AMPK-PINK1/Parkin Mediated Mitophagy Is Necessary for Alleviating Oxidative Stress-Induced Intestinal Epithelial Barrier Damage and Mitochondrial Energy Metabolism Dysfunction in IPEC-J2

The imbalance of redox biology and oxidative stress leads to intestinal barrier injury and mitophagy. However, much uncertainty still exists about the role of mitophagy in oxidative stress and intestinal function. Here, we showed the effects of hydrogen peroxide (H2O2)-induced oxidative stress on intestinal epithelial cell oxidation balance, intestinal barrier function and mitochondrial energy metabolism and its underlying mechanism. In this study, we found that H2O2-induced oxidative stress activated adenosine monophosphate-activated protein kinase (AMPK) and enhanced mitophagy in intestinal porcine epithelial cells (IPEC-J2). While compound C (AMPK inhibitor) and mdivi-1 (mitophagy inhibitor) significantly reduced the activity of superoxide dismutase (SOD) and increased mitochondrial reactive oxygen species (ROS) levels in H2O2 treated cells. Moreover, compound C and mdivi-1 significantly reduced the trans-epithelium electrical resistant (TER) and increased the fluorescein isothiocyanate-dextran (FD4) flux in H2O2 treated IPEC-J2. Furthermore, compound C and mdivi-1 significantly reduced the activity of mitochondrial complex II. Seahorse XF96 data showed that compound C + mdivi-1+ H2O2 treatment significantly reduced maximum respiratory oxygen consumption and spare respiratory capacity. Additionally, compound C or mdivi-1 treatment reduced the formation of mitochondrial autophagosomes. These results unveiled that AMPK and PINK1/Parkin mediated mitophagy is necessary for alleviating oxidative stress induced intestinal epithelial barrier damage and mitochondrial energy metabolism dysfunction in IPEC-J2.

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Plumericin Protects against Experimental Inflammatory Bowel Disease by Restoring Intestinal Barrier Function and Reducing Apoptosis

Biomedicines ◽

10.3390/biomedicines9010067 ◽

2021 ◽

Vol 9 (1) ◽

pp. 67 ◽

Cited By ~ 1

Author(s):

Shara Francesca Rapa ◽

Rosanna Di Paola ◽

Marika Cordaro ◽

Rosalba Siracusa ◽

Ramona D’Amico ◽

...

Keyword(s):

Barrier Function ◽

Structural Integrity ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Bowel Diseases ◽

Inflammatory Bowel

Intestinal epithelial barrier impairment plays a key pathogenic role in inflammatory bowel diseases (IBDs). In particular, together with oxidative stress, intestinal epithelial barrier alteration is considered as upstream event in ulcerative colitis (UC). In order to identify new products of natural origin with a potential activity for UC treatment, this study evaluated the effects of plumericin, a spirolactone iridoid, present as one of the main bioactive components in the bark of Himatanthus sucuuba (Woodson). Plumericin was evaluated for its ability to improve barrier function and to reduce apoptotic parameters during inflammation, both in intestinal epithelial cells (IEC-6), and in an animal experimental model of 2, 4, 6-dinitrobenzene sulfonic acid (DNBS)-induced colitis. Our results indicated that plumericin increased the expression of adhesion molecules, enhanced IEC-6 cells actin cytoskeleton rearrangement, and promoted their motility. Moreover, plumericin reduced apoptotic parameters in IEC-6. These results were confirmed in vivo. Plumericin reduced the activity of myeloperoxidase, inhibited the expression of ICAM-1, P-selectin, and the formation of PAR, and reduced apoptosis parameters in mice colitis induced by DNBS. These results support a pharmacological potential of plumericin in the treatment of UC, due to its ability to improve the structural integrity of the intestinal epithelium and its barrier function.

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Collagen peptides ameliorate intestinal epithelial barrier dysfunction in immunostimulatory Caco-2 cell monolayers via enhancing tight junctions

Food & Function ◽

10.1039/c6fo01347c ◽

2017 ◽

Vol 8 (3) ◽

pp. 1144-1151 ◽

Cited By ~ 21

Author(s):

Qianru Chen ◽

Oliver Chen ◽

Isabela M. Martins ◽

Hu Hou ◽

Xue Zhao ◽

...

Keyword(s):

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Cell Monolayers ◽

Collagen Peptides ◽

Epithelial Barrier Dysfunction

Alaska pollock skin derived collagen peptides could be considered as dietary supplements for intestinal barrier function promotion and associated diseases.

