The PI3K pathway as a therapeutic intervention point in inflammatory bowel disease

Abstract

With glucose being the preferred source of energy in activated T cells, targeting glycolysis has become an attractive therapeutic intervention point for chronic inflammatory bowel diseases (IBD). The switch to glycolysis is mediated by phosphoinositide-3-kinases (PI3K) which relay signals from surface receptors to the AKT pathway. We first confirmed by analysis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) that metabolism is shifted towards glycolysis in IBD patients as compared to non-IBD donors. In contrast to non-IBD donors, OCR correlated with ECAR (IBD: cor = 0.79, p = 2E-10; non-IBD: cor = 0.37, p = n.s.), in IBD patients. Second, we tested the PI3K inhibitor copanlisib as a potential therapeutic. Ex vivo, copanlisib suppressed the ECAR significantly in T cells activated by anti-CD3 antibodies and significantly decreased ECAR rates in the presence of copanlisib (anti-CD3: 58.24 ± 29.06; copanlisib: 43.16 ± 20.23, p