Mitochondrial Dysfunction and Reduced TCA Cycle Metabolite Levels in Inflammatory Bowel Disease Patients

Ewa Dudzińska,1 Agnieszka Madro,2 Ann Katrin Sauer,3,4 Andreas M Grabrucker,3– 5 Aneta Strachecka6 1Department of Dietetics and Nutrition Education, Medical University of Lublin, Lublin, Poland; 2Department of Gastroenterology with Endoscopic Unit, Medical University of Lublin, Lublin, Poland; 3Department of Biological Sciences, University of Limerick, Limerick, Co, Ireland; 4Bernal Institute, University of Limerick, Limerick, Co. Limerick, Ireland; 5Health Research Institute (HRI), University of Limerick, Limerick, Co, Ireland; 6Department of Invertebrate Ecophysiology and Experimental Biology, University of Life Sciences in Lublin, Lublin, PolandCorrespondence: Ewa Dudzińska, Department of Dietetics and Nutrition Education, Medical University of Lublin, Lublin, 20-059, Poland, Email [email protected]: Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn’s disease (CD). These diseases are classified as chronic and recurrent inflammatory diseases affecting the digestive tract. An energy deficiency in intestinal cells is believed to be associated with IBD pathology.Methods: Our study investigated the bioenergetic functionality of mitochondria using the plasma of patients with CD and UC by determining the concentration of intermediates of the tricarboxylic acid cycle (TCA), such as acetyl coenzyme A, succinate, fumarate, α-ketoglutarate, NADH2, IDH2, Cytochrome C Oxidase, Cytochrome C Reductase, and ATP.Results: Our results show an imbalance in mitochondrial homeostasis and bioenergetics, demonstrated by reduced activity of respiratory complexes and reduced production of TCA intermediates in the plasma of patients with CD and UC. In the group of patients with CD, treatment with corticosteroids had a significant positive effect, as significantly higher IDH2 and succinate levels were found. Correlation analyses of mitochondrial functionality biomarkers with other blood markers revealed a significant relationship between CRP and ATP levels, with higher CRP significantly linked to lower ATP and a similar trend for succinate levels. Using the disease activity scale, we show that biomarkers such as IDH2, α-ketoglutarate, and succinate levels are significantly lower in patients with higher disease activity.Conclusion: We conclude that reduced metabolites and respiratory complexes associated with the TCA indicate mitochondrial bioenergetic failure in IBD patients. Besides, Krebs cycle metabolites can be a good marker of predisposition to the disease and the course of IBD. They can be easily determined in a blood sample taken from the patient. Pharmacological protection of mitochondria in individuals predisposed to IBD development and compensation for the changed function of mitochondria in persons with the developed disease may become a new approach to personalized therapies focused on restoring the proper activity of mitochondrial enzymes.Keywords: inflammatory bowel disease, Krebs cycle, respiratory complexes