Intestinal organoids in co-culture: Redefining the boundaries of gut mucosa ex vivo modeling

2021 ◽  
Author(s):  
Viktoria Hentschel ◽  
Thomas Seufferlein ◽  
Milena Armacki
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Intestinal Barrier ◽  
Mucosal Barrier ◽  
Intestinal Barrier Function ◽  
Cell Populations ◽  
Tissue Destruction ◽  
Health Maintenance ◽  
Gut Mucosa ◽  
Joint Event

All-time preservation of an intact mucosal barrier is crucial to ensuring intestinal homeostasis and, hence, the organism's overall health maintenance. This complex process relies on an equilibrated signaling system between the intestinal epithelium and numerous cell populations inhabiting the gut mucosa. Any perturbations of this delicate crosstalk, particularly regarding the immune cell compartment and microbiota, may sustainably debilitate the intestinal barrier function. As a final joint event, a critical rise in epithelial permeability facilitates the exposure of submucosal immunity to microbial antigens, resulting in uncontrolled inflammation, collateral tissue destruction and dysbiosis. Organoid-derived intestinal co-culture models have established themselves as convenient tools to re-enact such pathophysiological events, explore interactions between selected cell populations and assess their roles with a central focus on intestinal barrier recovery and stabilization.

Introduction

ESC CardioMed ◽  
2018 ◽  
pp. 1081-1082
Author(s):  
Gerhard Rogler
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Chronic Heart Failure ◽  
Bacterial Translocation ◽  
Gastrointestinal Disease ◽  
Intestinal Barrier ◽  
Mucosal Barrier ◽  
Intestinal Barrier Function ◽  
Oral Drug ◽  
Intestinal Microcirculation

Gastrointestinal disease and heart disease seem to be two groups of diseases that do not have much in common. However, recent insights have changed this assumption: the intestine’s basic functions, digestion and absorption, are obviously clinically relevant for almost all oral drug treatments of diseases. An impairment of intestinal barrier function is followed by increased bacterial translocation across the intestinal mucosa leading to increased levels of circulating bacteria and bacterial products. This is assumed to be associated with atherosclerosis and chronic heart failure. Vice versa, an impaired cardiac function in the setting of chronic heart failure may lead to a defect in the mucosal barrier and increased bacterial translocation via changes in intestinal microcirculation. In addition, recent evidence indicates that conditions such as metabolic syndrome or obesity—certainly risk factors for heart disease—are influenced by intestinal microbiota composition.

scholarly journals Intestinal Mucosal Barrier Function Restoration in Mice by Maize Diet Containing Enriched Flavan-4-Ols

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 896 ◽  
Author(s):  
Binning Wu ◽  
Rohil Bhatnagar ◽  
Vijaya V. Indukuri ◽  
Shara Chopra ◽  
Kylie March ◽  
...  
Keyword(s):  
Barrier Function ◽  
Control Diet ◽  
Intestinal Barrier ◽  
Mucosal Barrier ◽  
Intestinal Barrier Function ◽  
Low Grade ◽  
Colonic Inflammation ◽  
Mucosal Barrier Function ◽  
Inflammatory Bowel ◽  
Histology Score

Inflammatory bowel disease (IBD), a chronic intestinal inflammatory condition, awaits safe and effective preventive strategies. Naturally occurring flavonoid compounds are promising therapeutic candidates against IBD due to their great antioxidant potential and ability to reduce inflammation and improve immune signaling mediators in the gut. In this study, we utilized two maize near-isogenic lines flavan-4-ols-containing P1-rr (F+) and flavan-4-ols-lacking p1-ww (F−) to investigate the anti-inflammatory property of flavan-4-ols against carboxymethylcellulose (CMC)-induced low-grade colonic inflammation. C57BL/6 mice were exposed to either 1% CMC (w/v) or water for a total of 15 weeks. After week six, mice on CMC treatment were divided into four groups. One group continued on the control diet. The second and third groups were supplemented with F+ at 15% or 25% (w/w). The fourth group received diet supplemented with F− at 15%. Here we report that mice consuming F+(15) and F+(25) alleviated CMC-induced increase in epididymal fat-pad, colon histology score, pro-inflammatory cytokine interleukin 6 expression and intestinal permeability compared to mice fed with control diet and F−(15). F+(15) and F+(25) significantly enhanced mucus thickness in CMC exposed mice (p < 0.05). These data collectively demonstrated the protective effect of flavan-4-ol against colonic inflammation by restoring intestinal barrier function and provide a rationale to breed for flavan-4-ols enriched cultivars for better dietary benefits.

scholarly journals Macrophage Deficiency Makes Intestinal Epithelial Cells Susceptible to NSAID-Induced Damage

