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17 pages, 2505 KiB

Open AccessArticle

Macrophages Inability to Mediate Adherent-Invasive E. coli Replication is Linked to Autophagy in Crohn’s Disease Patients

by Anthony Buisson, Clara Douadi, Lemlih Ouchchane, Marion Goutte, Jean-Pierre Hugot, Anaëlle Dubois, Régine Minet-Quinard, Damien Bouvier, Gilles Bommelaer, Emilie Vazeille and Nicolas Barnich

Cells 2019, 8(11), 1394; https://doi.org/10.3390/cells8111394 - 5 Nov 2019

Cited by 20 | Viewed by 3656

Abstract

The macrophages from Crohn’s Disease (CD) patients are defective to control the replication of CD-associated adherent-invasive E. coli (AIEC). We aimed to identify the host factors associated with AIEC replication focusing on polymorphisms related to autophagy. Peripheral blood monocyte-derived macrophages (MDM), obtained from [...] Read more.

The macrophages from Crohn’s Disease (CD) patients are defective to control the replication of CD-associated adherent-invasive E. coli (AIEC). We aimed to identify the host factors associated with AIEC replication focusing on polymorphisms related to autophagy. Peripheral blood monocyte-derived macrophages (MDM), obtained from 95 CD patient, 30 ulcerative colitis (UC) patients and 15 healthy subjects, were genotyped for several CD-associated polymorphisms. AIEC bacteria survival increased within MDM from CD patients compared to UC (p = 0.0019). AIEC bacteria survival increased in patients with CD-associated polymorphism IRGM (p = 0.05) and reduced in those with CD-associated polymorphisms XBP-1 (p = 0.026) and ULK-1 (p = 0.033). AIEC infection led to an increase of pro-inflammatory cytokines IL-1β (p < 0.0001) and TNF-α (p < 0.0001) in CD macrophages. ULK-1 expression increased in AIEC-infected MDM from CD patients compared to MDM from UC patients or healthy subjects (p = 0.0056) and correlated with AIEC survival (p = 0.0013). Moreover, the expression of ULK-1 phosphorylation on Serine 757 decreased following to AIEC infection (p < 0.0001). Short-term silencing of ULK-1 and IRGM genes restricted and promote, respectively, AIEC survival within MDM (p = 0.0018 and p = 0.0291). In conclusion, the macrophage defect to mediate AIEC clearance in CD patients is linked to polymorphisms related to autophagy such as IRGM and ULK-1. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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15 pages, 2405 KiB

Open AccessArticle

Target-Specific Fluorescence-Mediated Tomography for Non-Invasive and Dynamic Assessment of Early Neutrophil Infiltration in Murine Experimental Colitis

by Tobias M. Nowacki, Philipp Lenz, Dominik Bettenworth, Markus Brückner, Arne Bokemeyer, Phil R. Tepasse, Anne Helfen, Moritz Wildgruber and Michel Eisenblätter

Cells 2019, 8(11), 1328; https://doi.org/10.3390/cells8111328 - 28 Oct 2019

Cited by 4 | Viewed by 3054

Abstract

The role of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) is still only incompletely understood. Here, we evaluated target-specific fluorescence-mediated tomography (FMT) for visualization of neutrophil infiltration in murine experimental DSS-induced colitis. Colitis was assessed using clinical, endoscopic, and histopathological parameters. [...] Read more.

The role of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) is still only incompletely understood. Here, we evaluated target-specific fluorescence-mediated tomography (FMT) for visualization of neutrophil infiltration in murine experimental DSS-induced colitis. Colitis was assessed using clinical, endoscopic, and histopathological parameters. Intestinal neutrophil infiltration was determined at day 0, 4, and 10 by targeted FMT after injection of a neutrophil-specific fluorescence-labelled monoclonal antibody (Gr-1). Complementary, immunofluorescence tissue sections with Gr-1 and ELISA-based assessment of tissue myeloperoxidase (MPO) served as the gold standard for the quantification of neutrophil infiltration. Colitic animals showed decreasing body weight, presence of fecal occult blood, and endoscopic signs of inflammation. FMT revealed a significantly increased level of fluorescence only four days after colitis induction as compared to pre-experimental conditions (pmol tracer 73.2 ± 18.1 versus 738.6 ± 80.7; p < 0.05), while neither body weight nor endoscopic assessment showed significant changes at this early time. Confirmatory, post-mortem immunofluorescence studies and measurements of tissue MPO confirmed the presence of increased neutrophil infiltration in colitic mice compared to controls. Concluding, Gr-1 targeted FMT can detect early colonic infiltration of neutrophils in experimental colitis even before clinical symptoms or endoscopic alterations occur. Therefore, FMT might be an important tool for repetitive and non-invasive monitoring of inflammatory cell infiltrate in intestinal inflammation. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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19 pages, 2516 KiB

Open AccessArticle

Phosphoinositide 3-Kinase P110δ-Signaling Is Critical for Microbiota-Activated IL-10 Production by B Cells that Regulate Intestinal Inflammation

by Akihiko Oka, Yoshiyuki Mishima, Bo Liu, Jeremy W. Herzog, Erin C. Steinbach, Taku Kobayashi, Scott E. Plevy and R. Balfour Sartor

Cells 2019, 8(10), 1121; https://doi.org/10.3390/cells8101121 - 21 Sep 2019

Cited by 13 | Viewed by 3895

Abstract

The phosphoinositide 3-kinase catalytic subunit p110δ (PI3Kδ) gene maps to a human inflammatory bowel diseases (IBD) susceptibility locus, and genetic deletion of PI3Kδ signaling causes spontaneous colitis in mice. However, little is known regarding the role of PI3Kδ on IL-10-producing B cells that [...] Read more.

