Epithelial EP4 plays an essential role in maintaining homeostasis in colon

Abstract Colonic epithelial cells comprise the mucosal barrier, and their dysfunction promotes microbial invasion from the gut lumen and induces the development of intestinal inflammation. The EP4 receptor is known to mediate the protective effect of prostaglandin (PG) E2 in the gastrointestinal tract; however, the exact role of epithelial EP4 in intestinal pathophysiology remains unknown. In the present study, we aimed to investigate the role of epithelial EP4 in maintaining colonic homeostasis by characterizing the intestinal epithelial cell-specific EP4 knockout (EP4 cKO) mice. Mice harboring the epithelial EP4 deletion showed significantly lower colonic crypt depth and lower numbers of secretory cell lineages, as well as impaired epithelial cells in the colon. Interestingly, EP4-deficient colon epithelia showed a higher number of apoptotic cells. Consistent with the defect in mucosal barrier function of colonic epithelia and secretory cell lineages, EP4 cKO colon stroma showed enhanced immune cell infiltration, which was accompanied by increased production of inflammatory cytokines. Furthermore, EP4-deficient colons were susceptible to dextran sulfate sodium (DSS)-induced colitis. Our study is the first to demonstrate that epithelial EP4 loss resulted in potential “inflammatory” status under physiological conditions. These findings provided insights into the crucial role of epithelial PGE2/EP4 axis in maintaining intestinal homeostasis.

Download Full-text

Proinflammatory role of vasopressin through V1b receptors in hapten-induced experimental colitis in rodents: implication in IBD

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00022.2010 ◽

2010 ◽

Vol 299 (6) ◽

pp. G1298-G1307 ◽

Cited By ~ 14

Author(s):

Laurent Ferrier ◽

Claudine Serradeil-Le Gal ◽

Anke M. Schulte ◽

Valentina Vasina ◽

Eric Gaultier ◽

...

Keyword(s):

Mast Cell ◽

Intestinal Inflammation ◽

Experimental Colitis ◽

Paracellular Permeability ◽

Mast Cell Activation ◽

Receptor Interaction ◽

Trinitrobenzene Sulfonic Acid ◽

Inflammatory Status ◽

V1b Receptor

Vasopressin and its receptors modulate several gut functions, but their role in intestinal inflammation is unknown. Our aims were to determine 1) the localization of V1b receptors in human and rodent colon, 2) the role of vasopressin and V1b receptors in experimental colitis using two approaches: V1b−/− mice and a selective V1b receptor antagonist, SSR149415, and 3) the mechanisms involved. V1b receptors were localized in normal and inflamed colon from humans and rats. Experimental colitis was induced in rats and mice and some groups were treated before or after colitis induction with oral SSR149415 (3–30 mg/kg). Other groups of mice were submitted to dehydration to increase vasopressin plasma levels, prior to colitis induction. Body weight, damage scores, MPO, and TNF-α tissue levels were determined. Finally, colonic segments of wild-type (WT) and V1b−/− mice were mounted in Ussing chambers and paracellular permeability in response to vasopressin was studied. V1b receptors were expressed in enterocytes and ganglia cells of the enteric nervous system of human and rat intestine. Expression levels were independent from inflammatory status. Colitis was less severe in rodents treated by either preventive or curative SSR149415 and in V1b−/− mice. 2,4,6-Trinitrobenzene sulfonic acid induced a strong mortality in dehydrated animals that was reversed by preventive SSR149415 or mast cell stabilizer. Vasopressin significantly increased paracellular permeability in WT, but not in V1b−/− mice. Preincubation of colon tissues with SSR149415 abolished the vasopressin effect. Similarly, vasopressin had no effect in colonic preparations from WT mice pretreated with mast cell stabilizers. Vasopressin, through V1b receptor interaction, has proinflammatory properties linked to mast cell activation and downstream alterations of the colonic epithelial barrier. These findings underline the potential interest of V1b receptor blockers in gut inflammatory diseases.

Download Full-text

High-Fat Diet Promotes DSS-Induced Ulcerative Colitis by Downregulated FXR Expression through the TGFB Pathway

BioMed Research International ◽

10.1155/2020/3516128 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Di Zhao ◽

Chenwen Cai ◽

Qiyi Chen ◽

Shuang Jin ◽

Bo Yang ◽

...