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xinxin Wang ◽  
Jiayang Wang ◽  
Tianyu Xie ◽  
Shuo Li ◽  
Di Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Barrier Function ◽  
Molecular Mechanisms ◽  
Intestinal Barrier ◽  
Mucosal Barrier ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Epithelial Proliferation ◽  
Gm Csf ◽  
Mucosal Barrier Function

Objectives. In Crohn’s disease (CD), the mechanisms underlying the regulation by granulocyte-macrophage colony-stimulating factor (GM-CSF) of mucosal barrier function in the ileum are unclear. We analyzed the molecular mechanisms underlying the regulation by GM-CSF of the mucosal barrier function. Methods. We examined the role of GM-CSF in the intestinal barrier function in CD at the molecular-, cellular-, and animal-model levels. Results. Macrophages directly secreted GM-CSF, promoting intestinal epithelial proliferation and inhibiting apoptosis, which maintained intestinal barrier function. Macrophages were absent in NSAID-induced ileitis, causing GM-CSF deficiency, increasing the apoptosis rate, decreasing the proliferation rate, increasing inter- and paracellular permeabilities, decreasing the TJP levels, and reducing the numbers of mesenteric lymph nodes, memory T cells, and regulatory T cells in Csf1op/op transgenic mice. Conclusions. GM-CSF is required for the maintenance of intestinal barrier function. Macrophages directly secrete GM-CSF, promoting intestinal epithelial proliferation and inhibiting apoptosis.

scholarly journals Intestinal Barrier Function in Gluten-Related Disorders

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2325 ◽  
Author(s):  
Danielle Cardoso-Silva ◽  
Deborah Delbue ◽  
Alice Itzlinger ◽  
Renée Moerkens ◽  
Sebo Withoff ◽  
...  
Keyword(s):  
Immune Response ◽  
Celiac Disease ◽  
Immunoglobulin E ◽  
Intestinal Barrier ◽  
Causative Factor ◽  
Mucosal Barrier ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Barrier Dysfunction ◽  
Wheat Sensitivity

Gluten-related disorders include distinct disease entities, namely celiac disease, wheat-associated allergy and non-celiac gluten/wheat sensitivity. Despite having in common the contact of the gastrointestinal mucosa with components of wheat and other cereals as a causative factor, these clinical entities have distinct pathophysiological pathways. In celiac disease, a T-cell mediate immune reaction triggered by gluten ingestion is central in the pathogenesis of the enteropathy, while wheat allergy develops as a rapid immunoglobulin E- or non-immunoglobulin E-mediated immune response. In non-celiac wheat sensitivity, classical adaptive immune responses are not involved. Instead, recent research has revealed that an innate immune response to a yet-to-be-defined antigen, as well as the gut microbiota, are pivotal in the development in this disorder. Although impairment of the epithelial barrier has been described in all three clinical conditions, its role as a potential pathogenetic co-factor, specifically in celiac disease and non-celiac wheat sensitivity, is still a matter of investigation. This article gives a short overview of the mucosal barrier of the small intestine, summarizes the aspects of barrier dysfunction observed in all three gluten-related disorders and reviews literature data in favor of a primary involvement of the epithelial barrier in the development of celiac disease and non-celiac wheat sensitivity.

scholarly journals Autocrine, Not Paracrine, Interferon-Gamma Gene Delivery Enhances Ex Vivo Antigen-Specific Cytotoxic T Lymphocyte Stimulation and Killing

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Dazhi Zhang ◽  
Yong Liu ◽  
Min Shi ◽  
Chang Xuan You ◽  
Maohua Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Delivery ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Ex Vivo ◽  
Cell Populations ◽  
Adeno Associated Virus ◽  
Th1 Response ◽  
Compare And Contrast

The adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTL) shows promise in the treatment of cancer and infectious diseases. We utilize adeno-associated virus-(AAV-) based antigen gene-loaded dendritic cells (DCs) to stimulate such antigen-specific CTL. Yet further improvements in CTL stimulation and killing may result by gene delivery of various Th1-response interferons/cytokines, such as interferonγ(IFN-γ), as the delivered gene can continuously produce that interferon. However which immune cell type should optimally express IFN-γis unclear as the phenotypes of both DC and T cells are enhanced by it. Here, we used AAV to compare and contrast IFN-γgene delivery into DC or T cells, and versus the addition of exogenous IFN-γ, for stimulating carcinoembryonic antigen-(CEA-) specific CTL. It was found that AAV/IFN-γdelivery into T cells (autocrine) resulted in T cell populations with the highest CD8(+)/CD4(+) ratio, highest IFN-γ(+)/IL-4(+) ratio, highest CD69(+),CD8(+) levels, and lowest CD4(+)/CD25(+) levels, all consistent with the strongest Th1 response. Most importantly, AAV/IFN-γtransduction of T cells resulted in antigen-specific T cell populations with the highest killing capabilities, 49% above other treatments. These data strongly suggest that AAV/IFN-γautocrine gene delivery into T cells is worthy of further study towards maximizing the generation of antigen-specific anticancer CTL killers.

