Deletion of the Casp8 gene in mice results in ileocolitis, gut barrier dysfunction, and malassimilation, which can be partially attenuated by inulin or sodium butyrate

2019 ◽  
Vol 317 (4) ◽  
pp. G493-G507 ◽  
Author(s):  
Valentina Kaden-Volynets ◽  
Claudia Günther ◽  
Julia Zimmermann ◽  
Julia Beisner ◽  
Christoph Becker ◽  
...  
Keyword(s):  
Body Weight ◽  
Sodium Butyrate ◽  
Barrier Function ◽  
Liver Steatosis ◽  
Caspase 8 ◽  
Free Access ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Inflammatory Bowel ◽  
The Impact

Genetically modified mice have been successfully used as models for inflammatory bowel diseases; however, dietary effects were poorly examined. Here, we studied the impact of particular nutrients and supplements on gut functions related to the knockout of the epithelial caspase-8 gene. Caspase-8 knockout (Casp8∆IEC) and control (Casp8fl) mice were fed for 4 wk a control diet (CD) enriched with 10% inulin (CD-Inu) or 5% sodium butyrate (CD-But) while having free access to plain water or water supplemented with 30% fructose (+F). Body weight changes, intestinal inflammation, and selected markers for barrier function and of liver steatosis were assessed. Casp8∆IEC mice developed ileocolitis accompanied by changes in intestinal barrier morphology and reduced expression of barrier-related genes such as mucin-2 ( Muc2) and defensins in the ileum and Muc2 in the colon. Casp8∆IEC mice fed a CD also showed impaired body weight gain compared with Casp8fl mice, which was even more pronounced in mice receiving water supplemented with fructose. Furthermore, we observed a marked liver steatosis and inflammation in some but not all Casp8∆IEC mice under a CD, which was on average similar to that observed in control mice under a fructose-rich diet. Hepatic lipid accumulation, as well as markers of ileal barrier function, but not intestinal pathohistology or body weight loss, were attenuated by diets enriched with inulin or butyrate, especially in the absence of fructose supplementation. Our data show that ileocolitis, barrier dysfunction, and malassimilation in Caspase-8 knockout mice can be partially attenuated by oral inulin or butyrate supplementation. NEW & NOTEWORTHY Genetic mouse models for ileocolitis are important to understand inflammatory bowel disease in humans. We examined dietetic factors that might aggravate or attenuate ileocolitis and related pathologies in such a model. Deletion of the caspase-8 gene results not only in ileocolitis but also in gut barrier dysfunction, liver steatosis, and malassimilation, which can be partially attenuated by oral inulin or sodium butyrate. Our data indicate that diet modifications can contribute to disease variability and therapy.

The Impact of Ultraviolet Radiation on Barrier Function in Human Skin: Molecular Mechanisms and Topical Therapeutics

2019 ◽  
Vol 25 (40) ◽  
pp. 5503-5511 ◽  
Author(s):  
Abdulaziz Alhasaniah ◽  
Michael J. Sherratt ◽  
Catherine A. O'Neill
Keyword(s):  
Ultraviolet Radiation ◽  
Barrier Function ◽  
Molecular Mechanisms ◽  
Transepidermal Water Loss ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Epidermal Barrier ◽  
Positive Effects ◽  
Terrestrial Mammals ◽  
The Impact

A competent epidermal barrier is crucial for terrestrial mammals. This barrier must keep in water and prevent entry of noxious stimuli. Most importantly, the epidermis must also be a barrier to ultraviolet radiation (UVR) from the sunlight. Currently, the effects of ultraviolet radiation on epidermal barrier function are poorly understood. However, studies in mice and more limited work in humans suggest that the epidermal barrier becomes more permeable, as measured by increased transepidermal water loss, in response UVR, at doses sufficiently high to induce erythema. The mechanisms may include disturbance in the organisation of lipids in the stratum corneum (the outermost layer of the epidermis) and reduction in tight junction function in the granular layer (the first living layer of the skin). By contrast, suberythemal doses of UVR appear to have positive effects on epidermal barrier function. Topical sunscreens have direct and indirect protective effects on the barrier through their ability to block UV and also due to their moisturising or occlusive effects, which trap water in the skin, respectively. Some topical agents such as specific botanical extracts have been shown to prevent the loss of water associated with high doses of UVR. In this review, we discuss the current literature and suggest that the biology of UVR-induced barrier dysfunction, and the use of topical products to protect the barrier, are areas worthy of further investigation.

