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.