Novel Therapeutic Approaches in Inflammatory Bowel Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 23002

Special Issue Editor

Special Issue Information

Dear Colleagues,

Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are chronic diseases of the gastrointestinal tract characterized by inflammation of the enteric wall, abdominal pain, diarrhea, bleeding, and malabsorption.

Conventional therapies for IBD include anti-inflammatory drugs, corticosteroids, thiopurines, methotrexate, and anti-tumor necrosis factor agents. The long-term use of these drugs can induce severe side effects with a negative impact on patients’ quality of life. For this reason, there is great interest in finding new therapeutic strategies with fewer side effects for the treatment of IBDs.

The purpose of this Special Issue is to publish original research papers and/or relevant updates of literature data on the beneficial effects of novel and safe treatments in gastrointestinal disorders.

Dr. Giovanni Pallio
Guest Editor

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Keywords

  • IBD
  • colitis
  • Crohn’s disease
  • inflammation
  • cytokines
  • ROS
  • oxidative stress

Published Papers (6 papers)

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Research

16 pages, 3167 KiB  
Article
Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties
by Hansol Joo, Mi-Kyung Oh, Ji Yeon Kang, Hyun Sung Park, Dong-Hoon Chae, Jieun Kim, Jong-Hee Lee, Hee Min Yoo, Uimook Choi, Do-Kyun Kim, Hakmo Lee, Sungjoo Kim and Kyung-Rok Yu
Biomedicines 2021, 9(2), 209; https://doi.org/10.3390/biomedicines9020209 - 18 Feb 2021
Cited by 11 | Viewed by 3551
Abstract
Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human [...] Read more.
Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton’s jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-β1 (TGFβ), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases)
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11 pages, 2145 KiB  
Article
Extracellular Vesicles Derived from Kefir Grain Lactobacillus Ameliorate Intestinal Inflammation via Regulation of Proinflammatory Pathway and Tight Junction Integrity
by Eun Ae Kang, Hye-In Choi, Seung Wook Hong, Seokwoo Kang, Hyeon-Young Jegal, Eun Wook Choi, Byung-Soon Park and Joo Sung Kim
Biomedicines 2020, 8(11), 522; https://doi.org/10.3390/biomedicines8110522 - 20 Nov 2020
Cited by 30 | Viewed by 3547
Abstract
The aim of this study was to demonstrate the anti-inflammatory effect of Lactobacillus kefirgranum PRCC-1301-derived extracellular vesicles (PRCC-1301 EVs) on intestinal inflammation and intestinal barrier function. Human intestinal epithelial cells (IECs) Caco-2 were treated with PRCC-1301 EVs and then stimulated with dextran sulfate [...] Read more.
The aim of this study was to demonstrate the anti-inflammatory effect of Lactobacillus kefirgranum PRCC-1301-derived extracellular vesicles (PRCC-1301 EVs) on intestinal inflammation and intestinal barrier function. Human intestinal epithelial cells (IECs) Caco-2 were treated with PRCC-1301 EVs and then stimulated with dextran sulfate sodium (DSS). Real-time RT-PCR revealed that PRCC-1301 EVs inhibited the expression of pro-inflammatory cytokines in Caco-2 cells. PRCC-1301 EVs enhanced intestinal barrier function by maintaining intestinal cell integrity and the tight junction. Loss of Zo-1, claudin-1, and occludin in Caco-2 cells and the colitis tissues was recovered after PRCC-1301 EVs treatment, as evidenced by immunofluorescence analysis. Acute murine colitis was induced using 4% DSS and chronic colitis was generated in piroxicam-treated IL-10-/- mice. PRCC-1301 EVs attenuated body weight loss, colon shortening, and histological damage in acute and chronic colitis models in mice. Immunohistochemistry revealed that phosphorylated NF-κB p65 and IκBα were reduced in the colon tissue sections treated with PRCC-1301 EVs. Our results suggest that PRCC-1301 EVs may have an anti-inflammatory effect on colitis by inhibiting the NF-κB pathway and improving intestinal barrier function. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases)
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16 pages, 5235 KiB  
Article
Modulation of NLRP3 Inflammasome Attenuated Inflammatory Response Associated to Diarrhea-Predominant Irritable Bowel Syndrome
by Sarah Adriana Scuderi, Giovanna Casili, Marika Lanza, Alessia Filippone, Irene Paterniti, Emanuela Esposito and Michela Campolo
Biomedicines 2020, 8(11), 519; https://doi.org/10.3390/biomedicines8110519 - 20 Nov 2020
Cited by 18 | Viewed by 2760
Abstract