scholarly journals Anthocyanins and intestinal barrier function: a review

2019 ◽  
Vol 5 ◽  
pp. 18-30 ◽  
Author(s):  
Jonathan C. Valdez ◽  
Bradley W. Bolling
Keyword(s):  
Barrier Function ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Berry Anthocyanins ◽  
Chronic Intestinal Inflammation

Chronic intestinal inflammation, occurring in inflammatory bowel diseases (IBD), is associated with compromised intestinal barrier function. Inflammatory cytokines disrupt tight junctions and increase paracellular permeability of luminal antigens. Thus, chronic intestinal barrier dysfunction hinders the resolution of inflammation. Dietary approaches may help mitigate intestinal barrier dysfunction and chronic inflammation. A growing body of work in rodent models of colitis has demonstrated that berry consumption inhibits chronic intestinal inflammation. Berries are a rich dietary source of polyphenolic compounds, particularly anthocyanins. However, berry anthocyanins have limited bioavailability and are extensively metabolized by the gut microbiota and host tissue. This review summarizes the literature regarding the beneficial functions of anthocyanin-rich berries in treating and preventing IBD. Here, we will establish the role of barrier function in the pathogenesis of IBD and how dietary anthocyanins and their known microbial catabolites modulate intestinal barrier function.

scholarly journals Clinical Analysis of Gut Barrier Dysfunction in Patients with Advanced Colorectal Cancer Undergoing Cytoreductive Surgery and HIPEC

2021 ◽  
Author(s):  
Le lai Ping ◽  
Jiang xu Mian ◽  
Chen Wei
Keyword(s):  
Colorectal Cancer ◽  
Cytoreductive Surgery ◽  
Barrier Function ◽  
Intraperitoneal Injection ◽  
Advanced Colorectal Cancer ◽  
Patient Characteristics ◽  
Barrier Dysfunction ◽  
Large Area ◽  
Gut Barrier ◽  
Gut Barrier Function

Abstract Introduction: Hyperthermic intraperitoneal chemotherapy combinedwith cytoreductive surgery is a preferred treatment option for advanced colorectal cancer patients. However, little is known whether the HIPEC can cause the damage of gut barrier function.Methods: A total of 123 patients underwent surgical resection for advanced CRC. Sixty-five patients were treated HIPEC after cytoreductive surgery whereas 58 patients underwent surgery only. Gut barrier function were evaluated using the expression of serum DAO/D-la/ET on D1/D5/D10 after surgery. Both groups were compared for patient characteristics, perioperative data and gut barrier function. Moreover, rats received intraperitoneal injection of retetrexed to observe possible changes of colonic structure under optical microscope.Results: Both groups were comparable with respect to general patient characteristics and post-operative complications. The HIPEC+CRS group was associated with a higher postoperative serum level of DAO/D-la on D1/D5 (p < 0.05) and ET on D5 after surgery (p < 0.05) than that of the surgery only group. Ten days after surgery showed no statistical difference between the 2 groups (p > 0.05).A large area structure disorder, epithelial necrosis, glandular deformation and a large number of lymphocytes infiltration was found in the lamina propria in animals received intraperitoneal injection of retetrexed.Conclusion: In this study, CRS combined with HIPEC does have but only an irreversible impact on gut barrier for advanced CRC patients.

scholarly journals Effects of Anti-Cytokine Antibodies on Gut Barrier Function

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Fang Liu ◽  
Seul A. Lee ◽  
Stephen M. Riordan ◽  
Li Zhang ◽  
Lixin Zhu
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Barrier Function ◽  
Inflammatory Diseases ◽  
Immunomodulatory Effects ◽  
Gut Barrier ◽  
Barrier Integrity ◽  
Chronic Inflammatory Diseases ◽  
Gut Barrier Function ◽  
Inflammatory Bowel

