Targeting Mitochondria-Derived Reactive Oxygen Species to Reduce Epithelial Barrier Dysfunction and Colitis

Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon-derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coli with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)–induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and translocation of E. coli across epithelia and control colonic biopsy specimens, which was more striking in Crohn’s disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS-colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases. Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon-derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coli with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)–induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and translocation of E. coli across epithelia and control colonic biopsy specimens, which was more striking in Crohn’s disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS-colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases. The mammalian gut harbors an immense and diverse microbiota, and host-bacteria interactions are key determinants of digestive health and general well-being.1Hooper L.V. Gordon J.I. Commensal host-bacterial relationships in the gut.Science. 2001; 292: 1115-1118Crossref PubMed Scopus (1863) Google Scholar, 2Lozupone C.A. Stombaugh J.I. Gordon J.I. Jansson J.K. Knight R. Diversity, stability and resilience of the human gut microbiota.Nature. 2012; 489: 220-230Crossref PubMed Scopus (3428) Google Scholar While providing distinct benefits to the host (eg, vitamin synthesis), commensal bacteria that cross the epithelium and enter the mucosa have the potential to provoke inflammation, and movement into the circulation can result in sepsis and death. Consequently, the barrier function of the epithelium, both intrinsic (eg, epithelial tight junctions and cell membranes) and extrinsic (eg, mucus) elements, is a critical component of innate defense. Thus, the commensal bacteria-host interaction pivots on the gut epithelium as a point of first contact and knowledge of the dynamic nature of this interface is important to understanding normal intestinal function and disease.3Turner J.R. Intestinal mucosal barrier function in health and disease.Nat Rev Immunol. 2009; 9: 799-809Crossref PubMed Scopus (2559) Google Scholar The epithelial barrier is not static; rather, it is highly dynamic and tightly regulated to maintain gut homeostasis. However, uncontrolled or prolonged increases in gut permeability have the potential to initiate or exaggerate enteric inflammatory disease. For example, the consensus on the etiology of inflammatory bowel disease (IBD; Crohn’s disease or ulcerative colitis) is that disease develops because of an inappropriate immune response to the gut microbiota in a genetically susceptible individual.4Jostins L. Ripke S. Weersma R.K. Duerr R.H. McGovern D.P. Hui K.Y. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3482) Google Scholar This suggests a barrier defect because microbes, or their products, in the gut lumen must access the mucosal immune system by crossing the epithelial cell layer. Although increased epithelial permeability as a primary cause of IBD remains unproved,3Turner J.R. Intestinal mucosal barrier function in health and disease.Nat Rev Immunol. 2009; 9: 799-809Crossref PubMed Scopus (2559) Google Scholar the leaky gut hypothesis5Hollander D. Crohn’s disease: a permeability disorder of the tight junction?.Gut. 1988; 29: 1621-1624Crossref PubMed Scopus (230) Google Scholar is supported by observations in experimental models of colitis3Turner J.R. Intestinal mucosal barrier function in health and disease.Nat Rev Immunol. 2009; 9: 799-809Crossref PubMed Scopus (2559) Google Scholar, 6Madsen K.L. Malfair D. Gray D. Doyle J.S. Jewell L.D. Fedorak R.N. Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora.Inflamm Bowel Dis. 1999; 5: 262-270Crossref PubMed Scopus (259) Google Scholar, 7Resta-Lenert S. Smitham J. Barrett K.E. Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a-/- mice.Am J Physiol Gastrointest Liver Physiol. 2005; 289: G153-G162Crossref PubMed Scopus (107) Google Scholar and increased epithelial permeability has been repeatedly demonstrated in active IBD.8Zeissig S. Bürgel N. Günzel D. Richter J. Mankertz J. Wahnschaffe U. Kroesen A.J. Fromm M. Schlzke J.D. Changes in expression and distribution of claudins 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease.Gut. 2007; 56: 61-72Crossref PubMed Scopus (916) Google Scholar, 9Söderholm J.D. Peterson K.H. Olaison G. Frazén L.E. Weström B. Magnusson K.E. Sjödahl R. Epithelial permeability to proteins in the non-inflamed ileum of Crohn’s disease.Gastroenterology. 1999; 117: 65-72Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Therefore, the ability to enhance the barrier property of the epithelium would be of value in ameliorating enteric inflammatory disease. Given that control of epithelial permeability (apical junction complex formation and transcellular permeation) is energy dependent, mitochondria should be essential for appropriate regulation of barrier function. Indeed, factors such as infection, nonsteroidal anti-inflammatory drugs, and smoking, which can contribute to the pathophysiological characteristics of Crohn’s disease, also perturb mitochondrial function.10Schoultz I. Söderholm J.D. McKay D.M. Is metabolic stress a common denominator in inflammatory bowel disease?.Inflamm Bowel Dis. 2011; 17: 2008-2018Crossref PubMed Scopus (22) Google Scholar, 11Rodiger W.E. The colonic epithelium in ulcerative colitis: an energy-deficiency disease?.Lancet. 