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16 pages, 3312 KiB

Open AccessArticle

Effect of a Flavonoid Combination of Apigenin and Epigallocatechin-3-Gallate on Alleviating Intestinal Inflammation in Experimental Colitis Models

by Mingrui Li and Benno Weigmann

Int. J. Mol. Sci. 2023, 24(22), 16031; https://doi.org/10.3390/ijms242216031 - 07 Nov 2023

Viewed by 984

Abstract

Inflammatory bowel disease (IBD) is an autoimmune disease that leads to severe bowel symptoms and complications. Currently, there is no effective treatment, and the exact cause of IBD remains unclear. In the last decades, numerous studies have confirmed that flavonoids can have a [...] Read more.

Inflammatory bowel disease (IBD) is an autoimmune disease that leads to severe bowel symptoms and complications. Currently, there is no effective treatment, and the exact cause of IBD remains unclear. In the last decades, numerous studies have confirmed that flavonoids can have a positive impact on the treatment of IBD. Therefore, this study investigated the protective effect of a flavonoid combination of apigenin and epigallocatechin-3-gallate (EGCG) on IBD. In vitro studies in which Caco-2 cell monolayers were incubated with different concentrations of flavonoids found that the flavonoid-treated group exhibited increased transepithelial electrical resistance (TEER) at high concentrations, indicating a protective effect on the barrier function of the intestinal epithelium. In vivo studies showed that flavonoids significantly attenuated inflammatory levels in both chronic and acute hapten-mediated experimental colitis models in a time- and dose-dependent manner. In addition, the activity of myeloperoxidase (MPO) and the level of proinflammatory cytokines in the colon tissue were significantly reduced. Interestingly, the levels of anti-inflammatory cytokines were also dramatically increased. Finally, flavonoids were found to positively modulate the composition of the gut microbiota in the colon. Therefore, a combination of flavonoids could be a promising therapeutic agent for the future adjunctive treatment of IBD. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)

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19 pages, 6562 KiB

Open AccessArticle

Humanized NSG Mouse Models as a Preclinical Tool for Translational Research in Inflammatory Bowel Diseases

by Veronika Weß, Paula Schuster-Winkelmann, Yasemin Hazal Karatekin, Simge Malik, Florian Beigel, Florian Kühn and Roswitha Gropp

Int. J. Mol. Sci. 2023, 24(15), 12348; https://doi.org/10.3390/ijms241512348 - 02 Aug 2023

Cited by 2 | Viewed by 1372

Abstract

The development of animal models reflecting the pathologies of ulcerative colitis (UC) and Crohn’s disease (CD) remains a major challenge. The NOD/SCID/IL2rγ^null (NSG) mouse strain, which is immune-compromised, tolerates the engraftment of human peripheral blood mononuclear cells (PBMC) derived from patients with [...] Read more.

The development of animal models reflecting the pathologies of ulcerative colitis (UC) and Crohn’s disease (CD) remains a major challenge. The NOD/SCID/IL2rγ^null (NSG) mouse strain, which is immune-compromised, tolerates the engraftment of human peripheral blood mononuclear cells (PBMC) derived from patients with UC (NSG-UC) or CD (NSG-CD). This offers the opportunity to examine the impact of individual immunological background on the development of pathophysiological manifestations. When challenged with ethanol, NSG-UC mice exhibited a strong pro-inflammatory response, including the development of edemas, influx of human T cells, B cells and monocytes into the mucosa and submucosa, and elevated expression of the inflammatory markers CRP and CCL-7. Fibrotic alterations were characterized by an influx of fibroblasts and a thickening of the muscularis mucosae. In contrast, the development of pathological manifestations in NSG-CD mice developed without challenge and was signified by extensive collagen deposition between the muscularis propria and muscularis mucosae, as observed in the areas of strictures in CD patients. Vimentin-expressing fibroblasts supplanting colonic crypts and elevated expression of HGF and TGFß corroborated the remodeling phenotype. In summary, the NSG-UC and NSG-CD models partially reflect these human diseases and are powerful tools to examine the mechanism underlying the inflammatory processes in UC and CD. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)