The phosphoinositide 3-kinase catalytic subunit p110δ (PI3Kδ) gene maps to a human inflammatory bowel diseases (IBD) susceptibility locus, and genetic deletion of PI3Kδ signaling causes spontaneous colitis in mice. However, little is known regarding the role of PI3Kδ on IL-10-producing B cells that help regulate mucosal inflammation in IBD. We investigated the role of PI3Kδ signaling in B cell production of IL-10, following stimulation by resident bacteria and B cell regulatory function against colitis. In vitro, B cells from PI3Kδ^D910A/D910A mice or wild-type B cells treated with PI3K specific inhibitors secreted significantly less IL-10 with greater IL-12p40 following bacterial stimulation. These B cells failed to suppress inflammatory cytokines by co-cultured microbiota-activated macrophages or CD4⁺ T cells. In vivo, co-transferred wild-type B cells ameliorated T cell-mediated colitis, while PI3Kδ^D910A/D910A B cells did not confer protection from mucosal inflammation. These results indicate that PI3Kδ-signaling mediates regulatory B cell immune differentiation when stimulated with resident microbiota or their components, and is critical for induction and regulatory function of IL-10-producing B cells in intestinal homeostasis and inflammation. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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18 pages, 4031 KiB

Open AccessFeature PaperArticle

Hyaluronan Accelerates Intestinal Mucosal Healing through Interaction with TSG-6

by Giusy Sammarco, Mohammad Shalaby, Sudharshan Elangovan, Luciana Petti, Giulia Roda, Silvia Restelli, Vincenzo Arena, Federica Ungaro, Gionata Fiorino, Anthony J. Day, Silvia D’Alessio and Stefania Vetrano

Cells 2019, 8(9), 1074; https://doi.org/10.3390/cells8091074 - 12 Sep 2019

Cited by 14 | Viewed by 4660

Abstract

Hyaluronan (HA) has proven to be beneficial in the treatment of several diseases. Recently, it has been shown that the local application of HA (IBD98E) improves endoscopic and clinical outcomes in subjects with active distal ulcerative colitis (UC). However, the mechanisms by which [...] Read more.

Hyaluronan (HA) has proven to be beneficial in the treatment of several diseases. Recently, it has been shown that the local application of HA (IBD98E) improves endoscopic and clinical outcomes in subjects with active distal ulcerative colitis (UC). However, the mechanisms by which this polysaccharide exerts its beneficial effects are unclear. Here, we demonstrated that HA treatment in vitro and in vivo improved mucosal healing by accelerating intestinal epithelial regeneration. Indeed, mice treated with HA showed a faster recovery from colitis and reduced endoscopic signs of mucosal inflammation compared to those receiving saline. Furthermore, histological analysis revealed less ulcerated mucosa in mice treated with HA, characterized by re-epithelialized areas. TSG-6, the secreted product of TNF-stimulated gene-6, is an HA-binding protein shown previously to have tissue-protective properties and promote wound healing. Mucosal levels of TSG-6 increased in UC patients compared to the healthy controls and also after wounding in mice. TSG-6 deletion prevented the beneficial properties of HA in mucosal wound repair, suggesting that the interaction of HA with TSG-6 is crucial for intestinal epithelial regeneration. Overall these results are consistent with HA having a therapeutic effect via the promotion of mucosal healing in patients with ulcerative colitis. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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12 pages, 3329 KiB

Open AccessArticle

mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn’s Disease

by Federica Ungaro, Valentina Garlatti, Luca Massimino, Antonino Spinelli, Michele Carvello, Matteo Sacchi, Salvatore Spanò, Gaia Colasante, Nicholas Valassina, Stefania Vetrano, Alberto Malesci, Laurent Peyrin-Biroulet, Silvio Danese and Silvia D’Alessio

Cells 2019, 8(8), 924; https://doi.org/10.3390/cells8080924 - 18 Aug 2019

Cited by 12 | Viewed by 4549

Abstract

Crohn’s disease (CD) is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract. Lymphatic drainage was demonstrated to be dysfunctional in CD pathogenesis, ultimately causing the failure of the resolution of intestinal inflammation. To investigate the molecular mechanisms underlying [...] Read more.

Crohn’s disease (CD) is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract. Lymphatic drainage was demonstrated to be dysfunctional in CD pathogenesis, ultimately causing the failure of the resolution of intestinal inflammation. To investigate the molecular mechanisms underlying these dysfunctions, we isolated human intestinal lymphatic endothelial cells (HILECs) from surgical specimens of patients undergoing resection for complicated CD (CD HILEC) and from a disease-free margin of surgical specimens of patients undergoing resection for cancer (healthy HILEC). Both cell types underwent transcriptomic profiling, and their barrier functionality was tested using a transwell-based co-culture system between HILEC and lamina propria mononuclear cells (LPMCs). Results showed CD HILEC displayed a peculiar transcriptomic signature that highlighted mTOR signaling as an orchestrator of leukocyte trafficking through the lymphatic barrier of CD patients. Moreover, we demonstrated that LPMC transmigration through the lymphatic endothelium of patients with CD depends on the capability of mTOR to trigger interleukin 20 receptor subunit α (IL20RA)-mediated intracellular signaling. Conclusively, our study suggests that leukocyte trafficking through the intestinal lymphatic microvasculature can be controlled by modulating IL20RA, thus leading to the resolution of chronic inflammation in patients with CD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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18 pages, 2188 KiB

Open AccessArticle

Serum Bile Acids Profiling in Inflammatory Bowel Disease Patients Treated with Anti-TNFs

by Giulia Roda, Emanuele Porru, Konstantinos Katsanos, Alexandros Skamnelos, Kallirroi Kyriakidi, Gionata Fiorino, Dimitrios Christodoulou, Silvio Danese and Aldo Roda

Cells 2019, 8(8), 817; https://doi.org/10.3390/cells8080817 - 2 Aug 2019

Cited by 16 | Viewed by 3672

Abstract

Background: Inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s disease (CD), represent systematic chronic conditions with a deficient intestinal absorption. We first attempt to investigate the serum bile acids (sBAs) profile in a large cohort of IBD patients to evaluate changes under [...] Read more.

