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14 pages, 2748 KiB

Open AccessArticle

Smectite as a Preventive Oral Treatment to Reduce Clinical Symptoms of DSS Induced Colitis in Balb/c Mice

by Anne Breitrück, Markus Weigel, Jacqueline Hofrichter, Kai Sempert, Claus Kerkhoff, Nooshin Mohebali, Steffen Mitzner, Torsten Hain and Bernd Kreikemeyer

Int. J. Mol. Sci. 2021, 22(16), 8699; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168699 - 13 Aug 2021

Cited by 3 | Viewed by 2732

Abstract

Natural smectites have demonstrated efficacy in the treatment of diarrhea. The present study evaluated the prophylactic effect of a diosmectite (FI5pp) on the clinical course, colon damage, expression of tight junction (TJ) proteins and the composition of the gut microbiota in dextran sulfate [...] Read more.

Natural smectites have demonstrated efficacy in the treatment of diarrhea. The present study evaluated the prophylactic effect of a diosmectite (FI5pp) on the clinical course, colon damage, expression of tight junction (TJ) proteins and the composition of the gut microbiota in dextran sulfate sodium (DSS) colitis. Diosmectite was administered daily to Balb/c mice from day 1 to 7 by oral gavage, followed by induction of acute DSS-colitis from day 8 to 14 (“Control”, n = 6; “DSS”, n = 10; “FI5pp + DSS”, n = 11). Mice were sacrificed on day 21. Clinical symptoms (body weight, stool consistency and occult blood) were checked daily after colitis induction. Colon tissue was collected for histological damage scoring and quantification of tight junction protein expression. Stool samples were collected for microbiome analysis. Our study revealed prophylactic diosmectite treatment attenuated the severity of DSS colitis, which was apparent by significantly reduced weight loss (p = 0.022 vs. DSS), disease activity index (p = 0.0025 vs. DSS) and histological damage score (p = 0.023 vs. DSS). No significant effects were obtained for the expression of TJ proteins (claudin-2 and claudin-3) after diosmectite treatment. Characterization of the microbial composition by 16S amplicon NGS showed that diosmectite treatment modified the DSS-associated dysbiosis. Thus, diosmectites are promising candidates for therapeutic approaches to target intestinal inflammation and to identify possible underlying mechanisms of diosmectites in further studies. Full article

(This article belongs to the Special Issue Elucidation of Leaky Gut Syndrome and the Discovery of Therapeutic Targets)

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19 pages, 10215 KiB

Open AccessArticle

Increase in Epithelial Permeability and Cell Metabolism by High Mobility Group Box 1, Inflammatory Cytokines and TPEN in Caco-2 Cells as a Novel Model of Inflammatory Bowel Disease

by Maki Miyakawa, Takumi Konno, Takayuki Kohno, Shin Kikuchi, Hiroki Tanaka and Takashi Kojima

Int. J. Mol. Sci. 2020, 21(22), 8434; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228434 - 10 Nov 2020

Cited by 9 | Viewed by 2890

Abstract

High mobility group box 1 protein (HMGB1) is involved in the pathogenesis of inflammatory bowel disease (IBD). Patients with IBD develop zinc deficiency. However, the detailed roles of HMGB1 and zinc deficiency in the intestinal epithelial barrier and cellular metabolism of IBD remain [...] Read more.

High mobility group box 1 protein (HMGB1) is involved in the pathogenesis of inflammatory bowel disease (IBD). Patients with IBD develop zinc deficiency. However, the detailed roles of HMGB1 and zinc deficiency in the intestinal epithelial barrier and cellular metabolism of IBD remain unknown. In the present study, Caco-2 cells in 2D culture and 2.5D Matrigel culture were pretreated with transforming growth factor-β (TGF-β) type 1 receptor kinase inhibitor EW-7197, epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 and a TNFα antibody before treatment with HMGB1 and inflammatory cytokines (TNFα and IFNγ). EW-7197, AG-1478 and the TNFα antibody prevented hyperpermeability induced by HMGB1 and inflammatory cytokines in 2.5D culture. HMGB1 affected cilia formation in 2.5D culture. EW-7197, AG-1478 and the TNFα antibody prevented the increase in cell metabolism induced by HMGB1 and inflammatory cytokines in 2D culture. Furthermore, ZnSO₄ prevented the hyperpermeability induced by zinc chelator TPEN in 2.5D culture. ZnSO₄ and TPEN induced cellular metabolism in 2D culture. The disruption of the epithelial barrier induced by HMGB1 and inflammatory cytokines contributed to TGF-β/EGF signaling in Caco-2 cells. The TNFα antibody and ZnSO₄ as well as EW-7197 and AG-1478 may have potential for use in therapy for IBD. Full article