scholarly journals Intestinal Barrier Dysfunction, Bacterial Translocation and Inflammation: Deathly Triad in Sepsis

2021 ◽  
Author(s):  
Bercis Imge Ucar ◽  
Gulberk Ucar
Keyword(s):  
Bacterial Translocation ◽  
Current Knowledge ◽  
Intestinal Barrier ◽  
Intestinal Bacteria ◽  
Mucosal Barrier ◽  
High Morbidity ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Gut Mucosa ◽  
Sepsis Detection

Sepsis, as a complex entity, comprises multiple pathophysiological mechanisms which bring about high morbidity and mortality. The previous studies showed that the gastrointestinal tract is damaged during sepsis, and its main symptoms include increased permeability, bacterial translocation (BT), and malabsorption. BT is the invasion of indigenous intestinal bacteria via the gut mucosa to other tissues. It occurs in pathological conditions such as disruption of the intestine’s ecological balance and mucosal barrier permeability, immunosuppression, and oxidative stress through transcellular/paracellular pathways and initiate an excessive systemic inflammatory response. Thereby, recent clinical and preclinical studies focus on the association between sepsis and intestinal barrier dysfunction. This chapter overviews the current knowledge about the molecular basis of BT of the intestine, its role in the progress of sepsis, detection of BT, and actual therapeutic approaches.

scholarly journals Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

2020 ◽  
Author(s):  
Elliot Yi-Hsin Lin ◽  
Hsuan-Ju Lai ◽  
Yuan-Kai Cheng ◽  
Kai-Quan Leong ◽  
Li-Chieh Cheng ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Experimental Colitis ◽  
Neutrophil Extracellular Trap ◽  
Mucosal Barrier ◽  
Mucosal Inflammation ◽  
Intestinal Barrier Function ◽  
Trinitrobenzene Sulfonic Acid ◽  
Barrier Integrity

Aberrant neutrophil extracellular trap (NET) formation and the loss of barrier integrity in inflamed intestinal tissues have long been associated with inflammatory bowel disease (IBD). However, whether NETs alter intestinal epithelium permeability during colitis remains elusive. Here, we demonstrated that NETs promote the breakdown in intestinal barrier function for the pathogenesis of intestinal inflammation in mouse models of colitis. NETs were abundant in the colon of mice with colitis experimentally induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Analysis of the intestinal barrier integrity revealed that NETs impaired gut permeability, enabling the initiation of luminal bacterial translocation and inflammation. Furthermore, NETs induced the apoptosis of epithelial cells and disrupted the integrity of tight junctions and adherens junctions. Intravenous administration of DNase I, an enzyme that dissolves the web-like DNA filaments of NETs, during colitis restored the mucosal barrier integrity which reduced the dissemination of luminal bacteria, and attenuated intestinal inflammation in both DSS and TNBS models. We conclude that NETs serve a detrimental factor in the gut epithelial barrier function leading to the pathogenesis of mucosal inflammation during acute colitis.

scholarly journals Perfluoroalkyl substances are increased in patients with late-onset ulcerative colitis and induce intestinal barrier defects ex vivo in murine intestinal tissue

2020 ◽  
Author(s):  
Frida Fart ◽  
Samira Salihovic ◽  
Aidan McGlinchey ◽  
Melanie G. Gareau ◽  
Matej Orešič ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Bile Acids ◽  
Late Onset ◽  
Ex Vivo ◽  
Intestinal Barrier ◽  
Perfluoroalkyl Substances ◽  
Intestinal Barrier Function ◽  
Healthy Controls ◽  
Murine Tissue ◽  
Inflammatory Bowel

AbstractBackground and aimEnvironmental factors are strongly implicated in late-onset inflammatory bowel disease. By measuring perfluoroalkyl substances we investigate whether high exposure correlates with late-onset inflammatory bowel disease, and disturbances of the bile acid pool. We further explore the effect of perfluoronoctanoic acid on intestinal barrier function in murine tissue.MethodsSerum levels of perfluoroalkyl substances and bile acids were assessed in matched samples from patients with ulcerative colitis (n = 20) and Crohn’s disease (n = 20) diagnosed at the age of ≥55 years. Blood donors (n = 20), were used as healthy controls. The metabolites were assessed by ultra-performance liquid chromatography coupled to a triple-quadrupole mass spectrometer. Ex vivo exposure of perfluoronoctanoic acid in ileal and colonic murine tissue was assessed with the Ussing Chamber methodology (n = 5).ResultsThe total level of perfluoroalkyl substances was significantly increased in patients with ulcerative colitis compared to healthy controls or patients with Crohn’s disease (p< 0.05). Ex vivo exposure of 100 μM perfluoronoctanoic acid induced a significantly increased paracellular permeability across ileum (p< 0.05) and an enhanced carbachol-induced ion secretion in colon. The distribution of bile acids as well as the correlation pattern between perfluoroalkyl substances and bile acids differed between patient groups and controls.ConclusionOur results demonstrate that the levels of perfluoroalkyl substances are increased in patients with late-onset ulcerative colitis and might contribute to the disease by inducing a dysfunctional intestinal barrier or indirectly by interfering with the bile acid metabolism and thereby alter the intestinal barrier function.