Background: Inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s disease (CD), represent systematic chronic conditions with a deficient intestinal absorption. We first attempt to investigate the serum bile acids (sBAs) profile in a large cohort of IBD patients to evaluate changes under anti-TNF alpha treatment. Methods: Forty CD and 40 UC patients were enrolled and BAs were quantified by high-pressure liquid chromatography-electrospray-tandem mass spectrometry (HPLC-ES-MS/MS). Up to 15 different sBAs concentrations and clinical biomarkers where added to a Principal Component Analysis (PCA) to discriminate IBD from healthy conditions and treatment. Results: PCA allowed a separation into two clusters within CD (biologic-free patients and patients treated with anti-TNF alpha drugs and healthy subjects) but not UC. The first included CD. CD patients receiving anti-TNF alpha have an increase in total sBAs (4.11 ± 1.23 μM) compared to patients not exposed. Secondary BAs significantly increase after anti-TNF alpha treatment (1.54 ± 0.83 μM). Furthermore, multivariate analysis based on sBA concentration highlighted a different qualitative sBAs profile for UC and CD patients treated with conventional therapy. Conclusion: According to our results, anti-TNF alpha in CD restores the sBA profile by re-establishing the physiological levels. These findings indicate that, secondary BAs might serve as an indirect biomarker of the healing process. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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20 pages, 2351 KiB

Open AccessArticle

Inflammatory Bowel Disease Types Differ in Markers of Inflammation, Gut Barrier and in Specific Anti-Bacterial Response

by Stepan Coufal, Natalie Galanova, Lukas Bajer, Zuzana Gajdarova, Dagmar Schierova, Zuzana Jiraskova Zakostelska, Klara Kostovcikova, Zuzana Jackova, Zuzana Stehlikova, Pavel Drastich, Helena Tlaskalova-Hogenova and Miloslav Kverka

Cells 2019, 8(7), 719; https://doi.org/10.3390/cells8070719 - 13 Jul 2019

Cited by 31 | Viewed by 6830

Abstract

Crohn’s disease (CD), ulcerative colitis (UC) and inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC-IBD), share three major pathogenetic mechanisms of inflammatory bowel disease (IBD)-gut dysbiosis, gut barrier failure and immune system dysregulation. While clinical differences among them are well known, [...] Read more.

Crohn’s disease (CD), ulcerative colitis (UC) and inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC-IBD), share three major pathogenetic mechanisms of inflammatory bowel disease (IBD)-gut dysbiosis, gut barrier failure and immune system dysregulation. While clinical differences among them are well known, the underlying mechanisms are less explored. To gain an insight into the IBD pathogenesis and to find a specific biomarker pattern for each of them, we used protein array, ELISA and flow cytometry to analyze serum biomarkers and specific anti-microbial B and T cell responses to the gut commensals. We found that decrease in matrix metalloproteinase (MMP)-9 and increase in MMP-14 are the strongest factors discriminating IBD patients from healthy subjects and that PSC-IBD patients have higher levels of Mannan-binding lectin, tissue inhibitor of metalloproteinases 1 (TIMP-1), CD14 and osteoprotegerin than patients with UC. Moreover, we found that low transforming growth factor-β1 (TGF-β1) is associated with disease relapse and low osteoprotegerin with anti-tumor necrosis factor-alpha (TNF-α) therapy. Patients with CD have significantly decreased antibody and increased T cell response mainly to genera Eubacterium, Faecalibacterium and Bacteroides. These results stress the importance of the gut barrier function and immune response to commensal bacteria and point at the specific differences in pathogenesis of PSC-IBD, UC and CD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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24 pages, 17104 KiB

Open AccessArticle

Galectin-3 Regulates Indoleamine-2,3-dioxygenase-Dependent Cross-Talk between Colon-Infiltrating Dendritic Cells and T Regulatory Cells and May Represent a Valuable Biomarker for Monitoring the Progression of Ulcerative Colitis

by Vladislav Volarevic, Natasa Zdravkovic, Carl Randall Harrell, Nebojsa Arsenijevic, Crissy Fellabaum, Valentin Djonov, Miodrag L. Lukic and Bojana Simovic Markovic

Cells 2019, 8(7), 709; https://doi.org/10.3390/cells8070709 - 12 Jul 2019

Cited by 22 | Viewed by 4546

Abstract

Galectin-3 regulates numerous biological processes in the gut. We investigated molecular mechanisms responsible for the Galectin-3-dependent regulation of colon inflammation and evaluated whether Galectin-3 may be used as biomarker for monitoring the progression of ulcerative colitis (UC). The differences in disease progression between [...] Read more.

Galectin-3 regulates numerous biological processes in the gut. We investigated molecular mechanisms responsible for the Galectin-3-dependent regulation of colon inflammation and evaluated whether Galectin-3 may be used as biomarker for monitoring the progression of ulcerative colitis (UC). The differences in disease progression between dextran sodium sulphate-treated wild type and Galectin-3-deficient mice were investigated and confirmed in clinical settings, in 65 patients suffering from mild, moderate, and severe colitis. During the induction phase of colitis, Galectin-3 promoted interleukin-1β-induced polarization of colonic macrophages towards inflammatory phenotype. In the recovery phase of colitis, Galectin-3 was required for the immunosuppressive function of regulatory dendritic cells (DCs). Regulatory DCs in Galectin-3:Toll-like receptor-4:Kynurenine-dependent manner promoted the expansion of colon-infiltrated T regulatory cells (Tregs) and suppressed Th1 and Th17 cell-driven colon inflammation. Concentration of Galectin-3 in serum and stool samples of UC patients negatively correlated with clinical, endoscopic, and histological parameters of colitis. The cutoff serum values of Galectin-3 that allowed the discrimination of mild from moderate and moderate from severe colitis were 954 pg/mL and 580 pg/mL, respectively. Fecal levels of Galectin-3 higher than 553.44 pg/mL indicated attenuation of UC. In summing up, Galectin-3 regulates the cross-talk between colon-infiltrating DCs and Tregs and represents a new biomarker for monitoring the progression of UC. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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19 pages, 7295 KiB

Open AccessCommunication

The Role of Adipose Tissue in the Pathogenesis and Therapeutic Outcomes of Inflammatory Bowel Disease

by Piotr Eder, Maciej Adler, Agnieszka Dobrowolska, Julian Kamhieh-Milz and Janusz Witowski

Cells 2019, 8(6), 628; https://doi.org/10.3390/cells8060628 - 21 Jun 2019

Cited by 55 | Viewed by 14358

Abstract

Though historically regarded as an inert energy store, adipose tissue is a complex endocrine organ, which is increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD). Accumulating evidence points to visceral adipose tissue and specifically to its mesenteric component, or “creeping fat” [...] Read more.