Anti-cytokine antibodies are used in treating chronic inflammatory diseases and autoimmune diseases such as inflammatory bowel disease and rheumatic diseases. Patients with these diseases often have a compromised gut barrier function, suggesting that anti-cytokine antibodies may contribute to the re-establishment of gut barrier integrity, in addition to their immunomodulatory effects. This paper reviews the effects of anti-cytokine antibodies on gut barrier function and their mechanisms.

scholarly journals 2’-fucosyllactose (2’-FL) Supplementation Improves Gut Barrier Function and Lipid Metabolism in HF-fed Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 425-425
Author(s):  
Sunhye Lee ◽  
Michael Goodson ◽  
Wendie Vang ◽  
Karen Kalanetra ◽  
Daniela Barile ◽  
...  
Keyword(s):  
Body Weight ◽  
Lipid Metabolism ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Gut Barrier ◽  
Low Fat ◽  
Barrier Integrity ◽  
Gut Barrier Function

Abstract Objectives 2’-fucosyllactose (2’-FL), the most predominant oligosaccharide found in human milk, acts as a prebiotic with beneficial effects on the host. The aim of this study was to determine the beneficial effect of 2’-FL on intestinal barrier integrity and metabolic functions in low-fat (LF)- and high-fat (HF)-fed mice. Methods Male C57/BL6 mice (n = 32, 8/group; 6 weeks old, JAX, CA) were counter-balanced into four weight-matched groups and fed either a low-fat (LF; 10% kcal fat with 7% kcal sucrose) or HF (45% kcal fat with 17% kcal sucrose) with or without supplementation of 2’-FL in the diet [10% (w/w), 8 weeks; LF/2’-FL or HF/2’-FL; BASF, Germany]. General phenotypes (body weight, energy intake, fat and lean mass), intestinal permeability (ex vivo in Ussing chambers), lipid profiles, and microbial metabolites were assessed. Results 2’-FL significantly attenuated the HF-induced increase in body fat mass with a trend to decrease body weight gain. 2’-FL significantly decreased intestinal permeability in LF-fed mice with a trend for a decrease in HF-fed mice. This was associated with a significant increase in interleukin-22, a cytokine known to have a protective role in intestinal barrier function. Visceral adipocyte size was significantly decreased by 2’-FL in both LF- and HF-fed mice. 2’-FL suppressed HF-induced upregulation of adipogenic transcription factors peroxisome proliferator-activated receptor gamma and sterol regulatory element binding protein-1c in the liver. Lastly, 2’-FL supplementation led to a significant elevation of lactic acid concentration in the cecum of HF-fed mice, which is known to be a product from beneficial microbes. Conclusions 2’-FL supplementation improved gut barrier integrity and lipid metabolism in mice with and without the metabolic challenge of HF feeding. These findings support the use of 2’-FL in the control of gut barrier function and metabolic homeostasis under normal and abnormal physiological conditions. Funding Sources BASF (Germany).

scholarly journals Hypoxia-inducible factor hydroxylase inhibition enhances the protective effects of cyclosporine in colitis

2019 ◽  
Vol 317 (2) ◽  
pp. G90-G97 ◽  
Author(s):  
Doug N. Halligan ◽  
Mohammed N. Khan ◽  
Eric Brown ◽  
Catherine R. Rowan ◽  
Ivan S. Coulter ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune System ◽  
Protective Effect ◽  
Barrier Function ◽  
Epithelial Barrier ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Inflammatory Bowel ◽  
Anti Inflammatory