1980; 2: 712-715Abstract PubMed Scopus (588) Google Scholar, 12Singh S. Graff L.A. Bernstein C.N. Do NSAIDs, antibiotics, infections or stress trigger flares in IBD?.Am J Gastroenterol. 2009; 4: 1298-1313Crossref Scopus (142) Google Scholar Furthermore, structurally abnormal mitochondria have been observed in tissue from patients with gut inflammation,13Nazli J. Söderholm J.D. McKay D.M. metabolic stress commensal bacteria as a J Full Text Full Text PDF PubMed Scopus Google Scholar in models of gut J. E. R. barrier function by in is by increased colonic mitochondrial 9: Scopus Google Scholar and in epithelial with or J. K.L. both mitochondrial dysfunction and epithelial barrier in of mitochondrial associated Scopus Google Scholar However, these findings and the in mitochondria in the pathophysiological characteristics of disease, and R. The of mitochondrial in Dis. PubMed Scopus Google Scholar, E. D. and a and J 2011; PubMed Scopus Google Scholar, S. Mitochondrial and 2005; PubMed Scopus Google Scholar are on the of mitochondria in We have that epithelia with dinitrophenol to barrier as by transepithelial of increased and the internalization and translocation of commensal E. J. Söderholm J.D. McKay D.M. metabolic stress commensal bacteria as a J Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Söderholm J.D. McKay D.M. changes are for translocation of Escherichia coli across gut PubMed Scopus Google Scholar The is for of commensal bacteria into the likely a and the response (eg, IL-8 could and the of transcellular permeability to a barrier defect is not and to be assessed and to consideration of the epithelial barrier and innate defense. Thus, the was to the the increased internalization and translocation of commensal Escherichia coli across gut which as a of metabolic stress evoked by targeted of mitochondrial function. tissue was and with the on of human tissue the of and the were the of and to as by the J. of J Immunol. 2011; PubMed Scopus Google Scholar and dextran were from was by coli and were from sodium sulfate was from MitoTEMPO or was from J. Söderholm J.D. McKay D.M. metabolic stress commensal bacteria as a J Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Söderholm J.D. McKay D.M. changes are for translocation of Escherichia coli across gut PubMed Scopus Google Scholar, J. of J Immunol. 2011; PubMed Scopus Google Scholar, J. D. Söderholm J.D. McKay D.M. epithelial barrier function evoked by to metabolic stress and E. coli is by J Physiol Gastrointest Liver Physiol. PubMed Scopus Google Scholar, I. McKay R. Söderholm J.D. 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Bürgel N. Günzel D. Richter J. Mankertz J. Wahnschaffe U. Kroesen A.J. Fromm M. Schlzke J.D. Changes in expression and distribution of claudins 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease.Gut. 2007; 56: 61-72Crossref PubMed Scopus (916) Google Scholar, 9Söderholm J.D. Peterson K.H. Olaison G. Frazén L.E. Weström B. Magnusson K.E. Sjödahl R. Epithelial permeability to proteins in the non-inflamed ileum of Crohn’s disease.Gastroenterology. 1999; 117: 65-72Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar that was increased by to stress J.D. Peterson K.H. Olaison G. Frazén L.E. Weström B. Magnusson K.E. Sjödahl R. Epithelial permeability to proteins in the non-inflamed ileum of Crohn’s disease.Gastroenterology. 1999; 117: 65-72Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar MitoTEMPO reduced the transepithelial flux of E. coli in patients by to However, the increased translocation of E. coli was by MitoTEMPO were to the impact of of MitoTEMPO on colitis of mice after 3 days of to as disease and of and of colonic architecture and However, was a significant in the flux of and a in epithelial mitochondrial expression These epithelial could be important in the of MitoTEMPO colitis that is by barrier function by flux and translocation of bacteria into the mucosa 5 to The of MitoTEMPO in the prolonged MitoTEMPO as a or a and disease. are as to mice from and mice from in the and control DSS. lumen of colitis was in mice to for 5 days days normal MitoTEMPO as a and or a disease. 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PubMed Scopus Google Scholar that perturbed mitochondrial increases epithelial permeability by for the first to that mitochondria-derived superoxide is for the increased transcellular of commensal bacteria and that this can be by In perturbed epithelial mitochondria and increased gut permeability are as in colitis and MitoTEMPO reduced the severity of with barrier function and an ability to proinflammatory cytokine These the of mitochondria-derived as a in the control of epithelial barrier function and host-bacteria interactions in the Although increases in permeability are in models of colitis and J.R. Intestinal mucosal barrier function in health and disease.Nat Rev Immunol. 2009; 9: 799-809Crossref PubMed Scopus (2559) Google Scholar a from increased transcellular to a barrier defect is mitochondrial dysfunction increases to on transcellular permeability because of the of in this of metabolic J. Söderholm J.D. 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