Though historically regarded as an inert energy store, adipose tissue is a complex endocrine organ, which is increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD). Accumulating evidence points to visceral adipose tissue and specifically to its mesenteric component, or “creeping fat” as impacting on the disease course through its immunomodulatory properties. On the one hand, mesenteric fat acts as a physical barrier to inflammation and is involved in controlling host immune response to translocation of gut bacteria. On the other hand, however, there exists a strong link between visceral fat and complicated course of the disease with unfavorable therapeutic outcomes. Furthermore, “creeping fat” appears to play different roles in different IBD phenotypes, with the greatest pathogenetic contribution probably to an ileal form of Crohn’s disease. In this review, we summarize and discuss the existing literature on the subject and identify high-priority areas for future research. It may be that a better understanding of the role of mesenteric fat in IBD will determine new therapeutic targets and translate into improved clinical outcomes. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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20 pages, 4488 KiB

Open AccessArticle

Contribution of the Gut Microbiota in P28GST-Mediated Anti-Inflammatory Effects: Experimental and Clinical Insights

by Benoît Foligné, Coline Plé, Marie Titécat, Arnaud Dendooven, Aurélien Pagny, Catherine Daniel, Elisabeth Singer, Muriel Pottier, Benjamin Bertin, Christel Neut, Dominique Deplanque, Laurent Dubuquoy, Pierre Desreumaux, Monique Capron and Annie Standaert

Cells 2019, 8(6), 577; https://doi.org/10.3390/cells8060577 - 12 Jun 2019

Cited by 15 | Viewed by 5456

Abstract

An original immuno-regulatory strategy against inflammatory bowel diseases based on the use of 28 kDa glutathione S-transferase (P28GST), a unique schistosome protein, was recently proposed. Improvement of intestinal inflammation occurs through restoration of the immunological balance between pro-inflammatory T-helper 1 (Th1) responses and [...] Read more.

An original immuno-regulatory strategy against inflammatory bowel diseases based on the use of 28 kDa glutathione S-transferase (P28GST), a unique schistosome protein, was recently proposed. Improvement of intestinal inflammation occurs through restoration of the immunological balance between pro-inflammatory T-helper 1 (Th1) responses and both T-helper 2 (Th2) and regulatory responses. However, detailed mechanisms explaining how P28GST prevents colitis and promotes gut homeostasis remain unknown. Considering the complex interplay between the adaptive and innate immune system and the intestinal microbiota, we raised the question of the possible role of the microbial ecosystem in the anti-inflammatory effects mediated by the helminth-derived P28GST protein. We first analyzed, by 16S rRNA sequencing, the bacterial profiles of mice fecal microbiota at several time points of the P28GST-immunomodulation period prior to trinitrobenzene sulfonic acid (TNBS)-colitis. The influence of gut microbiota in the P28GST-mediated anti-inflammatory effects was then assessed by fecal microbiota transplantation experiments from P28GST-immunized mice to either conventional or microbiota depleted naïve recipient mice. Finally, the experimental data were supplemented by the temporal fecal microbiota compositions of P28GST-treated Crohn’s disease patients from a pilot clinical study (NCT02281916). The P28GST administration slightly modulated the diversity and composition of mouse fecal microbiota while it significantly reduced experimental colitis in mice. Fecal microbiota transplantation experiments failed to restore the P28GST-induced anti-inflammatory effects. In Crohn’s disease patients, P28GST also induced slight changes in their overall fecal bacterial composition. Collectively, these results provide key elements in both the anti-inflammatory mechanisms and the safe therapeutic use of immunomodulation with such promising helminth-derived molecules. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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11 pages, 502 KiB

Open AccessArticle

A Phase 2a, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial of IBD98-M Delayed-Release Capsules to Induce Remission in Patients with Active and Mild to Moderate Ulcerative Colitis

by Gionata Fiorino, Giacomo Carlo Sturniolo, Fabrizio Bossa, Andrea Cassinotti, Antonio Di Sabatino, Paolo Giuffrida and Silvio Danese

Cells 2019, 8(6), 523; https://doi.org/10.3390/cells8060523 - 30 May 2019

Cited by 8 | Viewed by 4418

Abstract

IBD98-M is a delayed-release formulation of mesalamine (mesalazine) and SH with a potential therapeutic role in ulcerative colitis (UC). A total of 51 patients with a modified Ulcerative Colitis Disease Activity Index (UCDAI) score of ≥4 and ≤10, and a modified UCDAI endoscopy [...] Read more.

