Although obesity is associated with inflammatory bowel disease (IBD), the underlying molecular mechanism still remains unclear. In this study, we evaluated the effects of high-fat diet (HFD)-induced obesity on the development of experimental colitis in mice. The C57BL/6 mice were fed with a HFD for 12 weeks to develop obesity. The concentrations of free fatty acids (FFA), triglycerides, and cholesterol in plasma were significantly increased in HFD-fed mice compared to low-fat diet (LFD)-fed mice. We found that HFD-induced obesity could exacerbate 2,4,6-trinitro-benzene-sulfonic acid (TNBS)-induced experimental colitis in mice resembling Crohn’s disease (CD). HFD-fed mice showed shorter colon length, higher clinical scores and histological scores, more production of mucosal tumor necrosis factor-α (TNF-α), and greater destruction of colonic epithelial barrier than LFD-fed mice after TNBS induction. HFD feeding also promoted reactive oxygen species (ROS) production in colonic epithelial cells, thus activating the pro-apoptotic pathway to damage colonic epithelial barrier induced by TNBS. After HCT116 cells were treated with palmitate acid (PA) and/or TNF-α for 24 h, the combination of PA and TNF-α increased ROS production, promoted mitochondrial dysfunction, and activated the pro-apoptotic pathway, but these effects were markedly attenuated by a ROS inhibitor. Taken together, these observations suggest that HFD-induced obesity promotes experimental colitis by increasing oxidative stress and mitochondrial dysfunction, which triggers the activation of pro-apoptotic pathway in the colon.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Gibson, P.R. 2004. Increased gut permeability in Crohn disease: Is TNF the link? Gut 53: 1724–1725.
Wu, X.X., X.L. Huang, R.R. Chen, T. Li, H.J. Ye, W. Xie, Z.M. Huang, and G.Z. Cao. 2019. Paeoniflorin prevents intestinal barrier disruption and inhibits lipopolysaccharide (LPS)-induced inflammation in Caco-2 cell monolayers. Inflammation 42: 2215–2225.
Fasano, A., and T. Sheadonohue. 2005. Mechanisms of disease: The role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nature Clinical Practice. Gastroenterology & Hepatology 2: 416–422.
He, L., T. Liu, Y. Shi, F. Tian, H. Hu, D.K. Deb, Y. Chen, M. Bissonnette, and Y.C. Li. 2018. Gut epithelial vitamin D receptor regulates microbiota-dependent mucosal inflammation by suppressing intestinal epithelial cell apoptosis. Endocrinology 159: 967–979.
Capaldo, C.T., D.N. Powell, and D. Kalman. 2017. Layered defense: How mucus and tight junctions seal the intestinal barrier. Journal of Molecular Medicine 95: 927–934.
Du, J., Y. Chen, Y. Shi, T. Liu, Y. Cao, Y. Tang, X. Ge, H. Nie, C. Zheng, and Y.C. Li. 2015. 1,25-Dihydroxyvitamin D protects intestinal epithelial barrier by regulating the myosin light chain kinase signaling pathway. Inflammatory Bowel Diseases 21: 2495–2506.
Sabatino, A.D., R. Ciccocioppo, O. Luinetti, L. Ricevuti, R. Morera, M. Cifone, E. Solcia, and G. Corazza. 2003. Increased enterocyte apoptosis in inflamed areas of Crohn’s disease. Diseases of the Colon & Rectum 46: 1498–1507.
Nenci, A., C. Becker, A. Wullaert, R. Gareus, G. van Loo, S. Danese, M. Huth, A. Nikolaev, C. Neufert, and B. Madison. 2007. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446: 557–561.
Shi, Y., T. Liu, L. He, U. Dougherty, L. Chen, S. Adhikari, L. Alpert, G. Zhou, W. Liu, J. Wang, D.K. Deb, J. Hart, S.Q. Liu, J. Kwon, J. Pekow, D.T. Rubin, Q. Zhao, M. Bissonnette, and Y.C. Li. 2016. Activation of the renin-angiotensin system promotes colitis development. Scientific Reports 6: 27552.
Colombo, B.B., V. Fattori, C.F.S. Guazelli, T.H. Zaninelli, T.T. Carvalh, C.R. Ferraz, A.J.C. Bussmann, K.W. Ruizmiyazawa, M.M. Baracat, R. Casaqrande, and W.A. Verri Jr. 2018. Vinpocetine ameliorates acetic acid-induced colitis by inhibiting NF-κB activation in mice. Inflammation 41: 1276–1289.
Komaki, Y., F. Komaki, A. Sakuraba, and R. Cohen. 2016. Approach to optimize anti-TNF-α therapy in patients with IBD. Current Treatment Options in Gastroenterology 14: 83–90.
Al-Sadi, R., S. Guo, D. Ye, M. Rawat, and T.Y. Ma. 2016. TNF-α modulation of intestinal tight junction permeability is mediated by NIK/IKK-α Axis activation of the canonical NF-κB pathway. American Journal of Pathology 186: 1151–1165.
Suski, J.M., M. Lebiedzinska, M. Bonora, P. Pinton, and M.R. Wieckowski. 2012. Relation between mitochondrial membrane potential and ROS formation. Methods in Molecular Biology 810: 83–205.
Ye, L., S. Mao, S. Fang, J. Zhang, Y. Tan, and W. Gu. 2019. Increased serum Romo1 was correlated with lung function, inflammation, and oxidative stress in chronic obstructive pulmonary disease. Inflammation 42: 1555–1560.
