scholarly journals Giardia duodenalis induces paracellular bacterial translocation and causes postinfectious visceral hypersensitivity

2016 ◽  
Vol 310 (8) ◽  
pp. G574-G585 ◽  
Author(s):  
Marie C. M. Halliez ◽  
Jean-Paul Motta ◽  
Troy D. Feener ◽  
Gaetan Guérin ◽  
Laetitia LeGoff ◽  
...  
Keyword(s):  
Giardia Duodenalis ◽  
Intestinal Barrier ◽  
Gastrointestinal Disorder ◽  
Intraepithelial Lymphocytes ◽  
Visceral Hypersensitivity ◽  
New Model ◽  
Infectious Gastroenteritis ◽  
Irritable Bowel

Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder. It is characterized by abdominal hypersensitivity, leading to discomfort and pain, as well as altered bowel habits. While it is common for IBS to develop following the resolution of infectious gastroenteritis [then termed postinfectious IBS (PI-IBS)], the mechanisms remain incompletely understood. Giardia duodenalis is a cosmopolitan water-borne enteropathogen that causes intestinal malabsorption, diarrhea, and postinfectious complications. Cause-and-effect studies using a human enteropathogen to help investigate the mechanisms of PI-IBS are sorely lacking. In an attempt to establish causality between giardiasis and postinfectious visceral hypersensitivity, this study describes a new model of PI-IBS in neonatal rats infected with G. duodenalis. At 50 days postinfection with G. duodenalis (assemblage A or B), long after the parasite was cleared, rats developed visceral hypersensitivity to luminal balloon distension in the jejunum and rectum, activation of the nociceptive signaling pathway (increased c- fos expression), histological modifications (villus atrophy and crypt hyperplasia), and proliferation of mucosal intraepithelial lymphocytes and mast cells in the jejunum, but not in the rectum. G. duodenalis infection also disrupted the intestinal barrier, in vivo and in vitro, which in turn promoted the translocation of commensal bacteria. Giardia-induced bacterial paracellular translocation in vitro correlated with degradation of the tight junction proteins occludin and claudin-4. The extensive observations associated with gut hypersensitivity described here demonstrate that, indeed, in this new model of postgiardiasis IBS, alterations to the gut mucosa and c- fos are consistent with those associated with PI-IBS and, hence, offer avenues for new mechanistic research in the field.

scholarly journals Crosstalk between Inflammation and ROCK/MLCK Signaling Pathways in Gastrointestinal Disorders with Intestinal Hyperpermeability

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Lijun Du ◽  
John J. Kim ◽  
Jinhua Shen ◽  
Ning Dai
Keyword(s):  
Intestinal Permeability ◽  
Barrier Function ◽  
Coiled Coil ◽  
Intestinal Barrier ◽  
Mucosal Inflammation ◽  
Intestinal Barrier Function ◽  
Gastrointestinal Disorders ◽  
Irritable Bowel

The barrier function of the intestine is essential for maintaining the normal homeostasis of the gut and mucosal immune system. Abnormalities in intestinal barrier function expressed by increased intestinal permeability have long been observed in various gastrointestinal disorders such as Crohn’s disease (CD), ulcerative colitis (UC), celiac disease, and irritable bowel syndrome (IBS). Imbalance of metabolizing junction proteins and mucosal inflammation contributes to intestinal hyperpermeability. Emerging studies exploringin vitroandin vivomodel system demonstrate that Rho-associated coiled-coil containing protein kinase- (ROCK-) and myosin light chain kinase- (MLCK-) mediated pathways are involved in the regulation of intestinal permeability. With this perspective, we aim to summarize the current state of knowledge regarding the role of inflammation and ROCK-/MLCK-mediated pathways leading to intestinal hyperpermeability in gastrointestinal disorders. In the near future, it may be possible to specifically target these specific pathways to develop novel therapies for gastrointestinal disorders associated with increased gut permeability.

scholarly journals Multi-target Treatment for Irritable Bowel Syndrome with STW 5: Pharmacological Modes of Action