IBD98-M is a delayed-release formulation of mesalamine (mesalazine) and SH with a potential therapeutic role in ulcerative colitis (UC). A total of 51 patients with a modified Ulcerative Colitis Disease Activity Index (UCDAI) score of ≥4 and ≤10, and a modified UCDAI endoscopy subscore ≥1 were randomized for 6 weeks of double-blind treatment with IBD98 0.8 g/day or IBD 1.2 g/day or placebo. The efficacy and safety of IBD98-M in mild to moderate active UC were primarily evaluated. At week 6, 1 (5.9%), 2 (12.5%), and 2 (11.1%) patients receiving IBD98-M 0.8 g, IBD98-M 1.2 g, and placebo, respectively, (p > 0.999) achieved clinical remission. Higher clinical response was seen in IBD98-M 1.2 g (31.3%) versus placebo (16.7%) and endoscopic improvement in IBD98-M 0.8 g (29.4%) versus placebo (22.2%) was seen. Fecal calprotectin levels were reduced in IBD98-M groups versus placebo (p > 0.05). IBD98-M patients achieved significant improvement in physical health summary score component of the SF-36 (p = 0.01 and p = 0.03 respectively) compared to placebo. IBD98-M did not meet the primary end point but had higher clinical response (1.2 g/day) and endoscopic improvement (0.8 g/day) compared to placebo. The safety result shown that IBD98-M treatment was safe and well tolerated in this patient population. No new safety signals or unexpected safety findings were observed during the study. Further trials with different stratification and longer follow-up may be needed to evaluate the efficacy. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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13 pages, 1908 KiB

Open AccessArticle

A Direct Effect of Sex Hormones on Epithelial Barrier Function in Inflammatory Bowel Disease Models

by Janine van der Giessen, C. Janneke van der Woude, Maikel P. Peppelenbosch and Gwenny M. Fuhler

Cells 2019, 8(3), 261; https://doi.org/10.3390/cells8030261 - 19 Mar 2019

Cited by 60 | Viewed by 6959

Abstract

Background: Pregnancy is often described as an immune-tolerant state, and a disease modulatory role for pregnancy on inflammatory bowel disease (IBD) has been suggested. The direct effect of estrogen and progesterone on the intestinal epithelial barrier is underexplored. We investigated the direct consequences [...] Read more.

Background: Pregnancy is often described as an immune-tolerant state, and a disease modulatory role for pregnancy on inflammatory bowel disease (IBD) has been suggested. The direct effect of estrogen and progesterone on the intestinal epithelial barrier is underexplored. We investigated the direct consequences of these pregnancy hormones on barrier cells and their function. Methods: We used IBD patient-derived inflammatory organoid models and 2D cell lines models. Epithelial barrier function was analyzed by measuring transepithelial electrical resistance; wound closure was determined by scratch assay; and cell viability was measured by MTT assays. Pro-inflammatory cytokine production was determined by enzyme-linked immunosorbent assays. Molecular modulation of endoplasmic reticulum (ER) stress induced by tunicamycin was studied by western blot analysis of the ER stress markers GRP78, CHOP and p-IRE1. Results: Progesterone and estrogen improved wound healing and epithelial barrier function in intestinal epithelial cells via upregulation of tight junction proteins. Furthermore, these sex hormones significantly reduced ER-stress and reduce pro-inflammatory cytokine production in intestinal epithelial models. Conclusion: Our study shows that estrogen and progesterone alleviate ER stress, decrease pro-inflammatory cytokine production, stimulate wound healing, and increase barrier function of epithelial cells. Combined, these data suggest that pregnancy hormones can have beneficial effects on disease activity by positively modulating the intestinal epithelial lining. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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17 pages, 2214 KiB

Open AccessArticle

Lack of Small Intestinal Dysbiosis Following Long-Term Selective Inhibition of Cyclooxygenase-2 by Rofecoxib in the Rat

by Bernadette Lázár, Gábor B. Brenner, András Makkos, Mihály Balogh, Szilvia B. László, Mahmoud Al-Khrasani, Barbara Hutka, Emese Bató, Eszter Ostorházi, János Juhász, Ágnes Kemény, Terézia László, László Tiszlavicz, Zoltán Bihari, Zoltán Giricz, Dóra Szabó, Zsuzsanna Helyes, Péter Ferdinandy, Klára Gyires and Zoltán S. Zádori

Cells 2019, 8(3), 251; https://doi.org/10.3390/cells8030251 - 15 Mar 2019

Cited by 7 | Viewed by 4230

Abstract

Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective [...] Read more.

Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective inhibition of COX-2 on the small intestinal microbiota in the rat. In order to avoid mucosal damage due to topical effects and inflammation-driven microbial alterations, rofecoxib, a nonacidic compound, was used. The direct inhibitory effect of rofecoxib on the growth of bacteria was ruled out in vitro. The mucosa-sparing effect of rofecoxib was confirmed by macroscopic and histological analysis, as well as by measuring the intestinal levels of cytokines and tight junction proteins. Deep sequencing of bacterial 16S rRNA revealed that chronic rofecoxib treatment had no significant influence on the composition and diversity of jejunal microbiota. In conclusion, this is the first demonstration that long-term selective inhibition of COX-2 by rofecoxib does not cause small intestinal dysbiosis in rats. Moreover, inhibition of COX-2 activity is not likely to be responsible per se for microbial alterations caused by some coxibs, but other drug-specific properties may contribute to it. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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13 pages, 2486 KiB

Open AccessArticle

Crohn’s Disease Patients in Remission Display an Enhanced Intestinal IgM⁺ B Cell Count in Concert with a Strong Activation of the Intestinal Complement System

by Sophie Preisker, Ann-Kathrin Brethack, Arne Bokemeyer, Dominik Bettenworth, Christian Sina and Stefanie Derer

Cells 2019, 8(1), 78; https://doi.org/10.3390/cells8010078 - 21 Jan 2019

Cited by 8 | Viewed by 6061

Abstract

Inflammatory bowel disease (IBD) is an umbrella term that comprises Crohn’s disease (CD) and ulcerative colitis (UC). Both entities are characterized by a disturbed mucosal immune response and an imbalance of intestinal microbiota composition. The complement system (C) plays a critical role in [...] Read more.

