Abstract
Inflammatory bowel disease (IBD) characterized by inflammation of the gastrointestinal tract. It includes Crohn’s disease and ulcerative colitis. In 2015, 3 million U.S. adults have been diagnosed with IBD and many people go undiagnosed due to mild symptoms. Women appear to have more severe and recurring symptoms of IBD compared to men, most likely due to hormonal fluctuations. Several studies show mitochondrial alterations in IBD patients. Our hypothesis is mitochondrial dysfunction in IBD could have a sex‐specific effect. Male and female rats received two doses of indomethacin (7.5 mg/kg) 24 hour apart to induce IBD. Colon tissues were collected for mitochondrial isolation two days after injections. Mitochondrial respiration and reactive oxygen species (mtROS) production were measured simultaneously by an Oroboros Fluorespirometer using glutamate/malate, succinate, oleate (long‐chain fatty acid; LCFA), or octanoate (medium chain fatty acid; MCFA). Complex IV activity, a marker of oxidative phosphorylation capacity, was measured. Data were normalized to mitochondrial content using citrate synthase (CS) activity, which confirms that the observed changes are not due to loss of mitochondrial content. CS activity showed no change in females but a significant decrease in male IBD rats compared to controls (2425 ± 200.2 vs. 3586 ± 214.4 nmol citrate/min/g tissue, p<0.05). When respiration was normalized to CS activity, males showed no significant difference compared to controls with complex I and complex II‐driven respiration. However, IBD females showed a significant decrease in Complex I‐driven respiration (0.4258 ± 0.02903 vs 0.5437 ± 0.03939 nmol e‐/nmol citrate, p<0.5) and Complex II ‐driven respiration (0.7489 ± 0.035118 vs. 0.9029 ± 0.04664 nmol e‐/nmol citrate, p<0.05). For LCFA oxidation, males (0.6912 ± 0.07261 vs. 0.2554 ± 0.01185 nmol e‐/nmol citrate, p<0.05) and females (0.3984 ± 0.03192 vs. 0.2389 ± 0.02243 nmol e‐/nmol citrate, p<0.05) showed a significant increase in activity compared to controls. Both males and females showed no significant decrease in LCFA or MCFA oxidation. Males and females both showed a significant increase in mtROS with all substrates. Complex IV activity was not different than controls in males but female activity was significantly decreased (1.099 ± 0.09693 vs. 1.379 ± 0.05922 nmol e‐/nmol citrate, p<0.05). Alterations to mitochondrial function and mitochondrial content observed in the indomethacin‐induced IBD rat model suggests a link between mitochondrial dysfunction and IBD. There are differences in male and female rats suggesting a potential mechanism for the observed differences in male and female patients. Our study provides a better understanding of the role mitochondria in the development of IBD. It also opens an avenue for the development of strategies to re‐establish normal mitochondrial function that could provide more options for preventive and therapeutic interventions for IBD.
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