2020 ◽  
Vol 29 (2) ◽  
pp. 227-233
Author(s):  
Hans-Dieter Allescher ◽  
Rebecca Burgell ◽  
Peter Malfertheiner ◽  
Fermin Mearin
Keyword(s):  
Irritable Bowel Syndrome ◽  
Treatment Options ◽  
Smooth Muscles ◽  
Gastrointestinal Disorder ◽  
In Vivo Studies ◽  
Afferent Nerves ◽  
Target Treatment ◽  
Irritable Bowel

Irritable bowel syndrome (IBS) is a heterogeneous and complex functional gastrointestinal disorder with aglobal prevalence of approximately 11% and high geographic variation. IBS encompasses various symptomclusters considered to reflect complex patho-etiological mechanisms, and effective treatment options arelimited, with most medications targeting individual mechanisms and symptoms. Therefore, multi-targetedtreatment is required. IBS is currently viewed as a disorder of disturbed gut–brain interactions withabnormalities at different sites along the gut–brain axis, including altered gastrointestinal motility, visceralhypersensitivity, increased intestinal permeability, and altered gut microbiota. All of these abnormalitiesrepresent individual targets for STW 5, a herbal preparation with nine different extracts indicated for thetreatment of functional dyspepsia and IBS. As a multi-targeted medicinal drug, STW 5 possesses multiplepharmacodynamic effects. Several in vitro and in vivo studies have demonstrated STW 5 efficacy on numerousIBS patho-mechanisms targeting gastrointestinal smooth muscles, visceral afferent nerves, inflammation, gutpermeability, and the gut microbiome.

Exosome as a Natural Gene Delivery Vector for Cancer Treatment

2020 ◽  
Vol 20 (11) ◽  
pp. 821-830
Author(s):  
Prasad Pofali ◽  
Adrita Mondal ◽  
Vaishali Londhe
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Nucleic Acids ◽  
Cancer Treatment ◽  
Intestinal Barrier ◽  
Gene Carrier ◽  
Gene Delivery Vector ◽  
Delivery Vector

Background: Current gene therapy vectors such as viral, non-viral, and bacterial vectors, which are used for cancer treatment, but there are certain safety concerns and stability issues of these conventional vectors. Exosomes are the vesicles of size 40-100 nm secreted from multivesicular bodies into the extracellular environment by most of the cell types in-vivo and in-vitro. As a natural nanocarrier, exosomes are immunologically inert, biocompatible, and can cross biological barriers like the blood-brain barrier, intestinal barrier, and placental barrier. Objective: This review focusses on the role of exosome as a carrier to efficiently deliver a gene for cancer treatment and diagnosis. The methods for loading of nucleic acids onto the exosomes, advantages of exosomes as a smart intercellular shuttle for gene delivery and therapeutic applications as a gene delivery vector for siRNA, miRNA and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and also the limitations of exosomes as a gene carrier are all reviewed in this article. Methods: Mostly, electroporation and chemical transfection are used to prepare gene loaded exosomes. Results: Exosome-mediated delivery is highly promising and advantageous in comparison to the current delivery methods for systemic gene therapy. Targeted exosomes, loaded with therapeutic nucleic acids, can efficiently promote the reduction of tumor proliferation without any adverse effects. Conclusion: In the near future, exosomes can become an efficient gene carrier for delivery and a biomarker for the diagnosis and treatment of cancer.

scholarly journals HO-1/CO Maintains Intestinal Barrier Integrity through NF-κB/MLCK Pathway in Intestinal HO-1-/- Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Zhenling Zhang ◽  
Lijing Zhang ◽  
Qiuping Zhang ◽  
Bojia Liu ◽  
Fang Li ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Intestinal Barrier ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Barrier Integrity ◽  
Tnf Α ◽  
Intestinal Barrier Integrity ◽  
Deficient Mice