Diarrhea-predominant irritable bowel syndrome (IBS-D) is a multifactorial chronic gastrointestinal disorder characterized by inflammation and immune response. In this context, NLRP3 over-activation is associated with a breakdown of enteric-immune balance related to IBS-D. The aim of this study was to evaluate the effect [...] Read more.
Diarrhea-predominant irritable bowel syndrome (IBS-D) is a multifactorial chronic gastrointestinal disorder characterized by inflammation and immune response. In this context, NLRP3 over-activation is associated with a breakdown of enteric-immune balance related to IBS-D. The aim of this study was to evaluate the effect of the inflammasome inhibitor, BAY 11-7082, in a rat model of IBS-D. Syndrome was induced by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and sacrificed 2 weeks after IBS-D induction. BAY 11-7082 (10 and 30 mg/kg) was administered daily by oral gavage. The results obtained showed that the treatment with BAY 11-7082 (30 mg/kg) significantly reduced tissue injury characterized by edema, neutrophil infiltration, and loss of colon structure. We demonstrated that BAY 11-7082 treatment inhibited NLRP3 inflammasome activation and NF-kB translocation, reducing inflammatory mediators. Moreover, treatment with BAY 11-7082 restored tight junction alteration following IBS-D induction and reduced the restraint stress. Taken together, our data demonstrate that IBS-D induced NLRP3 inflammasome pathway activation, accompanied by the production of proinflammatory response. The modulation of the inflammosome pathway with BAY 11-7082 inhibitor significantly reduced pathological signs of IBS-D, therefore, can be considered a valuable strategy to reduce the development of IBS-D. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases)
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21 pages, 4696 KiB  
Article
Anti-MAP Triple Therapy Supports Immunomodulatory Therapeutic Response in Crohn’s Disease through Downregulation of NF-κB Activation in the Absence of MAP Detection
by Ahmad Qasem, Erij Elkamel and Saleh A. Naser
Biomedicines 2020, 8(11), 513; https://doi.org/10.3390/biomedicines8110513 - 18 Nov 2020
Cited by 15 | Viewed by 6049
Abstract
We previously reported that the triple antibiotic formulation, known as anti-MAP therapy, exhibits unique synergistic antimicrobial activity and should be effective for treatment of Crohn’s disease (CD) associated with Mycobacterium avium subspecies paratuberculosis (MAP). The absence of MAP detection in some CD cases [...] Read more.
We previously reported that the triple antibiotic formulation, known as anti-MAP therapy, exhibits unique synergistic antimicrobial activity and should be effective for treatment of Crohn’s disease (CD) associated with Mycobacterium avium subspecies paratuberculosis (MAP). The absence of MAP detection in some CD cases may be linked to poor diagnostics or lack of association with the disease. To understand the therapeutic response of some CD patients to anti-MAP therapy in absence of MAP detection, we investigated the immunomodulatory potency of anti-MAP therapy and its major ingredients, clarithromycin (CLA) and rifabutin (RIF), in THP-1, Caco-2, and Jurkat T-cells. Anti-MAP formulation at 2.0 μg/mL decreased MAP viability in macrophages by 18-fold over 72 h. Additionally, M1/M2 macrophage polarization ratio was reduced by 6.7-fold, and expression and protein levels of TNF-α and IL-6 were reduced by 2.9-fold, whereas IL-10 increased by 5.0-fold in these cells. Mechanistically, the effect of anti-MAP formulation on NF-κB p65 activation was dose-dependent and decreased to 13.4% at 2.0 μg/mL. Most importantly, anti-MAP therapy also reversed pro-inflammatory response in lipopolysaccharide (LPS)-induced macrophages, which shows that the anti-inflammatory effect of the treatment is not just due to a decrease in MAP viability. To study the anti-cytotoxic effects of anti-MAP therapy in Caco-2 monolayers infected with MAP or treated with dextran sodium sulfate (DSS), we showed a 45% decrease in lactate dehydrogenase (LDH) activity and an 84% increase in glutathione (GSH) activity, which supports anti-apoptotic activity of the drug. In Jurkat T-cells, anti-MAP therapy decreased T-cell proliferation by 4.8-fold following treatment with phytohemagglutinin (PHA) and by 2.9-fold with MAP purified protein derivative (PPD). Overall, the data demonstrate that anti-MAP therapy plays a significant role in modulating and eliciting a protective immune response in macrophages, endothelial cells, and T lymphocytes, even in absence of infection. This may explain the therapeutic response of some CD patients to treatment, even in absence of MAP detection, infection, or total eradication. The study supports anti-MAP therapy as an alternate treatment option in CD patients, especially in absence of reliable MAP diagnostics. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases)
