Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines
Sarah A. Smith, … , Hiroshi Nakagawa, Gary D. Wu
Sarah A. Smith, … , Hiroshi Nakagawa, Gary D. Wu
Published November 3, 2020
Citation Information: J Clin Invest. 2021;131(1):e133371. https://doi.org/10.1172/JCI133371.
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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 1

The reciprocal relationship between short- and long-chain fatty oxidation by the colonic epithelium.

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The reciprocal relationship between short- and long-chain fatty oxidatio...
(A) Quantification of oleic acid oxidation using a tritiated water release assay in inverted colonic and small intestinal mouse explant cultures harvested from mice. n = 3, mean ± SEM, *P < 0.05. Representative results of at least 2–3 independent experiments. (B–E) Quantification of the fatty acid oxidation intermediates, acyl-CoAs, by mass spectrometry in mouse intestinal tissues. (B) Short- and (C) long-chain acyl-CoAs in the small intestine and colon. (D) Short- and (E) long-chain acyl-CoAs in the colon of wild-type versus SCAD-deficient mice. Representative results of at least 3 experiments. n = 5, mean ± SEM, *P < 0.05, **P < 0.01. (F) Quantification of oleic acid oxidation using the tritiated water release assay in colonic explants isolated from wild-type versus SCAD-deficient mice. n = 3, mean ± SEM, *P < 0.05. The assays were repeated in the presence or absence of 10 mM sodium butyrate in using colonic explants isolated from (G) wild-type or (H) SCAD-deficient mice. n = 3, mean ± SEM, *P < 0.05. Representative results of 2 independent experiments. P values represent a 2-tailed Student’s t test and paired-sample t test.