scholarly journals Differential induction of apoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4261-4275 ◽  
Author(s):  
A Ayala ◽  
CD Herdon ◽  
DL Lehman ◽  
CA Ayala ◽  
IH Chaudry
Keyword(s):  
Bone Marrow ◽  
Immune Cell ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Marrow Cell ◽  
Cecal Ligation ◽  
Polymicrobial Sepsis ◽  
Cell Populations ◽  
Lymphoid Tissues ◽  
Marrow Cells

Apoptosis (Ao), is a process by which cells undergo a form of nonnecrotic cellular suicide. Although for most cells this is a constitutive process, it can be induced in immature and differentiating immune cell populations by stress mediators associated with inflammation. This inducible form of A(o) is referred to as programmed cell death. However, it is not clear whether hematopoietic cell populations such as the thymus and bone marrow are induced to undergo A(o) during polymicrobial sepsis. To assess this, thymocytes, bone marrow cells, or splenocytes (as a source of comparative nonhematopoietic cells) were harvested from C3H/HeN mice at 1, 4, or 24 hours after cecal ligation and puncture (CLP; to induce polymicrobial sepsis) or sham-CLP (Sham). The results showed that mixed bone marrow cells ex vivo, although not to the same extent as thymus, showed a marked increase in the percentage of cells in A(o), increased endonuclease activity, and a significant decrease in cell yield at 24 hours but not at 4 hours after CLP. Similar changes were not evident in splenocytes. Phenotypic, as well as morphologic assessment, indicated that most of the increase in apoptotic cells in the thymus was associated with the immature T cells (CD4+CD8+) and CD8-CD4- cells. In contrast, the increase in bone marrow cell A(o) was associated with only the B220+ cells, with no significant contribution from myeloid cells. Treatment of CLP mice in vivo with either RU-38486 or PEG-(rsTNF- R1)2 was unable to reverse the increased A(o) in the bone marrow of these animals. Taken together, these findings indicate that A(o) as a process induced by polymicrobial sepsis is not limited to the thymus, but can also be detected in the bone marrow. However, unlike thymic A(o), bone marrow is not affected directly/indirectly by glucocorticoids or tumor necrosis factor released during sepsis.

Ischemia-reperfusion in feline small intestine: a role for nitric oxide

1993 ◽  
Vol 264 (1) ◽  
pp. G143-G149 ◽  
Author(s):  
P. Kubes
Keyword(s):  
Nitric Oxide ◽  
Ischemia Reperfusion ◽  
Intestinal Barrier ◽  
Microvascular Dysfunction ◽  
Mucosal Barrier ◽  
Intestinal Barrier Function ◽  
Nitric Oxide Synthesis ◽  
Barrier Dysfunction ◽  
Synthesis Inhibitor ◽  
Arginine Infusion

The objective of this study was to assess whether nitric oxide synthesis inhibition affects intestinal barrier function after ischemia-reperfusion of the feline small bowel. Local intra-arterial infusion of the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 25 nmol.ml-1.min-1) was performed in autoperfused segments of cat ileum for 60 min after 90 min of ischemia and 60 min of reperfusion. Epithelial permeability was quantitated by measuring blood-to-lumen clearance of 51Cr-labeled EDTA, and microvascular dysfunction was assessed by measuring the clearance of protein from the vasculature into the interstitium. 125I-labeled albumin clearance from blood to lumen and histology were performed to further characterize the extent of intestinal dysfunction after reperfusion of the postischemic intestine in the presence and absence of L-NAME. Ischemia-reperfusion-induced mucosal and microvascular permeability increases were dramatically augmented by L-NAME infusion, and this effect was reversed by infusion of L-arginine (125 nmol.ml-1.min-1). Initiating L-arginine (but not D-arginine) infusion alone 10 min before reperfusion provided protection against ischemia-reperfusion-induced mucosal barrier dysfunction; however, this was not associated with a reduction in endogenous levels of L-arginine during ischemia-reperfusion. These data suggest that basal nitric oxide production is important in minimizing mucosal and microvascular barrier dysfunction associated with reperfusion of postischemic intestine.

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