Inflammatory bowel disease (IBD) is an umbrella term that comprises Crohn’s disease (CD) and ulcerative colitis (UC). Both entities are characterized by a disturbed mucosal immune response and an imbalance of intestinal microbiota composition. The complement system (C) plays a critical role in the detection, and clearance of bacteria and dysregulation of single complement components has been linked to IBD. Here, we asked if the C contributes to distinct subtypes of inflammation observed in CD and UC. We performed systematical expression analyses of the intestinal C in IBD patients and controls. Immunohistochemistry or immunoblot experiments were performed to verify qPCR data. Activity of the three activation pathways of C was studied in sera samples. In CD patients a strong upregulation of the C was observed enabling the definition of unique expression patterns being associated either with remission or active disease. These data were reflected by an enhanced C activation in sera and fecal samples. An excessive mucosal presence of immunoglobulin M (IgM) and CR2/CD21 positive B cells in concert with decreased fecal IgA level was identified in CD patients in remission. These findings point to an exacerbated induction of the intestinal C that may potentially be involved in the etiology of CD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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15 pages, 4151 KiB

Open AccessArticle

Crohn’s Disease-Associated Adherent-Invasive Escherichia coli Manipulate Host Autophagy by Impairing SUMOylation

by Guillaume Dalmasso, Hang T. T. Nguyen, Tiphanie Faïs, Sébastien Massier, Nicolas Barnich, Julien Delmas and Richard Bonnet

Cells 2019, 8(1), 35; https://doi.org/10.3390/cells8010035 - 9 Jan 2019

Cited by 31 | Viewed by 5023

Abstract

The intestinal mucosa of Crohn’s disease (CD) patients is abnormally colonized with adherent-invasive Escherichia coli (AIEC) that are able to adhere to and to invade intestinal epithelial cells (IECs), to survive in macrophages, and to induce a pro-inflammatory response. AIEC persist in the [...] Read more.

The intestinal mucosa of Crohn’s disease (CD) patients is abnormally colonized with adherent-invasive Escherichia coli (AIEC) that are able to adhere to and to invade intestinal epithelial cells (IECs), to survive in macrophages, and to induce a pro-inflammatory response. AIEC persist in the intestine, and induce inflammation in CEABAC10 transgenic mice expressing human CAECAM6, the receptor for AIEC. SUMOylation is a eukaryotic-reversible post-translational modification, in which SUMO, an ubiquitin-like polypeptide, is covalently linked to target proteins. Here, we investigated the role of SUMOylation in host responses to AIEC infection. We found that infection with the AIEC LF82 reference strain markedly decreased the levels of SUMO-conjugated proteins in human intestinal epithelial T84 cells. This was also observed in IECs from LF82-infected CEABAC10 transgenic mice. LF82-induced deSUMOylation in IECs was due in part to increased level of microRNA (miR)-18, which targets PIAS3 mRNA encoding a protein involved in SUMOylation. Over-expression of SUMOs in T84 cells induced autophagy, leading to a significant decrease in the number of intracellular LF82. Consistently, a decreased expression of UBC9, a protein necessary for SUMOylation, was accompanied with a decrease of LF82-induced autophagy, increasing bacterial intracellular proliferation and inflammation. Finally, the inhibition of miR-18 significantly decreased the number of intracellular LF82. In conclusion, our results suggest that AIEC inhibits the autophagy response to replicate intracellularly by manipulating host SUMOylation. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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14 pages, 2184 KiB

Open AccessArticle

Preventive Effect of Spontaneous Physical Activity on the Gut-Adipose Tissue in a Mouse Model That Mimics Crohn’s Disease Susceptibility

by Florie Maillard, Emilie Vazeille, Pierre Sauvanet, Pascal Sirvent, Richard Bonnet, Lydie Combaret, Pierre Chausse, Caroline Chevarin, Yolanda Fernandez Otero, Geoffrey Delcros, Vivien Chavanelle, Nathalie Boisseau and Nicolas Barnich

Cells 2019, 8(1), 33; https://doi.org/10.3390/cells8010033 - 9 Jan 2019

Cited by 13 | Viewed by 5069

Abstract

Crohn’s disease is characterized by abnormal ileal colonization by adherent-invasive E. coli (AIEC) and expansion of mesenteric adipose tissue. This study assessed the preventive effect of spontaneous physical activity (PA) on the gut-adipose tissue in a mouse model that mimics Crohn’s disease susceptibility. [...] Read more.

Crohn’s disease is characterized by abnormal ileal colonization by adherent-invasive E. coli (AIEC) and expansion of mesenteric adipose tissue. This study assessed the preventive effect of spontaneous physical activity (PA) on the gut-adipose tissue in a mouse model that mimics Crohn’s disease susceptibility. Thirty-five CEABAC10 male mice performed spontaneous PA (wheel group; n = 24) or not (controls; n = 11) for 12 weeks. At week 12, mice were orally challenged with the AIEC LF82 strain for 6 days. Body composition, glycaemic control, intestinal permeability, gut microbiota composition, and fecal short-chain fatty acids were assessed in both groups. Animals were fed a high fat/high sugar diet throughout the study. After exposure to AIEC, mesenteric adipose tissue weight was lower in the wheel group. Tight junction proteins expression increased with spontaneous PA, whereas systemic lipopolysaccharides were negatively correlated with the covered distance. Bifidobacterium and Lactobacillus decreased in controls, whereas Oscillospira and Ruminococcus increased in the wheel group. Fecal propionate and butyrate were also higher in the wheel group. In conclusion, spontaneous physical activity promotes healthy gut microbiota composition changes and increases short-chain fatty acids in CEABAC10 mice fed a Western diet and exposed to AIEC to mimic Crohn’s disease. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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Review

Jump to: Research

30 pages, 1292 KiB

Open AccessReview

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

by Irma Tindemans, Maria E. Joosse and Janneke N. Samsom

Cells 2020, 9(1), 110; https://doi.org/10.3390/cells9010110 - 2 Jan 2020

Cited by 99 | Viewed by 10202

Abstract

Infiltration of the lamina propria by inflammatory CD4⁺ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4⁺ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with [...] Read more.