Keyword(s):

Ulcerative Colitis ◽

High Fat Diet ◽

Target Genes ◽

Intestinal Inflammation ◽

Farnesoid X Receptor ◽

Mucosal Barrier ◽

High Fat ◽

Colon Rectal Cancer ◽

Chronic Intestinal Inflammation

Ulcerative colitis is one of the IBD which cause a chronic intestinal inflammation and dysfunctional of the mucosal barrier. For now, the incident of UC was steadily increased all over the world. It has become a novel independent risk factor of several severe diseases especially colon-rectal cancer. However, the etiology of UC was still obscure. Previous studies show that high-fat diet contributed to the pathogenesis of immune system dysregulation, and farnesoid X receptor (FXR) was also implicated in the pathogenesis of various inflammatory symptoms. Yet, their inner roles in the pathogenesis of UC have not been mentioned. In this study, we aim to investigate the role of FXR in UC. High-fat diet (HFD) promotes the progression of DSS-induced UC, shows an increasing secretion of bile acid in serum, and leads to a downregulation of FXR target genes (FXRα, Shp, and lbabp). Adding FXR agonist FexD rescues the phenotype induced by high-fat diet, whereas TGFBRI inhibitor SB431542 abrogates the restoration by FexD in DSS-induced UC mice. To further verify the relationship between the FXR and TGFB signaling pathway, we made a UC-HFD model in the Caco2 cell line. Results shows the same conclusion that FXR mitigate UC inflammation through a TGFB-dependent pathway. These results expand the role of FXR in ulcerative colitis and suggest that FXR activation may be considered a therapeutic strategy for UC.

Download Full-text

Role of Epithelial Cells in Initiation and Propagation of Intestinal Inflammation. Eliminating the static: tight junction dynamics exposed

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00439.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. G577-G582 ◽

Cited By ~ 103

Author(s):

Le Shen ◽

Jerrold R. Turner

Keyword(s):

Epithelial Cells ◽

Tight Junction ◽

Tight Junctions ◽

Plasma Membranes ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Barrier Properties ◽

Structural Modifications ◽

Mucosal Surfaces

Like all mucosal surfaces, the intestine forms a barrier that separates the external environment, i.e., the gut lumen, from the protected internal milieu. The intestinal barrier is formed by the epithelial cells that line the luminal surface. Plasma membranes of these cells prevent free passage of hydrophilic molecules across this barrier but do not seal the space between cells. This function is provided by the tight junction. Each cell is encircled at the apicolateral boundary by the tight junction, which seals the paracellular space. The tight junction does not form a completely impermeant seal, however, because that would prevent paracellular absorption of essential nutrients and ions; intestinal tight junctions are “leaky” and allow solutes to be transported paracellularly according to size and charge. Abundant data are available to demonstrate that barrier properties of tight junctions can be modulated in response to physiological, pharmacological, and pathophysiological stimuli, but the structural modifications responsible for these responses are poorly defined. Recent advances in understanding the role of tight junction dynamics in response to such stimuli are the focus of this review.

Download Full-text

Intestinal Inflammation and Mucosal Barrier Function

Inflammatory Bowel Diseases ◽

10.1097/mib.0000000000000204 ◽

2014 ◽

Vol 20 (12) ◽

pp. 2394-2404 ◽

Cited By ~ 120

Author(s):

Fermín Sánchez de Medina ◽

Isabel Romero-Calvo ◽

Cristina Mascaraque ◽

Olga Martínez-Augustin

Keyword(s):

Barrier Function ◽

Intestinal Inflammation ◽

Mucosal Barrier ◽

Mucosal Barrier Function

Download Full-text

REGULATION OF THE INTESTINAL INFLAMMATORY RESPONSE THROUGH THE INGESTION OF MAILLARD COMPOUNDS AND THEIR INTERACTION WITH RAGE AND GPR43 RECEPTORS

Anales de la Real Academia Nacional de Farmacia ◽

10.53519/analesranf.2021.87.02.04 ◽

2021 ◽

pp. 141-154

Author(s):

Silvia Pastoriza ◽

José Ángel Rufián-Henares

Keyword(s):