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Treatment of Nonalcoholic Fatty Liver Disease through Changes in Gut Microbiome and Intestinal Epithelial Barrier

10.5772/intechopen.97568 ◽

2021 ◽

Author(s):

Hassan M. Heshmati

Keyword(s):

Liver Disease ◽

Gut Microbiome ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Excess Body Weight ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is a leading liver disease worldwide with a prevalence of approximately 25% among adult population. The highest prevalence is observed in Middle East and the lowest prevalence in Africa. NAFLD is a spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Pro-inflammatory diet, overweight/obesity, inflammation, insulin resistance, prediabetes, type 2 diabetes, dyslipidemia, disrupted gut microbiome, and impaired intestinal barrier function are important risk factors associated with and/or contributing to NAFLD. Gut microbiome is a complex and diverse microbial ecosystem essential for the maintenance of human health. It is influenced by several factors including diet and medications. Gut microbiome can be disrupted in NAFLD. Intestinal epithelial barrier is the largest and most important barrier against the external environment and plays an important role in health and disease. Several factors including diet and gut microbiome impact intestinal barrier function. NAFLD can be associated with impaired intestinal barrier function (increased intestinal permeability). There are no specific drugs that directly treat NAFLD. The first-line therapy of NAFLD is currently lifestyle intervention. Weight loss is an important component in the treatment of NAFLD subjects who have excess body weight. Gut microbiome and intestinal epithelial barrier are becoming promising targets for the treatment of several diseases including NAFLD. In the absence of approved pharmacotherapy for the treatment of NAFLD/NASH, in addition to lifestyle intervention and weight loss (in case of excess body weight), focus should also be on correcting gut microbiome and intestinal permeability (directly and/or through gut microbiome modulation) using diet (e.g., low-fat diet, high-fiber diet, and Mediterranean diet), prebiotics (nondigestible food ingredients), probiotics (nonpathogenic living microorganisms), synbiotics (combination of prebiotics and probiotics), and fecal microbiota transplantation (transfer of healthy stool).

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Regulation of Oxygen Homeostasis at the Intestinal Epithelial Barrier Site

International Journal of Molecular Sciences ◽

10.3390/ijms22179170 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9170

Author(s):

Špela Konjar ◽

Miha Pavšič ◽

Marc Veldhoen

Keyword(s):

Hypoxia Inducible Factor ◽

Intestinal Barrier ◽

Oxygen Metabolism ◽

High Rate ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Surface ◽

Oxygen Homeostasis

The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO2), characterised by a high rate of metabolites circulating through the intestinal blood and the presence of a steep oxygen gradient across the epithelial surface. These characteristics require tight regulation of oxygen homeostasis, achieved in part by hypoxia-inducible factor (HIF)-dependent signalling. Furthermore, intestinal epithelial cells (IEC) possess metabolic identities that are reflected in changes in mitochondrial function. In recent years, it has become widely accepted that oxygen metabolism is key to homeostasis at the mucosae. In addition, the gut has a vast and diverse microbial population, the microbiota. Microbiome–gut communication represents a dynamic exchange of mediators produced by bacterial and intestinal metabolism. The microbiome contributes to the maintenance of the hypoxic environment, which is critical for nutrient absorption, intestinal barrier function, and innate and/or adaptive immune responses in the gastrointestinal tract. In this review, we focus on oxygen homeostasis at the epithelial barrier site, how it is regulated by hypoxia and the microbiome, and how oxygen homeostasis at the epithelium is regulated in health and disease.

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Decline in intestinal mucosal IL-10 expression and decreased intestinal barrier function in a mouse model of total parenteral nutrition

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00386.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. G139-G147 ◽

Cited By ~ 76

Author(s):

Xiaoyi Sun ◽

Hua Yang ◽

Keisuke Nose ◽

Satoko Nose ◽

Emir Q. Haxhija ◽

...

Keyword(s):

Parenteral Nutrition ◽

Tight Junction ◽

Total Parenteral Nutrition ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Junction Molecules

Loss of intestinal epithelial barrier function (EBF) is a major problem associated with total parenteral nutrition (TPN) administration. We have previously identified intestinal intraepithelial lymphocyte (IEL)-derived interferon-γ (IFN-γ) as a contributing factor to this barrier loss. The objective was to determine whether other IEL-derived cytokines may also contribute to intestinal epithelial barrier breakdown. C57BL6J male mice received TPN or enteral nutrition (control) for 7 days. IEL-derived interleukin-10 (IL-10) was then measured. A significant decline in IEL-derived IL-10 expression was seen with TPN administration, a cytokine that has been shown in vitro to maintain tight junction integrity. We hypothesized that this change in IEL-derived IL-10 expression could contribute to TPN-associated barrier loss. An additional group of mice was given exogenous recombinant IL-10. Ussing chamber experiments showed that EBF markedly declined in the TPN group. TPN resulted in a significant decrease of IEL-derived IL-10 expression. The expression of several tight junction molecules also decreased with TPN administration. Exogenous IL-10 administration in TPN mice significantly attenuated the TPN-associated decline in zonula occludens (ZO)-1, E-cadherin, and occludin expression, as well as a loss of intestinal barrier function. TPN administration led to a marked decline in IEL-derived IL-10 expression. This decline was coincident with a loss of intestinal EBF. As the decline was partially attenuated with the administration of exogenous IL-10, our findings suggest that loss of IL-10 may be a contributing mechanism to TPN-associated epithelial barrier loss.