Infiltration of the lamina propria by inflammatory CD4⁺ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4⁺ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4⁺ T-cell populations is crucial to prevent uncontrolled CD4⁺ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4⁺ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4⁺ T-cell responses arise, discuss the main phenotypes of CD4⁺ T helper responses, and review how they are implicated in IBD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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20 pages, 1022 KiB

Open AccessReview

The Role of MicroRNAs upon Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease

by Éva Boros and István Nagy

Cells 2019, 8(11), 1461; https://doi.org/10.3390/cells8111461 - 19 Nov 2019

Cited by 16 | Viewed by 4830

Abstract

Increasing evidence suggest the significance of inflammation in the progression of cancer, for example the development of colorectal cancer in Inflammatory Bowel Disease (IBD) patients. Long-lasting inflammation in the gastrointestinal tract causes serious systemic complications and breaks the homeostasis of the intestine, where [...] Read more.

Increasing evidence suggest the significance of inflammation in the progression of cancer, for example the development of colorectal cancer in Inflammatory Bowel Disease (IBD) patients. Long-lasting inflammation in the gastrointestinal tract causes serious systemic complications and breaks the homeostasis of the intestine, where the altered expression of regulatory genes and miRNAs trigger malignant transformations. Several steps lead from acute inflammation to malignancies: epithelial-to-mesenchymal transition (EMT) and inhibitory microRNAs (miRNAs) are known factors during multistage carcinogenesis and IBD pathogenesis. In this review, we outline the interactions between EMT components and miRNAs that may affect cancer development during IBD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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12 pages, 925 KiB

Open AccessFeature PaperReview

Mesenchymal Stem Cells for Perianal Crohn’s Disease

by Michele Carvello, Amy Lightner, Takayuki Yamamoto, Paulo Gustavo Kotze and Antonino Spinelli

Cells 2019, 8(7), 764; https://doi.org/10.3390/cells8070764 - 23 Jul 2019

Cited by 73 | Viewed by 10373

Abstract

Perianal fistulizing Crohn’s disease (PFCD) is associated with significant morbidity and might negatively impact the quality of life of CD patients. In the last two decades, the management of PFCD has evolved in terms of the multidisciplinary approach involving gastroenterologists and colorectal surgeons. [...] Read more.

Perianal fistulizing Crohn’s disease (PFCD) is associated with significant morbidity and might negatively impact the quality of life of CD patients. In the last two decades, the management of PFCD has evolved in terms of the multidisciplinary approach involving gastroenterologists and colorectal surgeons. However, the highest fistula healing rates, even combining surgical and anti-TNF agents, reaches 50% of treated patients. More recently, the administration of mesenchymal stem cells (MSCs) have shown notable promising results in the treatment of PFCD. The aim of this review is to describe the rationale and the possible mechanism of action of MSC application for PFCD and the most recent results of randomized clinical trials. Furthermore, the unmet needs of the current administration process and the expected next steps to improve the outcomes will be addressed. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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24 pages, 3404 KiB

Open AccessReview

Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity

by David J. Brinkman, Anne S. ten Hove, Margriet J. Vervoordeldonk, Misha D. Luyer and Wouter J. de Jonge

Cells 2019, 8(7), 670; https://doi.org/10.3390/cells8070670 - 2 Jul 2019

Cited by 66 | Viewed by 11208

Abstract

Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, [...] Read more.

Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, modulate the intestinal immune system, and thereby regulate the intestinal inflammatory processes. Although the autonomic nervous system is classically divided in a sympathetic and parasympathetic branch, both play a pivotal role in the crosstalk with the immune system, with the enteric nervous system acting as a potential interface. Pilot clinical trials that employ vagus nerve stimulation to reduce inflammation are met with promising results. In this paper, we review current knowledge on the innervation of the gut, the potential of cholinergic and adrenergic systems to modulate intestinal immunity, and comment on ongoing developments in clinical trials. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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26 pages, 802 KiB

Open AccessReview

Inflammatory Bowel Disease: A Stressed “Gut/Feeling”

by Yvonne Oligschlaeger, Tulasi Yadati, Tom Houben, Claudia Maria Condello Oliván and Ronit Shiri-Sverdlov

Cells 2019, 8(7), 659; https://doi.org/10.3390/cells8070659 - 30 Jun 2019

Cited by 76 | Viewed by 11318

Abstract

Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition, hallmarked by a disturbance in the bidirectional interaction between gut and brain. In general, the gut/brain axis involves direct and/or indirect communication via the central and enteric nervous system, host innate [...] Read more.

Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition, hallmarked by a disturbance in the bidirectional interaction between gut and brain. In general, the gut/brain axis involves direct and/or indirect communication via the central and enteric nervous system, host innate immune system, and particularly the gut microbiota. This complex interaction implies that IBD is a complex multifactorial disease. There is increasing evidence that stress adversely affects the gut/microbiota/brain axis by altering intestinal mucosa permeability and cytokine secretion, thereby influencing the relapse risk and disease severity of IBD. Given the recurrent nature, therapeutic strategies particularly aim at achieving and maintaining remission of the disease. Alternatively, these strategies focus on preventing permanent bowel damage and concomitant long-term complications. In this review, we discuss the gut/microbiota/brain interplay with respect to chronic inflammation of the gastrointestinal tract and particularly shed light on the role of stress. Hence, we evaluated the therapeutic impact of stress management in IBD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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20 pages, 3405 KiB

Open AccessReview

Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical Science

by Dario Sorrentino, Vu Q. Nguyen and Maithili V. Chitnavis

Cells 2019, 8(6), 548; https://doi.org/10.3390/cells8060548 - 6 Jun 2019

Cited by 7 | Viewed by 5367

Abstract

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)—both ulcerative colitis (UC) and Crohn’s Disease (CD)—as of today these conditions are still diagnosed only after they have become symptomatic. This [...] Read more.

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)—both ulcerative colitis (UC) and Crohn’s Disease (CD)—as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage—as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients’ first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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20 pages, 1330 KiB

Open AccessReview

Molecular Profiling of Inflammatory Bowel Disease: Is It Ready for Use in Clinical Decision-Making?

by Ho-Su Lee and Isabelle Cleynen

Cells 2019, 8(6), 535; https://doi.org/10.3390/cells8060535 - 4 Jun 2019

Cited by 30 | Viewed by 6958

Abstract

Inflammatory bowel disease (IBD) is a heterogeneous disorder in terms of age at onset, clinical phenotypes, severity, disease course, and response to therapy. This underlines the need for predictive and precision medicine that can optimize diagnosis and disease management, provide more cost-effective strategies, [...] Read more.