(This article belongs to the Special Issue Elucidation of Leaky Gut Syndrome and the Discovery of Therapeutic Targets)

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16 pages, 3021 KiB

Open AccessArticle

Interdependence between Chromogranin-A, Alternatively Activated Macrophages, Tight Junction Proteins and the Epithelial Functions. A Human and In-Vivo/In-Vitro Descriptive Study

by Nour Eissa, Hayam Hussein, Diane M. Tshikudi, Geoffrey N. Hendy, Charles N. Bernstein and Jean-Eric Ghia

Int. J. Mol. Sci. 2020, 21(21), 7976; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217976 - 27 Oct 2020

Cited by 6 | Viewed by 2757

Abstract

Background: Ulcerative colitis (UC) is characterized by altered chromogranin-A (CHGA), alternatively activated macrophages (M2) and intestinal epithelial cells (IECs). We previously demonstrated that CHGA is implicated in colitis progression by regulating the macrophages. Here, we investigated the interplay between CHGA, M2, tight junctions [...] Read more.

Background: Ulcerative colitis (UC) is characterized by altered chromogranin-A (CHGA), alternatively activated macrophages (M2) and intestinal epithelial cells (IECs). We previously demonstrated that CHGA is implicated in colitis progression by regulating the macrophages. Here, we investigated the interplay between CHGA, M2, tight junctions (TJ) and IECs in an inflammatory environment. Methods: Correlations between CHGA mRNA expression of and TJ proteins mRNA expressions of (Occludin [OCLN], zonula occludens-1 [ZO1], Claudin-1 [CLDN1]), epithelial associated cytokines (interleukin [IL]-8, IL-18), and collagen (COL1A2) were determined in human colonic mucosal biopsies isolated from active UC and healthy patients. Acute UC-like colitis (5% dextran sulphate sodium [DSS], five days) was induced in Chga-C57BL/6-deficient (Chga^−/−) and wild type (Chga^+/+) mice. Col1a2 TJ proteins, Il-18 mRNA expression and collagen deposition were determined in whole colonic sections. Naïve Chga^−/− and Chga^+/+ peritoneal macrophages were isolated and exposed six hours to IL-4/IL-13 (20 ng/mL) to promote M2 and generate M2-conditioned supernatant. Caco-2 epithelial cells were cultured in the presence of Chga^−/− and Chga^+/+ non- or M2-conditioned supernatant for 24 h then exposed to 5% DSS for 24 h, and their functional properties were assessed. Results: In humans, CHGA mRNA correlated positively with COL1A2, IL-8 and IL-18, and negatively with TJ proteins mRNA markers. In the experimental model, the deletion of Chga reduced IL-18 mRNA and its release, COL1A2 mRNA and colonic collagen deposition, and maintained colonic TJ proteins. Chga^−/− M2-conditioned supernatant protected caco-2 cells from DSS and oxidative stress injuries by improving caco-2 cells functions (proliferation, viability, wound healing) and by decreasing the release of IL-8 and IL-18 and by maintaining the levels of TJ proteins, and when compared with Chga^+/+ M2-conditioned supernatant. Conclusions: CHGA contributes to the development of intestinal inflammation through the regulation of M2 and epithelial cells. Targeting CHGA may lead to novel biomarkers and therapeutic strategies in UC. Full article

(This article belongs to the Special Issue Elucidation of Leaky Gut Syndrome and the Discovery of Therapeutic Targets)

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Review

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14 pages, 826 KiB

Open AccessReview

Redox and Metabolic Regulation of Intestinal Barrier Function and Associated Disorders

by Pei-Yun Lin, Arnold Stern, Hsin-Hsin Peng, Jiun-Han Chen and Hung-Chi Yang

Int. J. Mol. Sci. 2022, 23(22), 14463; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214463 - 21 Nov 2022

Cited by 12 | Viewed by 2275

Abstract

The intestinal epithelium forms a physical barrier assembled by intercellular junctions, preventing luminal pathogens and toxins from crossing it. The integrity of tight junctions is critical for maintaining intestinal health as the breakdown of tight junction proteins leads to various disorders. Redox reactions [...] Read more.