Immune Response ◽

Intestinal Inflammation ◽

Short Chain Fatty Acids ◽

Mucosal Barrier ◽

Intestinal Epithelial ◽

Inflammatory Status ◽

Mucosal Barrier Injury ◽

Inflammatory Bowel ◽

Molecular Damage

Molecular damage signals attract neutrophils to sites of infection or inflammation. The G-protein coupled receptor (GPR43) and the receptor for advanced glicosilation compounds (RAGE) recognize short-chain fatty acids (propionate and butyrate) and AGEs (advanced glycosylation compounds) respectively, both receptors being abundantly expressed in neutrophils and intestinal epithelial cells. The functional role that activation of these receptors plays in the in vivo orchestration of the immune response is unclear. Our work examines the effect of the ingestion of AGEs on the immune response, both in healthy mice and in mice that were induced to colitis, using transgenic mice deficient in GPR43 or RAGE receptors. One of the main findings is that both the GPR43 receptor and RAGE are necessary for the recruitment of neutrophils in a model of intestinal inflammation due to mucosal barrier injury. We have also verified that the AGEs ingested with the diet promote the appearance of an imbalance in the inflammatory balance at the intestinal level, giving rise to a pro-inflammatory status. We have also show that carboxymethylisine (CML), a specific type of AGE, is capable of stimulating the GPR43 receptor and acting as a neutrophil chemoattraction factor. Finally, we have tested the treatment with sRAGE, a protein capable of capturing free AGEs. This procedure could be a promising therapy for the treatment of inflammatory bowel disease.

Download Full-text

Alleviative Effects of Exopolysaccharide Produced by Lactobacillus helveticus KLDS1.8701 on Dextran Sulfate Sodium-Induced Colitis in Mice

Microorganisms ◽

10.3390/microorganisms9102086 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2086

Author(s):

Yin Liu ◽

Shujuan Zheng ◽

Jiale Cui ◽

Tingting Guo ◽

Jingtao Zhang ◽

...

Keyword(s):

Gut Microbiota ◽

Inflammatory Cytokines ◽

Intestinal Inflammation ◽

Activity Index ◽

Lactobacillus Helveticus ◽

Mucosal Barrier ◽

Microbiota Composition ◽

Mucosal Barrier Function ◽

Anti Inflammatory ◽

Gut Microbiota Composition

Ulcerative colitis (UC) is a non-specific chronic inflammatory disease with lesions located in the colon and rectum. The aim of this study was to evaluate the anti-inflammatory effects of exopolysaccharide-1 (EPS-1) isolated by L. helveticus KLDS1.8701 on UC. The anti-inflammatory effects of EPS-1 were studied using dextran sulphate sodium (DSS)-induced UC model. In vivo results showed that EPS-1 administration significantly ameliorated weight loss, colon shortening, disease activity index (DAI) score, myeloperoxidase (MPO) activity, and colon tissue damage. In addition, EPS-1 administration significantly decreased the levels of pro-inflammatory cytokines and increased levels of anti-inflammatory cytokines. Meanwhile, EPS-1 administration significantly up-regulated the expression of tight junction proteins and mucin. Furthermore, EPS-1 administration modulated gut microbiota composition caused by DSS and increased the short-chain fatty acids (SCFAs) levels. Collectively, our study showed the alleviative effects of EPS- isolated by L. helveticus KLDS1.8701 on DSS-induced UC via alleviating intestinal inflammation, improving mucosal barrier function, and modulating gut microbiota composition.

Download Full-text

Microbiota-Immune Interactions in Ulcerative Colitis and Colitis Associated Cancer and Emerging Microbiota-Based Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms222111365 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11365

Author(s):

Jelena Popov ◽

Valentina Caputi ◽

Nandini Nandeesha ◽

David Avelar Rodriguez ◽

Nikhil Pai

Keyword(s):

Ulcerative Colitis ◽

Intestinal Inflammation ◽

Autoimmune Disorder ◽

Mucosal Barrier ◽

Host Immune System ◽

Intestinal Dysbiosis ◽

Inflammatory Bowel ◽

Genetic And Environmental Factors

Ulcerative colitis (UC) is a chronic autoimmune disorder affecting the colonic mucosa. UC is a subtype of inflammatory bowel disease along with Crohn’s disease and presents with varying extraintestinal manifestations. No single etiology for UC has been found, but a combination of genetic and environmental factors is suspected. Research has focused on the role of intestinal dysbiosis in the pathogenesis of UC, including the effects of dysbiosis on the integrity of the colonic mucosal barrier, priming and regulation of the host immune system, chronic inflammation, and progression to tumorigenesis. Characterization of key microbial taxa and their implications in the pathogenesis of UC and colitis-associated cancer (CAC) may present opportunities for modulating intestinal inflammation through microbial-targeted therapies. In this review, we discuss the microbiota-immune crosstalk in UC and CAC, as well as the evolution of microbiota-based therapies.

