Abstract

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

J Clin Invest. 2020 Nov 3;133371.doi: 10.1172/JCI133371. Online ahead of print.

Sarah A Smith 1, Sayaka A Ogawa 1, Lillian Chau 1, Kelly A Whelan 1, Kathryn E Hamilton 2, Jie Chen 3, Lu Tan 3, Eric Z Chen 4, Sue Keilbaugh 1, Franz Fogt 5, Meenakshi Bewtra 1, Jonathan Braun 6, Ramnik J Xavier 7, Clary B Clish 8, Barry Slaff 9, Aalim M Weljie 9, Frederic D Bushman 10, James D Lewis 1, Hongzhe Li 11, Stephen R Master 3, Michael J Bennett 3, Hiroshi Nakagawa 12, Gary D Wu 1

 
     

Author information

  • 1Division of Gastroenterology, University of Pennsylvania, Philadelphia, United States of America.
  • 2Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, United States of America.
  • 3Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America.
  • 4Department of Informatics, Dana-Farber Cancer Institute, Boston, United States of America.
  • 5Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States of America.
  • 6Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America.
  • 7Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, United States of America.
  • 8Metabolite Profiling Initiative, Broad Institute of Harvard and MIT, Cambridge, United States of America.
  • 9Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America.
  • 10Department of Microbiology, University of Pennsylvania, Philadelphia, United States of America.
  • 11Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, United States of America.
  • 12Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, United States of America.

Abstract

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 can also oxidize long-chain fatty acids, and that luminally-delivered acylcarnitines in bile can 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.

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