The intestinal epithelium forms a physical barrier assembled by intercellular junctions, preventing luminal pathogens and toxins from crossing it. The integrity of tight junctions is critical for maintaining intestinal health as the breakdown of tight junction proteins leads to various disorders. Redox reactions are closely associated with energy metabolism. Understanding the regulation of tight junctions by cellular metabolism and redox status in cells may lead to the identification of potential targets for therapeutic interventions. In vitro and in vivo models have been utilized in investigating intestinal barrier dysfunction and in particular the free-living soil nematode, Caenorhabditis elegans, may be an important alternative to mammalian models because of its convenience of culture, transparent body for microscopy, short generation time, invariant cell lineage and tractable genetics. Full article

(This article belongs to the Special Issue Elucidation of Leaky Gut Syndrome and the Discovery of Therapeutic Targets)

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14 pages, 864 KiB

Open AccessReview

The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target

by Takaomi Kessoku, Takashi Kobayashi, Kosuke Tanaka, Atsushi Yamamoto, Kota Takahashi, Michihiro Iwaki, Anna Ozaki, Yuki Kasai, Asako Nogami, Yasushi Honda, Yuji Ogawa, Shingo Kato, Kento Imajo, Takuma Higurashi, Kunihiro Hosono, Masato Yoneda, Haruki Usuda, Koichiro Wada, Satoru Saito and Atsushi Nakajima

Int. J. Mol. Sci. 2021, 22(15), 8161; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158161 - 29 Jul 2021

Cited by 29 | Viewed by 3994

Abstract

The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by [...] Read more.

The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression. Full article

(This article belongs to the Special Issue Elucidation of Leaky Gut Syndrome and the Discovery of Therapeutic Targets)

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18 pages, 2516 KiB

Open AccessReview

Leaky Gut: Effect of Dietary Fiber and Fats on Microbiome and Intestinal Barrier

by Haruki Usuda, Takayuki Okamoto and Koichiro Wada

Int. J. Mol. Sci. 2021, 22(14), 7613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147613 - 16 Jul 2021

Cited by 84 | Viewed by 12991

Abstract

Intestinal tract is the boundary that prevents harmful molecules from invading into the mucosal tissue, followed by systemic circulation. Intestinal permeability is an index for intestinal barrier integrity. Intestinal permeability has been shown to increase in various diseases—not only intestinal inflammatory diseases, but [...] Read more.

Intestinal tract is the boundary that prevents harmful molecules from invading into the mucosal tissue, followed by systemic circulation. Intestinal permeability is an index for intestinal barrier integrity. Intestinal permeability has been shown to increase in various diseases—not only intestinal inflammatory diseases, but also systemic diseases, including diabetes, chronic kidney dysfunction, cancer, and cardiovascular diseases. Chronic increase of intestinal permeability is termed ‘leaky gut’ which is observed in the patients and animal models of these diseases. This state often correlates with the disease state. In addition, recent studies have revealed that gut microbiota affects intestinal and systemic heath conditions via their metabolite, especially short-chain fatty acids and lipopolysaccharides, which can trigger leaky gut. The etiology of leaky gut is still unknown; however, recent studies have uncovered exogenous factors that can modulate intestinal permeability. Nutrients are closely related to intestinal health and permeability that are actively investigated as a hot topic of scientific research. Here, we will review the effect of nutrients on intestinal permeability and microbiome for a better understanding of leaky gut and a possible mechanism of increase in intestinal permeability. Full article

(This article belongs to the Special Issue Elucidation of Leaky Gut Syndrome and the Discovery of Therapeutic Targets)