Liao, H.Y., C.M. Kao, C. Yao, P.W. Chiu, and S.C. Chen. 2017. 2,4,6-trinitrotoluene induces apoptosis via ROS-regulated mitochondrial dysfunction and endoplasmic reticulum stress in HepG2 and Hep3B cells. Scientific Reports 7: 8148.
Harper, J.W., and Z.T. L. 2016. Interaction of obesity and inflammatory bowel disease. World Journal of Gastroenterology 22: 7868–7881.
Okla, M., W. Zaher, M. Alfayez, and S. Chung. 2018. Inhibitory effects of toll-like receptor 4, NLRP3 inflammasome, and interleukin-1β on white adipocyte browning. Inflammation 41: 626–642.
Bournat, J.C., and C.W. Brown. 2015. Mitochondrial dysfunction in obesity. Current Opinion in Endocrinology, Diabetes, and Obesity 17: 446–452.
Cheng, L., H. Jin, Y. Qiang, S. Wu, C. Yan, M. Han, T. Xiao, N. Yan, H. An, and X. Zhou. 2016. High fat diet exacerbates dextran sulfate sodium induced colitis through disturbing mucosal dendritic cell homeostasis. International Immunopharmacology 40: 1–10.
Wunderlich, C.M., P.J. Ackermann, A.L. Ostermann, P. Adams-Quack, M.C. Vogt, M.-L. Tran, A. Nikolajev, A. Waisman, C. Garbers, and S. Theurich. 2018. Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment. Nature Communications 9: 1646.
Li, X., X. Wei, Y. Sun, J. Du, X. Li, Z. Xun, and Y.C. Li. 2019. High-fat diet promotes experimental colitis by inducing oxidative stress in the colon. American Journal of Physiology. Gastrointestinal and Liver Physiology 317: G453–G462.
Wirtz, S., V. Popp, M. Kindermann, K. Gerlach, B. Weigmann, S. Fichtner-Feigl, and M.F. Neurath. 2017. Chemically induced mouse models of acute and chronic intestinal inflammation. Nature Protocols 12: 1295–1309.
Alnahdi, A., A. John, and H. Raza. 2019. Augmentation of glucotoxicity, oxidative stress, apoptosis and mitochondrial dysfunction in HepG2 cells by palmitic acid. Nutrients 11: 1979.
Gulhane, M., L. Murray, R. Lourie, H. Tong, Y.H. Sheng, R. Wang, A. Kang, V. Schreiber, K.Y. Wong, and G. Magor. 2016. High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22. Scientific Reports 6: 28990.
Paik, J., Y. Fierce, P.M. Treuting, T. Brabb, and L. Maggio-Price. 2013. High-fat diet-induced obesity exacerbates inflammatory bowel disease in genetically susceptible Mdr1a−/− male mice. Journal of Nutrition 143: 1240–1247.
June-Chul, L., L. Hae-Youn, K.T. Kang, K. Min-Soo, P.Y. Mi, K. Jinyoung, P. Kihyoun, K. Mi-Na, K. Seok-Hyung, and B. Jin-Woo. 2017. Obesogenic diet-induced gut barrier dysfunction and pathobiont expansion aggravate experimental colitis. PLoS One 12: e0187515.
Crespo, I., B. San-Miguel, C. Prause, N. Marroni, M.J. Cuevas, J. González-Gallego, and M.J. Tuñón. 2012. Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis. PLoS One 7: e50407.
Qin, L., Z.Q. Yao, Q. Chang, Y.L. Zhao, and J. Li. 2016. Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis. Oncotarget 8: 7391–7404.
Coppack, S.W. 2001. Pro-inflammatory cytokines and adipose tissue. The Proceedings of the Nutrition Society 60: 349–356.
Ding, X., D. Li, M. Li, H. Wang, and Q. Yu. 2018. SLC26A3 (DRA) prevents TNF-alpha-induced barrier dysfunction and dextran sulfate sodium-induced acute colitis. Laboratory Investigation 98: 462–476.
Peterson, L.W., and D. Artis. 2014. Intestinal epithelial cells: Regulators of barrier function and immune homeostasis. Nature Reviews Immunology 14: 141–153.
Mcmurray, F., D.A. Patten, and M.-E. Harper. 2016. Reactive oxygen species and oxidative stress in obesity-recent findings and empirical approaches. Obesity 24: 2301–2310.
Yao, J., Z. Li, Y. Fu, R. Wu, Y. Wang, C. Liu, L. Yang, and H. Zhang. 2019. Involvement of obesity-associated upregulation of chemerin/chemokine-like receptor 1 in oxidative stress and apoptosis in ovaries and granulosa cells. Biochemical and Biophysical Research Communications 12: 449–455.
Ji, J., Y. Qin, J. Ren, C. Lu, R. Wang, X. Dai, R. Zhou, Z. Huang, M. Xu, and M. Chen. 2015. Mitochondria-related miR-141-3p contributes to mitochondrial dysfunction in HFD-induced obesity by inhibiting PTEN. Scientific Reports 5: 16262.
Zhan, M., C. Brooks, F. Liu, L. Sun, and Z. Dong. 2013. Mitochondrial dynamics: Regulatory mechanisms and emerging role in renal pathophysiology. Kidney International 83: 568–581.
This work was supported by the guiding Plan of Natural Science Foundation of Liaoning Province of China (Grant No. 20170520275).
Conflict of Interests
The authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Li, X., Li, X. Obesity Promotes Experimental Colitis by Increasing Oxidative Stress and Mitochondrial Dysfunction in the Colon. Inflammation (2020). https://doi.org/10.1007/s10753-020-01261-6
- high-fat diet
- inflammatory bowel disease
- oxidative stress
- mitochondrial dysfunction