Download Full-text

IL-33 regulates gene expression in intestinal epithelial cells independently of its nuclear localization

10.1101/291039 ◽

2018 ◽

Author(s):

Zhengxiang He ◽

Lili Chen ◽

Glaucia C. Furtado ◽

Sergio A. Lira

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Intestinal Inflammation ◽

Intestinal Epithelial Cells ◽

Full Length ◽

Nuclear Accumulation ◽

List Type ◽

Intestinal Epithelial ◽

Regulated Gene Expression

AbstractIL-33 is a cytokine found in the extracellular space (mature IL-33) or in the cell nucleus (full-length IL-33). Nuclear accumulation of IL-33 has been reported in intestinal epithelial cells (IEC) during intestinal inflammation and cancer, but a functional role for this nuclear form remains unclear. To study the role of nuclear IL-33inIEC, we generated transgenic mice expressing full-length IL-33inthe intestinal epithelium (Vfl33mice). Expression of full-length IL-33 in the epithelium resulted in accumulation of IL-33 protein in the nucleus and secretion of IL-33. Over-expression of full-length IL-33 by IEC did not promote gut inflammation, but induced expression of genes in the IEC and lamina propria lymphocytes (LPL) that correlated negatively with genes expressed in inflammatory bowel diseases (IBD). Because the IL-33 receptor ST2 is expressed by IEC, there was the potential that both the mature and full-length forms could mediate this effect. To specifically interrogate the transcriptional role of nuclear IL-33,weintercrossed theVfl33mice with ST2-deficient mice. ST2 deficiency completely abrogated the transcriptional effects elicited by IL-33 expression, suggesting that the transcriptional effects of IL-33 on IEC are mediated by its mature, not its nuclear form.HighlightsExpression of full-length IL-33 in the epithelium resulted in accumulation of IL-33 protein in the nucleus and secretion of IL-33.Full-length IL-33 induced differential gene expression in IEC and LPL that was negatively associated with intestinal inflammatory diseasesIL-33 regulated gene expression in IEC via its extracellular (mature) form not via its nuclearform.

Download Full-text

Intestinal Mucosal Barrier Is Regulated by Intestinal Tract Neuro-Immune Interplay

Frontiers in Pharmacology ◽

10.3389/fphar.2021.659716 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xin-yu You ◽

Han-yu Zhang ◽

Xu Han ◽

Fang Wang ◽

Peng-wei Zhuang ◽

...

Keyword(s):

Nervous System ◽

Metabolic Diseases ◽

Intestinal Inflammation ◽

Acute Stress ◽

Intestinal Barrier ◽

Cerebrovascular Diseases ◽

Mucosal Barrier ◽

Intestinal Mucosal Barrier ◽

Mucosal Barrier Function ◽

Irritable Bowel

Inflammatory bowel disease, irritable bowel syndrome and severe central nervous system injury can lead to intestinal mucosal barrier damage, which can cause endotoxin/enterobacteria translocation to induce infection and is closely related to the progression of metabolic diseases, cardiovascular and cerebrovascular diseases, tumors and other diseases. Hence, repairing the intestinal barrier represents a potential therapeutic target for many diseases. Enteral afferent nerves, efferent nerves and the intrinsic enteric nervous system (ENS) play key roles in regulating intestinal physiological homeostasis and coping with acute stress. Furthermore, innervation actively regulates immunity and induces inherent and adaptive immune responses through complex processes, such as secreting neurotransmitters or hormones and regulating their corresponding receptors. In addition, intestinal microorganisms and their metabolites play a regulatory role in the intestinal mucosal barrier. This paper primarily discusses the interactions between norepinephrine and β-adrenergic receptors, cholinergic anti-inflammatory pathways, nociceptive receptors, complex ENS networks, gut microbes and various immune cells with their secreted cytokines to summarize the key roles in regulating intestinal inflammation and improving mucosal barrier function.

Download Full-text