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17 pages, 475 KiB

Open AccessReview

Dietary Carbohydrates and Lipids in the Pathogenesis of Leaky Gut Syndrome: An Overview

by Agata Binienda, Agata Twardowska, Adam Makaro and Maciej Salaga

Int. J. Mol. Sci. 2020, 21(21), 8368; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218368 - 08 Nov 2020

Cited by 34 | Viewed by 8341

Abstract

This review summarizes the recent knowledge on the effects of dietary carbohydrates and lipids on the pathophysiology of leaky gut syndrome (LGS). Alterations in intestinal barrier permeability may lead to serious gastrointestinal (GI) disorders. LGS is caused by intestinal hyperpermeability due to changes [...] Read more.

This review summarizes the recent knowledge on the effects of dietary carbohydrates and lipids on the pathophysiology of leaky gut syndrome (LGS). Alterations in intestinal barrier permeability may lead to serious gastrointestinal (GI) disorders. LGS is caused by intestinal hyperpermeability due to changes in the expression levels and functioning of tight junctions. The influence of dietary habits on intestinal physiology is clearly visible in incidence rates of intestinal diseases in industrial and developing countries. Diseases which are linked to intestinal hyperpermeability tend to localize to Westernized countries, where a diet rich in fats and refined carbohydrates predominates. Several studies suggest that fructose is one of the key carbohydrates involved in the regulation of the intestinal permeability and its overuse may cause harmful effects, such as tight junction protein dysfunction. On the other hand, short chain fatty acids (mainly butyrate) at appropriate concentrations may lead to the reduction of intestinal permeability, which is beneficial in LGS. However, long chain fatty acids, including n-3 and n-6 polyunsaturated fatty acids have unclear properties. Some of those behave as components untightening and tightening the intestinal membrane. Full article

(This article belongs to the Special Issue Elucidation of Leaky Gut Syndrome and the Discovery of Therapeutic Targets)

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22 pages, 801 KiB

Open AccessReview

The Gut Barrier, Intestinal Microbiota, and Liver Disease: Molecular Mechanisms and Strategies to Manage

by Julio Plaza-Díaz, Patricio Solís-Urra, Fernando Rodríguez-Rodríguez, Jorge Olivares-Arancibia, Miguel Navarro-Oliveros, Francisco Abadía-Molina and Ana I. Álvarez-Mercado

Int. J. Mol. Sci. 2020, 21(21), 8351; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218351 - 07 Nov 2020

Cited by 64 | Viewed by 7034

Abstract

Liver disease encompasses pathologies as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcohol liver disease, hepatocellular carcinoma, viral hepatitis, and autoimmune hepatitis. Nowadays, underlying mechanisms associating gut permeability and liver disease development are not well understood, although evidence points to the involvement of intestinal [...] Read more.

Liver disease encompasses pathologies as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcohol liver disease, hepatocellular carcinoma, viral hepatitis, and autoimmune hepatitis. Nowadays, underlying mechanisms associating gut permeability and liver disease development are not well understood, although evidence points to the involvement of intestinal microbiota and their metabolites. Animal studies have shown alterations in Toll-like receptor signaling related to the leaky gut syndrome by the action of bacterial lipopolysaccharide. In humans, modifications of the intestinal microbiota in intestinal permeability have also been related to liver disease. Some of these changes were observed in bacterial species belonging Roseburia, Streptococcus, and Rothia. Currently, numerous strategies to treat liver disease are being assessed. This review summarizes and discusses studies addressed to determine mechanisms associated with the microbiota able to alter the intestinal barrier complementing the progress and advancement of liver disease, as well as the main strategies under development to manage these pathologies. We highlight those approaches that have shown improvement in intestinal microbiota and barrier function, namely lifestyle changes (diet and physical activity) and probiotics intervention. Nevertheless, knowledge about how such modifications are beneficial is still limited and specific mechanisms involved are not clear. Thus, further in-vitro, animal, and human studies are needed. Full article

(This article belongs to the Special Issue Elucidation of Leaky Gut Syndrome and the Discovery of Therapeutic Targets)

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