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A new role for reticulon-4B/NOGO-B in the intestinal epithelial barrier function and inflammatory bowel disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00309.2014 ◽

2015 ◽

Vol 308 (12) ◽

pp. G981-G993 ◽

Cited By ~ 8

Author(s):

Juan Antonio Rodríguez-Feo ◽

Marta Puerto ◽

Carolina Fernández-Mena ◽

Cristina Verdejo ◽

José Manuel Lara ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Inflammatory Bowel ◽

E Cadherin

Inflammatory bowel disease (IBD) is characterized by an impaired intestinal barrier function. We aimed to investigate the role of reticulon-4B (RTN-4B/NOGO-B), a structural protein of the endoplasmic reticulum, in intestinal barrier function and IBD. We used immunohistochemistry, confocal microscopy, real-time PCR, and Western blotting to study tissue distribution and expression levels of RTN-4B/NOGO-B in control and IBD samples from mouse and humans. We also targeted RTN-4B/NOGO-B using siRNAs in cultured human intestinal epithelial cell (IECs). Epithelial barrier permeability was assessed by transepithelial electrical resistance (TEER) measurement. RTN-4B/NOGO-B is expressed in the intestine mainly by IECs. Confocal microscopy revealed a colocalization of RTN-4B, E-cadherin, and polymerized actin fibers in tissue and cultured IECs. RTN-4B mRNA and protein expression were lower in the colon of IL-10−/− compared with wild-type mice. Colocalization of RTN-4B/E-cadherin/actin was reduced in the colon of IL-10−/− mice. Analysis of endoscopic biopsies from IBD patients showed a significant reduction of RTN-4B/NOGO-B expression in inflamed mucosa compared with control. Treatment of IECs with H2O2 reduced TEER values and triggered phosphorylation of RTN-4B in serine 107 residues as well as downregulation of RTN-4B expression. Acute RTN-4B/NOGO-B knockdown by siRNAs resulted in a decreased TEER values and reduction of E-cadherin and α-catenin expression and in the amount of F-actin-rich filaments in IECs. Epithelial RTN-4B/NOGO-B was downregulated in human and experimental IBD. RTN-4B participates in the intestinal epithelial barrier function, most likely via its involvement in E-cadherin, α-catenin expression, and actin cytoskeleton organization at sites of cell-to-cell contacts.

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Probiotics, Prebiotics and Epithelial Tight Junctions: A Promising Approach to Modulate Intestinal Barrier Function

International Journal of Molecular Sciences ◽

10.3390/ijms22136729 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6729

Author(s):

Elizabeth C. Rose ◽

Jack Odle ◽

Anthony T. Blikslager ◽

Amanda L. Ziegler

Keyword(s):

Tight Junctions ◽

Barrier Function ◽

Intestinal Barrier ◽

In Vivo Studies ◽

Intestinal Barrier Function ◽

Preterm Neonates ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Stimulation Of

Disruptions in the intestinal epithelial barrier can result in devastating consequences and a multitude of disease syndromes, particularly among preterm neonates. The association between barrier dysfunction and intestinal dysbiosis suggests that the intestinal barrier function is interactive with specific gut commensals and pathogenic microbes. In vitro and in vivo studies demonstrate that probiotic supplementation promotes significant upregulation and relocalization of interepithelial tight junction proteins, which form the microscopic scaffolds of the intestinal barrier. Probiotics facilitate some of these effects through the ligand-mediated stimulation of several toll-like receptors that are expressed by the intestinal epithelium. In particular, bacterial-mediated stimulation of toll-like receptor-2 modulates the expression and localization of specific protein constituents of intestinal tight junctions. Given that ingested prebiotics are robust modulators of the intestinal microbiota, prebiotic supplementation has been similarly investigated as a potential, indirect mechanism of barrier preservation. Emerging evidence suggests that prebiotics may additionally exert a direct effect on intestinal barrier function through mechanisms independent of the gut microbiota. In this review, we summarize current views on the effects of pro- and prebiotics on the intestinal epithelial barrier as well as on non-epithelial cell barrier constituents, such as the enteric glial cell network. Through continued investigation of these bioactive compounds, we can maximize their therapeutic potential for preventing and treating gastrointestinal diseases associated with impaired intestinal barrier function and dysbiosis.

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Neonatal intestinal injury induced by maternal separation: pathogenesis and pharmacological targets

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0370 ◽

2019 ◽

Vol 97 (3) ◽

pp. 193-196 ◽

Cited By ~ 1

Author(s):

Bo Li ◽

Fang Zhou Yu ◽

Adam Minich ◽

Alison Hock ◽

Carol Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Maternal Separation ◽

Intestinal Injury ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Axis Ii ◽

Physiological Processes ◽

Pharmacological Targets

Maternal separation (MS) is a well-studied phenomenon thought to play a role in the pathogenesis of many diseases ranging from neuropsychiatric to early intestinal disorders such as necrotizing enterocolitis. The existing evidence suggests that MS initiates a variety of processes that in turn lead to early intestinal injury. Although there are many theories as to how MS alters normal physiological processes, the exact mechanism of action remains to be elucidated. This review aims to describe some of the pathological processes affecting the intestine that are caused by MS, including (i) brain–gut axis, (ii) intestinal epithelial barrier function, (iii) microbiome, (iv) oxidative stress and endoplasmic reticulum stress, and (v) gut inflammation.

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