Background. Intestinal barrier injury is an important contributor to many diseases. We previously found that heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal barrier. This study is aimed at elucidating the molecular mechanisms of HO-1/CO in barrier loss. Materials and Methods. We induced gut leakiness by injecting carbon tetrachloride (CCl4) to wildtype or intestinal HO-1-deficient mice. In addition, we administrated tumor necrosis factor-α (TNF-α) to cells with gain- or loss-of-HO-1 function. The effects of HO-1/CO maintaining intestinal barrier integrity were investigated in vivo and in vitro. Results. Cobalt protoporphyrin and CO-releasing molecule-2 alleviated colonic mucosal injury and TNF-α levels; upregulated tight junction (TJ) expression; and inhibited epithelial IκB-α degradation and phosphorylation, NF-κB p65 phosphorylation, long MLCK expression, and MLC-2 phosphorylation after administration of CCl4. Zinc protoporphyrin completely reversed these effects. These findings were further confirmed in vitro, using Caco-2 cells with gain- or loss-of-HO-1-function after TNF-α. Pretreated with JSH-23 (NF-κB inhibitor) or ML-7 (long MLCK inhibitor), HO-1 overexpression prevented TNF-α-induced TJ disruption, while HO-1 shRNA promoted TJ damage even in the presence of JSH-23 or ML-7, thus suggesting that HO-1 dependently protected intestinal barrier via the NF-κB p65/MLCK/p-MLC-2 pathway. Intestinal HO-1-deficient mice further demonstrated the effects of HO-1 in maintaining intestinal barrier integrity and its relative mechanisms. Alleviated hepatic fibrogenesis and serum ALT levels finally confirmed the clinical significance of HO-1/CO repairing barrier loss in liver injury. Conclusion. HO-1/CO maintains intestinal barrier integrity through the NF-κB/MLCK pathway. Therefore, the intestinal HO-1/CO-NF-κB/MLCK system is a potential therapeutic target for diseases with a leaky gut.

scholarly journals Interleukin-15 May Be Responsible for Early Activation of Intestinal Intraepithelial Lymphocytes after Oral Infection with Listeria monocytogenes in Rats

1998 ◽  
Vol 66 (12) ◽  
pp. 5677-5683 ◽  
Author(s):  
Kenji Hirose ◽  
Hirohiko Suzuki ◽  
Hitoshi Nishimura ◽  
Akio Mitani ◽  
Junji Washizu ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Oral Infection ◽  
Epithelial Cell Line ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Interleukin 15 ◽  
Ifn Γ

ABSTRACT Exogenous interleukin-15 (IL-15) stimulates intestinal intraepithelial lymphocytes (i-IEL) from mice to proliferate and produce gamma interferon (IFN-γ) in vitro. To determine whether endogenous IL-15 is involved in activation of i-IEL during intestinal infection, we examined IL-15 synthesis by intestinal epithelial cells (i-EC) after infection with Listeria monocytogenes in rats. In in vitro experiments, invasion of L. monocytogenes into IEC-6 cells, a rat small intestine epithelial cell line, evidently induced IL-15 mRNA expression coincident with nuclear factor κB (NF-κB) activation, which is essential for IL-15 gene expression. IL-15 synthesis was detected in rat i-EC on day 1 after an oral inoculation of L. monocytogenes in vivo. The numbers of T-cell receptor (TCR) γδ+ T cells, NKR.P1+cells, and CD3+ CD8+ αα cells in i-IEL were significantly increased on day 1 after oral infection. The i-IEL from infected rats produced larger amounts of IFN-γ upon stimulation with immobilized anti-TCR γδ or anti-NKR.P1 monoclonal antibodies. These results suggest that IL-15 produced by i-EC may stimulate significant fractions of i-IEL to produce IFN-γ at an early phase of oral infection with L. monocytogenes.

scholarly journals A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage

2018 ◽  
Vol 115 (22) ◽  
pp. E5076-E5085 ◽  
Author(s):  
Vu L. Ngo ◽  
Hirohito Abo ◽  
Estera Maxim ◽  
Akihito Harusato ◽  
Duke Geem ◽  
...  
Keyword(s):  
Host Defense ◽  
Immune Cells ◽  
Intracellular Signaling ◽  
Intestinal Barrier ◽  
Intestinal Damage ◽  
Cytokine Network ◽  
Potent Inducer ◽  
Intracellular Signaling Cascade

The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36γ is a potent inducer of IL-23 both in vitro and in vivo. IL-36γ–induced IL-23 required Notch2-dependent (CD11b+CD103+) dendritic cells (DCs), but not Batf3-dependent (CD11b−CD103+) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-κB subunits c-Rel and p50. Consistent with in vitro observations, IL-36R– and IL-36γ–deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R or IL-36γ could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36γ, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense.