Inflammatory bowel disease (IBD) is characterized by epithelial barrier dysfunction with resultant inflammation as the mucosal immune system becomes exposed to luminal antigens. The hydroxylase inhibitor dimethyloxalylglycine (DMOG) reduces symptoms in experimental colitis through the upregulation of genes promoting barrier function and inhibition of epithelial cell apoptosis. The immunosuppressive drug cyclosporine reduces inflammation associated with IBD via suppression of immune cell activation. Given the distinct barrier protective effect of DMOG and the anti-inflammatory properties of cyclosporine, we hypothesized that combining these drugs may provide an enhanced protective effect by targeting both barrier dysfunction and inflammation simultaneously. We used the dextran sulfate sodium model of colitis in C57BL/6 mice to determine the combinatorial efficacy of cyclosporine and DMOG. While cyclosporine and DMOG ameliorated disease progression, in combination they had an additive protective effect that surpassed the level of protection afforded by either drug alone. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was largely due to preservation of barrier function and at least in part due to zonula occludens-1 regulation. We propose that combining the barrier protective effects of a hydroxylase inhibitor with the anti-inflammatory effects of cyclosporine provides added therapeutic benefit in colitis. NEW & NOTEWORTHY Inflammatory bowel disease is the result of decreased intestinal epithelial barrier function leading to exposure of the mucosal immune system to luminal antigens causing inflammation, which in turn further decreases epithelial barrier function. We demonstrate for the first time that strengthening the epithelial barrier with a hydroxylase inhibitor in combination with the administration of the immunosuppressive cyclosporine provides additive therapeutic advantage in a murine model of colitis

scholarly journals Prebiotic Inulin and Sodium Butyrate Attenuate Obesity-Induced Intestinal Barrier Dysfunction by Induction of Antimicrobial Peptides

2021 ◽  
Vol 12 ◽  
Author(s):  
Julia Beisner ◽  
Louisa Filipe Rosa ◽  
Valentina Kaden-Volynets ◽  
Iris Stolzer ◽  
Claudia Günther ◽  
...  
Keyword(s):  
Sodium Butyrate ◽  
Paneth Cell ◽  
Liver Steatosis ◽  
Intestinal Barrier ◽  
Histone Deacetylation ◽  
Mucosal Barrier ◽  
Barrier Dysfunction ◽  
Fermentation Products ◽  
Alcoholic Fatty Liver ◽  
Intestinal Barrier Dysfunction

Defects in the mucosal barrier have been associated with metabolic diseases such as obesity and non-alcoholic fatty liver disease (NAFLD). Mice fed a Western-style diet (WSD) develop obesity and are characterized by a diet-induced intestinal barrier dysfunction, bacterial endotoxin translocation and subsequent liver steatosis. To examine whether inulin or sodium butyrate could improve gut barrier dysfunction, C57BL/6 mice were fed a control diet or a WSD ± fructose supplemented with either 10% inulin or 5% sodium butyrate for 12 weeks respectively. Inulin and sodium butyrate attenuated hepatosteatitis in the WSD-induced obesity mouse model by reducing weight gain, liver weight, plasma and hepatic triglyceride level. Furthermore, supplementation with inulin or sodium butyrate induced expression of Paneth cell α-defensins and matrix metalloproteinase-7 (MMP7), which was impaired by the WSD and particularly the fructose-added WSD. Effects on antimicrobial peptide function in the ileum were accompanied by induction of β-defensin-1 and tight junction genes in the colon resulting in improved intestinal permeability and endotoxemia. Organoid culture of small intestinal crypts revealed that the short chain fatty acids (SCFA) butyrate, propionate and acetate, fermentation products of inulin, induce Paneth cell α-defensin expression in vitro, and that histone deacetylation and STAT3 might play a role in butyrate-mediated induction of α-defensins. In summary, inulin and sodium butyrate attenuate diet-induced barrier dysfunction and induce expression of Paneth cell antimicrobials. The administration of prebiotic fiber or sodium butyrate could be an interesting therapeutic approach to improve diet-induced obesity.

scholarly journals Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation

2014 ◽  
Vol 306 (8) ◽  
pp. C745-C752 ◽  
Author(s):  
Vladislav V. Makarenko ◽  
Peter V. Usatyuk ◽  
Guoxiang Yuan ◽  
May M. Lee ◽  
Jayasri Nanduri ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intermittent Hypoxia ◽  
Map Kinases ◽  
Fiber Formation ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction ◽  
The Impact ◽  
Junction Proteins