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15 pages, 13511 KiB  
Article
Combined Treatment with Polynucleotides and Hyaluronic Acid Improves Tissue Repair in Experimental Colitis
by Giovanni Pallio, Alessandra Bitto, Antonio Ieni, Natasha Irrera, Federica Mannino, Socrate Pallio, Domenica Altavilla, Francesco Squadrito, Carmelo Scarpignato and Letteria Minutoli
Biomedicines 2020, 8(10), 438; https://doi.org/10.3390/biomedicines8100438 - 20 Oct 2020
Cited by 14 | Viewed by 3137
Abstract
Inflammatory bowel diseases (IBDs) are chronic conditions that can benefit from the combined treatment of adenosine receptor agonists and hyaluronic acid (HA), which, binding the CD44, has pro-survival effects. Therefore, this study investigated the effects of a mixture of polynucleotides and HA in [...] Read more.
Inflammatory bowel diseases (IBDs) are chronic conditions that can benefit from the combined treatment of adenosine receptor agonists and hyaluronic acid (HA), which, binding the CD44, has pro-survival effects. Therefore, this study investigated the effects of a mixture of polynucleotides and HA in an experimental model of dinitrobenzenesulfonic acid (DNBS)-induced colitis. A group of 40 rats received a single intra-colonic instillation of DNBS, and after 6 h, animals were randomized to receive daily: (i) saline solution; (ii) polynucleotides (Poly; 8 mg/kg); (iii) polynucleotides (8 mg/kg) plus hyaluronic acid (HA; 15 mg/kg); and (iv) hyaluronic acid (HA; 15 mg/kg). Rats in the control group (n = 10) received saline solution only. Seven days after induction, animals receiving Poly plus HA showed reduced clinical signs, weight loss and colon shortening, ameliorated macroscopic and histological damage, and apoptosis. Moreover, the combined treatment reduced the positivity in the colonic infiltrate of CD3 positive T cells, CD20 positive B cells and CD44. Furthermore, Poly plus HA reduced colonic myeloperoxidase activity and malondialdehyde, indicating a dampening of the inflammatory infiltrate and oxidation products. Our research demonstrated that a combined treatment of polynucleotides with hyaluronic acid had a protective effect in a model of ulcerative colitis, suggesting that this association deserves further attention for the treatment of IBDs. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases)
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20 pages, 3708 KiB  
Article
Idebenone Protects against Spontaneous Chronic Murine Colitis by Alleviating Endoplasmic Reticulum Stress and Inflammatory Response
by Sonia Shastri, Tanvi Shinde, Agampodi Promoda Perera, Nuri Gueven and Rajaraman Eri
Biomedicines 2020, 8(10), 384; https://doi.org/10.3390/biomedicines8100384 - 28 Sep 2020
Cited by 8 | Viewed by 3224
Abstract
Endoplasmic reticulum (ER) stress in intestinal secretory goblet cells has been linked to the development of ulcerative colitis (UC). Emerging evidence suggests that the short chain quinone drug idebenone displays anti-inflammatory activity in addition to its potent antioxidant and mitochondrial electron donor properties. [...] Read more.
Endoplasmic reticulum (ER) stress in intestinal secretory goblet cells has been linked to the development of ulcerative colitis (UC). Emerging evidence suggests that the short chain quinone drug idebenone displays anti-inflammatory activity in addition to its potent antioxidant and mitochondrial electron donor properties. This study evaluated the impact of idebenone in Winnie mice, that are characterized by spontaneous chronic intestinal inflammation and ER stress caused by a missense mutation in the mucin MUC2 gene. Idebenone (200 mg/kg) was orally administered daily to 5–6 weeks old Winnie mice over a period of 21 days. Idebenone treatment substantially improved body weight gain, disease activity index (DAI), colon length and histopathology score. Immunohistochemistry revealed increased expression of MUC2 protein in goblet cells, consistent with increased MUC2 mRNA levels. Furthermore, idebenone significantly reduced the expression of the ER stress markers C/EBP homologous protein (CHOP), activating transcription factor 6 (ATF6) and X-box binding protein-1 (XBP-1) at both mRNA and protein levels. Idebenone also effectively reduced pro-inflammatory cytokine levels in colonic explants. Taken together, these results indicate that idebenone could represent a potential therapeutic approach against human UC by its strong anti-inflammatory activity and its ability to reduce markers of ER stress. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases)
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