Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines

• Published in: The Journal of clinical investigation Vol. 131; no. 1; pp. 1 - 15
• Main Authors: Smith, Sarah A, Ogawa, Sayaka A, Chau, Lillian, Whelan, Kelly A, Hamilton, Kathryn E, Chen, Jie, Tan, Lu, Chen, Eric Z, Keilbaugh, Sue, Fogt, Franz, Bewtra, Meenakshi, Braun, Jonathan, Xavier, Ramnik J, Clish, Clary B, Slaff, Barry, Weljie, Aalim M, Bushman, Frederic D, Lewis, James D, Li, Hongzhe, Master, Stephen R, Bennett, Michael J, Nakagawa, Hiroshi, Wu, Gary D
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.01.2021
• Subjects: Animals; Bile; Biological oxidation (Metabolism); Biomedical research; Caco-2 Cells; Carnitine - analogs & derivatives; Carnitine - immunology; Cell growth; Citrobacter rodentium - immunology; Colitis; Colon; Complications and side effects; Digestive system; Digestive tract; Energy; Energy metabolism; Energy resources; Enterobacteriaceae Infections - immunology; Enterobacteriaceae Infections - pathology; Epigenetics; Epithelium; Fatty acids; Feces; Female; Gene expression; Health aspects; Humans; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - microbiology; Inflammatory Bowel Diseases - pathology; Intestinal microflora; Intestinal mucosa; Intestinal Mucosa - immunology; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Intestine; Large intestine; Liver - immunology; Male; Metabolism; Metabolites; Mice; Mice, Inbred BALB C; Microbiota; Microbiota (Symbiotic organisms); Mitochondria; Mitochondria - immunology; Mitochondria - pathology; Mitochondrial diseases; Mucosal immunity; Oxidation; Pathogenesis; Physiological aspects; Small intestine; United States; Fatty acid oxidation; Inflammatory bowel disease; Mitochondria; Inflammation; Gastroenterology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI133371

As the interface between the gut microbiota and the mucosal immune system, there has been great interest in the maintenance of colonic epithelial integrity through mitochondrial oxidation of butyrate, a short-chain fatty acid produced by the gut microbiota. Herein, we showed that the intestinal epithelium could also oxidize long-chain fatty acids, and that luminally delivered acylcarnitines in bile could be consumed via apical absorption by the intestinal epithelium, resulting in mitochondrial oxidation. Finally, intestinal inflammation led to mitochondrial dysfunction in the apical domain of the surface epithelium that may reduce the consumption of fatty acids, contributing to higher concentrations of fecal acylcarnitines in murine Citrobacter rodentium-induced colitis and human inflammatory bowel disease. These results emphasized the importance of both the gut microbiota and the liver in the delivery of energy substrates for mitochondrial metabolism by the intestinal epithelium.