The objective of the present study was to determine the impact of simulated apnea with intermittent hypoxia (IH) on endothelial barrier function and assess the underlying mechanism(s). Experiments were performed on human lung microvascular endothelial cells exposed to IH-consisting alternating cycles of 1.5% O2 for 30s followed by 20% O2 for 5 min. IH decreased transendothelial electrical resistance (TEER) suggesting attenuated endothelial barrier function. The effect of IH on TEER was stimulus dependent and reversible after reoxygenation. IH-exposed cells exhibited stress fiber formation and redistribution of cortactin, vascular endothelial-cadherins, and zona occludens-1 junction proteins along with increased intercellular gaps at cell-cell boundaries. Extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) were phosphorylated in IH-exposed cells. Inhibiting either ERK or JNK prevented the IH-induced decrease in TEER and the reorganization of the cytoskeleton and junction proteins. IH increased reactive oxygen species (ROS) levels, and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride, a membrane-permeable antioxidant, prevented ERK and JNK phosphorylation as well as IH-induced changes in endothelial barrier function. These results demonstrate that IH via ROS-dependent activation of MAP kinases leads to reorganization of cytoskeleton and junction proteins resulting in endothelial barrier dysfunction.

scholarly journals Role of Gut Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Xin Dai ◽  
Bangmao Wang
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Barrier Function ◽  
Fatty Liver Disease ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Nonalcoholic Fatty Liver ◽  
Gut Barrier Function

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, and its incidence is increasing year by year. Many efforts have been made to investigate the pathogenesis of this disease. Since 1998 when Marshall proposed the conception of “gut-liver axis,” more and more researchers have paid close attention to the role of gut barrier function in the pathogenesis of NAFLD. The four aspects of gut barrier function, including physical, chemical, biological, and immunological barriers, are interrelated closely and related to NAFLD. In this paper, we present a summary of research findings on the relationship between gut barrier dysfunction and the development of NAFLD, aiming at illustrating the role of gut barrier function in the pathogenesis of this disease.

scholarly journals Effects of Human Milk Oligosaccharides on the Adult Gut Microbiota and Barrier Function

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2808
Author(s):  
Tanja Šuligoj ◽  
Louise Kristine Vigsnæs ◽  
Pieter Van den Abbeele ◽  
Athanasia Apostolou ◽  
Katia Karalis ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Human Milk ◽  
Barrier Function ◽  
Distal Colon ◽  
Human Milk Oligosaccharides ◽  
Gut Barrier ◽  
Milk Oligosaccharides ◽  
Caco2 Cell ◽  
Gut Barrier Function ◽  
The Impact

Human milk oligosaccharides (HMOs) shape the gut microbiota in infants by selectively stimulating the growth of bifidobacteria. Here, we investigated the impact of HMOs on adult gut microbiota and gut barrier function using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®), Caco2 cell lines, and human intestinal gut organoid-on-chips. We showed that fermentation of 2’-O-fucosyllactose (2’FL), lacto-N-neotetraose (LNnT), and combinations thereof (MIX) led to an increase of bifidobacteria, accompanied by an increase of short chain fatty acid (SCFA), in particular butyrate with 2’FL. A significant reduction in paracellular permeability of FITC-dextran probe was observed using Caco2 cell monolayers with fermented 2’FL and MIX, which was accompanied by an increase in claudin-8 gene expression as shown by qPCR, and a reduction in IL-6 as determined by multiplex ELISA. Using gut-on-chips generated from human organoids derived from proximal, transverse, and distal colon biopsies (Colon Intestine-Chips), we showed that claudin-5 was significantly upregulated across all three gut-on-chips following treatment with fermented 2’FL under microfluidic conditions. Taken together, these data show that, in addition to their bifidogenic activity, HMOs have the capacity to modulate immune function and the gut barrier, supporting the potential of HMOs to provide health benefits in adults.

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