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11 pages, 2559 KiB

Open AccessArticle

CRP in Outpatients with Inflammatory Bowel Disease Is Linked to the Blood Microbiota

by Jie Xu, Göran Molin, Sanna Davidson, Bodil Roth, Klas Sjöberg and Åsa Håkansson

Int. J. Mol. Sci. 2023, 24(13), 10899; https://doi.org/10.3390/ijms241310899 - 30 Jun 2023

Cited by 2 | Viewed by 1188

Abstract

The circulation is a closed system that has been assumed to be free from bacteria, but evidence for the existence of a low-density blood microbiota is accumulating. The present study aimed to map the blood microbiota of outpatients with Crohn’s disease (CD) or [...] Read more.

The circulation is a closed system that has been assumed to be free from bacteria, but evidence for the existence of a low-density blood microbiota is accumulating. The present study aimed to map the blood microbiota of outpatients with Crohn’s disease (CD) or with ulcerative colitis (UC) by 16S metagenomics. A diverse microbiota was observed in the blood samples. Regardless of the type of disease, the alpha diversity of the microbiota was positively associated with C-reactive protein (CRP). The blood microbiota had a surprisingly high proportion of Proteobacteria in comparison with human oral and colonic microbiotas. There was no clear difference in the overall pattern of the microbiota between CD and UC. A non-template control (NTC) was included in the whole process to control for the potential contamination from the environment and reagents. Certain bacterial taxa were concomitantly detected in both blood samples and NTC. However, Acinetobacter, Lactobacillus, Thermicanus and Paracoccus were found in blood from both CD and UC patients but not in NTC, indicating the existence of a specific blood-borne microbiota in the patients. Achromobacter dominated in all blood samples, but a minor amount was also found in NTC. Micrococcaceae was significantly enriched in CD, but it was also detected in high abundance in NTC. Whether the composition of the blood microbiota could be a marker of a particular phenotype in inflammatory bowel disease (IBD) or whether the blood microbiota could be used for diagnostic or therapeutic purposes deserves further attention. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)

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16 pages, 2465 KiB

Open AccessArticle

Preclinical In Vitro Model to Assess the Changes in Permeability and Cytotoxicity of Polarized Intestinal Epithelial Cells during Exposure Mimicking Oral or Intravenous Routes: An Example of Arsenite Exposure

by Pravin Parajuli, Kuppan Gokulan and Sangeeta Khare

Int. J. Mol. Sci. 2022, 23(9), 4851; https://doi.org/10.3390/ijms23094851 - 27 Apr 2022

Cited by 3 | Viewed by 2606

Abstract

The gastrointestinal tract (GIT) is exposed to xenobiotics, including drugs, through both: local (oral) and systemic routes. Despite the advances in drug discovery and in vitro pre-clinical models, there is a lack of appropriate translational models to distinguish the impact of these routes [...] Read more.

The gastrointestinal tract (GIT) is exposed to xenobiotics, including drugs, through both: local (oral) and systemic routes. Despite the advances in drug discovery and in vitro pre-clinical models, there is a lack of appropriate translational models to distinguish the impact of these routes of exposure. Changes in intestinal permeability has been observed in different gastrointestinal and systemic diseases. This study utilized one such xenobiotic, arsenic, to which more than 200 million people around the globe are exposed via their food, drinking water, work environment, soil, and air. The purpose of this study was to establish an in vitro model to mimic gastrointestinal tract exposure to xenobiotics via oral or intravenous routes. To achieve this, we compared the route (mimicking oral and intravenous exposure to GIT and the dose response (using threshold approach) of trivalent and pentavalent inorganic arsenic species on the permeability of in vitro cultured polarized T84 cells, an example of intestinal epithelial cells. Arsenic treatment to polarized T84 cells via the apical and basolateral compartment of the trans-well system reflected oral or intravenous routes of exposure in vivo, respectively. Sodium arsenite, sodium arsenate, dimethyl arsenic acid sodium salt (DMA^V), and disodium methyl arsonate hydrate (MMA^V) were assessed for their effects on intestinal permeability by measuring the change in trans-epithelial electrical resistance (TEER) of T-84 cells. Polarized T-84 cells exposed to 12.8 µM of sodium arsenite from the basolateral side showed a marked reduction in TEER. Cytotoxicity of sodium arsenite, as measured by release of lactate dehydrogenase (LDH), was increased when cells were exposed via the basolateral side. The mRNA expression of genes related to cell junctions in T-84 cells was analyzed after exposure with sodium arsenite for 72 h. Changes in TEER correlated with mRNA expression of focal-adhesion-, tight-junction- and gap-junction-related genes (upregulation of Jam2, Itgb3 and Notch4 genes and downregulation of Cldn2, Cldn3, Gjb1, and Gjb2). Overall, exposure to sodium arsenite from the basolateral side was found to have a differential effect on monolayer permeability and on cell-junction-related genes as compared to apical exposure. Most importantly, this study established a preclinical human-relevant in vitro translational model to assess the changes in permeability and cytotoxicity during exposure, mimicking oral or intravenous routes. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)

