Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines
Sarah A. Smith, Sayaka A. Ogawa, Lillian Chau, Kelly A. Whelan, Kathryn E. Hamilton, Jie Chen, Lu Tan, Eric Z. Chen, Sue Keilbaugh, Franz Fogt, Meenakshi Bewtra, Jonathan Braun, Ramnik J. Xavier, Clary B. Clish, Barry Slaff, Aalim M. Weljie, Frederic D. Bushman, James D. Lewis, Hongzhe Li, Stephen R. Master, Michael J. Bennett, Hiroshi Nakagawa, Gary D. Wu
Sarah A. Smith, Sayaka A. Ogawa, Lillian Chau, Kelly A. Whelan, Kathryn E. Hamilton, Jie Chen, Lu Tan, Eric Z. Chen, Sue Keilbaugh, Franz Fogt, Meenakshi Bewtra, Jonathan Braun, Ramnik J. Xavier, Clary B. Clish, Barry Slaff, Aalim M. Weljie, Frederic D. Bushman, James D. Lewis, Hongzhe Li, Stephen R. Master, Michael J. Bennett, Hiroshi Nakagawa, Gary D. Wu
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Research Article Gastroenterology Inflammation

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

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 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.

Authors

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

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Figure 6

Comparative morphological analysis of colonic epithelial mitochondria in healthy human subjects versus patients with IBD.

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Comparative morphological analysis of colonic epithelial mitochondria in...
MTCO1 staining of colonic tissue obtained from a representative healthy (control) human subject (A and C) and a representative patient with IBD (UC) (B and D). Electron microscopy of the superficial colonic epithelium obtained from a representative healthy human subject (E and G) and a representative patient with IBD (UC) (F and H). Scale bars: 400 μm (A and B), 200 μm (C and D), 2 μm (E and F), 500 nm (G and H). Symbols: crypt (C), goblet cell (G), nucleus (N), surface epithelium (SE), mitochondria (M), supranuclear mitochondria (black arrows), subnuclear mitochondria (black arrowheads).