We have found that muscle metabolites, probably resulting from sarcopenia, are found in urine and can be used to predict responses to anti-TNF therapeutics in RA patients. In vitro culture of differentiated macrophages and synovial fibroblasts identifies significant metabolic differences in macrophage subtypes and unique metabolic profiles in fibroblasts derived from RA. This suggests that both host tissue cells and infiltrating immune cells contribute to alterations in the profile of systemic metabolites. Metabolomics is probably the systems biology approach most readily applicable to the study of inflammatory disease. Such studies have already provided insights into interaction between inflammatory cells and organs, energy substrate use, tissue breakdown, the microbiome and drug metabolites, and will find widespread application in the investigation into the regulation of inflammatory diseases.