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Review

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21 pages, 1127 KiB

Open AccessReview

Investigating the Crime Scene—Molecular Signatures in Inflammatory Bowel Disease

by Vibeke Andersen, Tue B. Bennike, Corinna Bang, John D. Rioux, Isabelle Hébert-Milette, Toshiro Sato, Axel K. Hansen and Ole H. Nielsen

Int. J. Mol. Sci. 2023, 24(13), 11217; https://doi.org/10.3390/ijms241311217 - 07 Jul 2023

Cited by 3 | Viewed by 1717

Abstract

Inflammatory bowel diseases (IBD) are without cure and troublesome to manage because of the considerable diversity between patients and the lack of reliable biomarkers. Several studies have demonstrated that diet, gut microbiota, genetics and other patient factors are essential for disease occurrence and [...] Read more.

Inflammatory bowel diseases (IBD) are without cure and troublesome to manage because of the considerable diversity between patients and the lack of reliable biomarkers. Several studies have demonstrated that diet, gut microbiota, genetics and other patient factors are essential for disease occurrence and progression. Understanding the link between these factors is crucial for identifying molecular signatures that identify biomarkers to advance the management of IBD. Recent technological breakthroughs and data integration have fuelled the intensity of this research. This research demonstrates that the effect of diet depends on patient factors and gut microbial activity. It also identifies a range of potential biomarkers for IBD management, including mucosa-derived cytokines, gasdermins and neutrophil extracellular traps, all of which need further evaluation before clinical translation. This review provides an update on cutting-edge research in IBD that aims to improve disease management and patient quality of life. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)

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19 pages, 2736 KiB

Open AccessReview

Inflammatory Bowel Disease: A Review of Pre-Clinical Murine Models of Human Disease

by Brunette Katsandegwaza, William Horsnell and Katherine Smith

Int. J. Mol. Sci. 2022, 23(16), 9344; https://doi.org/10.3390/ijms23169344 - 19 Aug 2022

Cited by 44 | Viewed by 7112

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are both highly inflammatory diseases of the gastrointestinal tract, collectively known as inflammatory bowel disease (IBD). Although the cause of IBD is still unclear, several experimental IBD murine models have enabled researchers to make great inroads [...] Read more.

Crohn’s disease (CD) and ulcerative colitis (UC) are both highly inflammatory diseases of the gastrointestinal tract, collectively known as inflammatory bowel disease (IBD). Although the cause of IBD is still unclear, several experimental IBD murine models have enabled researchers to make great inroads into understanding human IBD pathology. Here, we discuss the current pre-clinical experimental murine models for human IBD, including the chemical-induced trinitrobenzene sulfonic acid (TNBS) model, oxazolone and dextran sulphate sodium (DSS) models, the gene-deficient I-kappa-B kinase gamma (Iκκ-γ) and interleukin(IL)-10 models, and the CD4⁺ T-cell transfer model. We offer a comprehensive review of how these models have been used to dissect the etiopathogenesis of disease, alongside their limitations. Furthermore, the way in which this knowledge has led to the translation of experimental findings into novel clinical therapeutics is also discussed. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)

