Immunometabolism and mitochondria in inflammatory bowel disease: a role for therapeutic intervention?

Abstract

Inflammatory bowel diseases (IBDs), incurable conditions characterised by recurrent episodes of immune-mediated gut inflammation and damage of unknown aetiology, are common. Current advanced therapies target key leukocyte-trafficking and cytokine-signalling hubs but are only effective in 50% of patients. With growing evidence of mitochondrial dysfunction in IBD and advances in our understanding of the role of metabolism in inflammation, we provide an overview of novel metabolic approaches to IBD therapy, challenging the current 'therapeutic ceiling', identifying critical pathways for intervention and re-imagining metabolic biomarkers for the 21st century.

Claire E. Adams, Duncan G. Rutherford, Gareth R. Jones and Gwo-tzer Ho (left to right)

Fig. 1.

Mechanisms and immunometabolic therapeutic targets in the gut and IBD. Pathological factors, such as genetic susceptibility, decreased homeostatic pathways, increased mitochondrial injurious stimuli, hypoxia, nutritional factors and PAMPs, can all lead to mitochondrial and metabolic dysfunction and inflammatory processes in relevant intestinal cells (epithelial, intestinal stem and immune cells). Metabolic and mitochondrial dysfunction in intestinal stem cells causes defective repair and regeneration of the epithelial layer and contributes to metabolic and mitochondrial dysfunction in intestinal epithelial cells. The resultant pro-inflammatory processes include increased ROS, inflammatory cell death, inflammasome activation, and release of inflammatory metabolites and DAMPs. DAMP, damage associated molecular pattern; FP, mitochondrial formylated peptide; IBD, inflammatory bowel disease; LPS, lipopolysaccharide; MDR1, multidrug resistance 1 (also known as ABCB1); PAMP, pathogen associated molecular pattern; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; TCA, tricarboxylic acid cycle; Th, T helper.