562 THE JAK INHIBITOR TOFACITINIB RESCUES INTESTINAL BARRIER DEFECTS AND DISRUPTED EPITHELIAL-MACROPHAGE CROSSTALK CAUSED BY LOSS OF PTPN2 ACTIVITY IN VITRO AND IN VIVO.

2020 ◽  
Vol 158 (6) ◽  
pp. S-115
Author(s):  
Anica Sayoc-Becerra ◽  
Marianne Spalinger ◽  
Christ Ordookhanian ◽  
Alina Santos ◽  
Vinicius Canale ◽  
...  
Keyword(s):  
Intestinal Barrier ◽  
Jak Inhibitor

scholarly journals Mycotoxins: Biotransformation and Bioavailability Assessment Using Caco-2 Cell Monolayer

Toxins ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 628
Author(s):  
Van Nguyen Tran ◽  
Jitka Viktorová ◽  
Tomáš Ruml
Keyword(s):  
Cell Monolayer ◽  
Intestinal Barrier ◽  
Intestinal Transport ◽  
Human Colon ◽  
In Vitro Models ◽  
Biologically Active ◽  
In Vitro Techniques ◽  
In Vivo Cytotoxicity

The determination of mycotoxins content in food is not sufficient for the prediction of their potential in vivo cytotoxicity because it does not reflect their bioavailability and mutual interactions within complex matrices, which may significantly alter the toxic effects. Moreover, many mycotoxins undergo biotransformation and metabolization during the intestinal absorption process. Biotransformation is predominantly the conversion of mycotoxins meditated by cytochrome P450 and other enzymes. This should transform the toxins to nontoxic metabolites but it may possibly result in unexpectedly high toxicity. Therefore, the verification of biotransformation and bioavailability provides valuable information to correctly interpret occurrence data and biomonitoring results. Among all of the methods available, the in vitro models using monolayer formed by epithelial cells from the human colon (Caco-2 cell) have been extensively used for evaluating the permeability, bioavailability, intestinal transport, and metabolism of toxic and biologically active compounds. Here, the strengths and limitations of both in vivo and in vitro techniques used to determine bioavailability are reviewed, along with current detailed data about biotransformation of mycotoxins. Furthermore, the molecular mechanism of mycotoxin effects is also discussed regarding the disorder of intestinal barrier integrity induced by mycotoxins.

Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier

2010 ◽  
Vol 298 (6) ◽  
pp. G851-G859 ◽  
Author(s):  
Jurgen Karczewski ◽  
Freddy J. Troost ◽  
Irene Konings ◽  
Jan Dekker ◽  
Michiel Kleerebezem ◽  
...  
Keyword(s):  
Tight Junction ◽  
Lactobacillus Plantarum ◽  
Transmembrane Protein ◽  
Intestinal Barrier ◽  
Protective Effects ◽  
Epithelial Tight Junction ◽  
Vitro Model ◽  
Probiotic Mechanisms

Lactobacillus plantarum , a commensal bacterium of humans, has been proposed to enhance the intestinal barrier, which is compromised in a number of intestinal disorders. To study the effect of L. plantarum strain WCFS1 on human barrier function, healthy subjects were administered L. plantarum or placebo in the duodenum for 6 h by means of a feeding catheter. The scaffold protein zonula occludens (ZO)-1 and transmembrane protein occludin were found to be significantly increased in the vicinity of the tight-junction (TJ) structures, which form the paracellular seal between cells of the epithelium. In an in vitro model of the human epithelium, L. plantarum induced translocation of ZO-1 to the TJ region; however, the effects on occludin were minor compared with those seen in vivo. L. plantarum was shown to activate Toll-like receptor 2 (TLR2) signaling, and treatment of Caco-2 monolayers with the TLR2 agonist Pam3-Cys-SK4(PCSK) significantly increased fluorescent staining of occludin in the TJ. Pretreatment of Caco-2 monolayers with L. plantarum or PCSK significantly attenuated the effects of phorbol ester-induced dislocation of ZO-1 and occludin and the associated increase in epithelial permeability. Our results identifying commensal bacterial stimulation of TLR2 in the gut epithelium as a regulator of epithelial integrity have important implications for understanding probiotic mechanisms and the control of intestinal homeostasis.

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