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25 pages, 1437 KiB

Open AccessReview

Inflammatory Bowel Disease Treatments and Predictive Biomarkers of Therapeutic Response

by Duaa Ahmed Elhag, Manoj Kumar, Marwa Saadaoui, Anthony K. Akobeng, Fatma Al-Mudahka, Mamoun Elawad and Souhaila Al Khodor

Int. J. Mol. Sci. 2022, 23(13), 6966; https://doi.org/10.3390/ijms23136966 - 23 Jun 2022

Cited by 32 | Viewed by 8469

Abstract

Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammation of the gastrointestinal tract with a highly heterogeneous presentation. It has a relapsing and remitting clinical course that necessitates lifelong monitoring and treatment. Although the availability of a variety of effective therapeutic options including [...] Read more.

Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammation of the gastrointestinal tract with a highly heterogeneous presentation. It has a relapsing and remitting clinical course that necessitates lifelong monitoring and treatment. Although the availability of a variety of effective therapeutic options including immunomodulators and biologics (such as TNF, CAM inhibitors) has led to a paradigm shift in the treatment outcomes and clinical management of IBD patients, some patients still either fail to respond or lose their responsiveness to therapy over time. Therefore, according to the recent Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations, continuous disease monitoring from symptomatic relief to endoscopic healing along with short- and long-term therapeutic responses are critical for providing IBD patients with a tailored therapy algorithm. Moreover, considering the high unmet need for novel therapeutic approaches for IBD patients, various new modulators of cytokine signaling events (for example, JAK/TYK inhibitors), inhibitors of cytokines (for example IL-12/IL-23, IL-22, IL-36, and IL-6 inhibitors), anti-adhesion and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors, and stem cells), as well as microbial-based therapeutics to decolonize the bed buds (for example, fecal microbiota transplantation and bacterial inhibitors) are currently being evaluated in different phases of controlled clinical trials. This review aims to offer a comprehensive overview of available treatment options and emerging therapeutic approaches for IBD patients. Furthermore, predictive biomarkers for monitoring the therapeutic response to different IBD therapies are also discussed. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)

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17 pages, 1346 KiB

Open AccessReview

Shigella Outer Membrane Vesicles as Promising Targets for Vaccination

by Muhammad Qasim, Marius Wrage, Björn Nüse and Jochen Mattner

Int. J. Mol. Sci. 2022, 23(2), 994; https://doi.org/10.3390/ijms23020994 - 17 Jan 2022

Cited by 9 | Viewed by 3736

Abstract

The clinical symptoms of shigellosis, a gastrointestinal infection caused by Shigella spp. range from watery diarrhea to fulminant dysentery. Endemic infections, particularly among children in developing countries, represent the majority of clinical cases. The situation is aggravated due to the high mortality rate [...] Read more.

The clinical symptoms of shigellosis, a gastrointestinal infection caused by Shigella spp. range from watery diarrhea to fulminant dysentery. Endemic infections, particularly among children in developing countries, represent the majority of clinical cases. The situation is aggravated due to the high mortality rate of shigellosis, the rapid dissemination of multi-resistant Shigella strains and the induction of only serotype-specific immunity. Thus, infection prevention due to vaccination, encompassing as many of the circulating serotypes as possible, has become a topic of interest. However, vaccines have turned out to be ineffective so far. Outer membrane vesicles (OMVs) are promising novel targets for vaccination. OMVs are constitutively secreted by Gram-negative bacteria including Shigella during growth. They are composed of soluble luminal portions and an insoluble membrane and can contain toxins, bioactive periplasmic and cytoplasmic (lipo-) proteins, (phospho-) lipids, nucleic acids and/or lipopolysaccharides. Thus, OMVs play an important role in bacterial cell–cell communication, growth, survival and pathogenesis. Furthermore, they modulate the secretion and transport of biomolecules, the stress response, antibiotic resistance and immune responses of the host. Thus, OMVs serve as novel secretion machinery. Here, we discuss the current literature and highlight the properties of OMVs as potent vaccine candidates because of their immunomodulatory, antigenic and adjuvant properties. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)

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