Inflammatory bowel disease (IBD) is a heterogeneous disorder in terms of age at onset, clinical phenotypes, severity, disease course, and response to therapy. This underlines the need for predictive and precision medicine that can optimize diagnosis and disease management, provide more cost-effective strategies, and minimize the risk of adverse events. Ideally, we can leverage molecular profiling to predict the risk to develop IBD and disease progression. Despite substantial successes of genome-wide association studies in the identification of genetic variants affecting IBD susceptibility, molecular profiling of disease onset and progression as well as of treatment responses has lagged behind. Still, thanks to technological advances and good study designs, predicting phenotypes using genomics and transcriptomics in IBD has been rapidly evolving. In this review, we summarize the current status of prediction of disease risk, clinical course, and response to therapy based on clinical case presentations. We also discuss the potential and limitations of the currently used approaches. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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21 pages, 1358 KiB

Open AccessReview

Pre-Treatment Biomarkers of Anti-Tumour Necrosis Factor Therapy Response in Crohn’s Disease—A Systematic Review and Gene Ontology Analysis

by Boris Gole and Uroš Potočnik

Cells 2019, 8(6), 515; https://doi.org/10.3390/cells8060515 - 28 May 2019

Cited by 16 | Viewed by 4135

Abstract

The most prominent treatment for the serious cases of Crohn’s disease (CD) are biological tumour necrosis factor (TNF) inhibitors. Unfortunately, therapy nonresponse is still a serious issue in ~1/3 of CD patients. Accurate prediction of responsiveness prior to therapy start would therefore be [...] Read more.

The most prominent treatment for the serious cases of Crohn’s disease (CD) are biological tumour necrosis factor (TNF) inhibitors. Unfortunately, therapy nonresponse is still a serious issue in ~1/3 of CD patients. Accurate prediction of responsiveness prior to therapy start would therefore be of great value. Clinical predictors have, however, proved insufficient. Here, we integrate genomic and expression data on potential pre-treatment biomarkers of anti-TNF nonresponse. We show that there is almost no overlap between genomic (annotated with tissue-specific expression quantitative trait loci data) and transcription (RNA and protein data) biomarkers. Furthermore, using interaction networks we demonstrate there is little direct interaction between the proposed biomarkers, though a majority do have common interactors connecting them into networks. Our gene ontology analysis shows that these networks have roles in apoptotic signalling, response to oxidative stress and inflammation pathways. We conclude that a more systematic approach with genome-wide search of genomic and expression biomarkers in the same patients is needed in future studies. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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23 pages, 975 KiB

Open AccessReview

Metabolite-Sensing G Protein-Coupled Receptors Connect the Diet-Microbiota-Metabolites Axis to Inflammatory Bowel Disease

by Hassan Melhem, Berna Kaya, C. Korcan Ayata, Petr Hruz and Jan Hendrik Niess

Cells 2019, 8(5), 450; https://doi.org/10.3390/cells8050450 - 14 May 2019

Cited by 50 | Viewed by 10693

Abstract

Increasing evidence has indicated that diet and metabolites, including bacteria- and host-derived metabolites, orchestrate host pathophysiology by regulating metabolism, immune system and inflammation. Indeed, autoimmune diseases such as inflammatory bowel disease (IBD) are associated with the modulation of host response to diets. One [...] Read more.

Increasing evidence has indicated that diet and metabolites, including bacteria- and host-derived metabolites, orchestrate host pathophysiology by regulating metabolism, immune system and inflammation. Indeed, autoimmune diseases such as inflammatory bowel disease (IBD) are associated with the modulation of host response to diets. One crucial mechanism by which the microbiota affects the host is signaling through G protein-coupled receptors (GPCRs) termed metabolite-sensing GPCRs. In the gut, both immune and nonimmune cells express GPCRs and their activation generally provide anti-inflammatory signals through regulation of both the immune system functions and the epithelial integrity. Members of GPCR family serve as a link between microbiota, immune system and intestinal epithelium by which all these components crucially participate to maintain the gut homeostasis. Conversely, impaired GPCR signaling is associated with IBD and other diseases, including hepatic steatosis, diabetes, cardiovascular disease, and asthma. In this review, we first outline the signaling, function, expression and the physiological role of several groups of metabolite-sensing GPCRs. We then discuss recent findings on their role in the regulation of the inflammation, their existing endogenous and synthetic ligands and innovative approaches to therapeutically target inflammatory bowel disease. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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22 pages, 375 KiB

Open AccessReview

Genetic Studies of Inflammatory Bowel Disease-Focusing on Asian Patients

by Sung Chul Park and Yoon Tae Jeen

Cells 2019, 8(5), 404; https://doi.org/10.3390/cells8050404 - 1 May 2019

Cited by 62 | Viewed by 6610

Abstract

The pathogenesis of inflammatory bowel disease (IBD) is not well-understood; however, increased and persistent intestinal inflammation, due to inappropriate immune responses that are caused by interactions between genetic factors, gut microbiota, and environmental factors, are thought to lead to IBD. Various studies have [...] Read more.

The pathogenesis of inflammatory bowel disease (IBD) is not well-understood; however, increased and persistent intestinal inflammation, due to inappropriate immune responses that are caused by interactions between genetic factors, gut microbiota, and environmental factors, are thought to lead to IBD. Various studies have identified more than 240 genetic variants related to IBD. These genetic variants are involved in innate and adaptive immunity, autophagy, defective bacterial handing, interleukin-23 and 10 signaling, and so on. According to several epidemiological and clinical studies, the phenotypes and clinical course of IBD differ between Asians and Europeans. Although the risk loci for IBD typically overlap between Asians and Westerners, genetic heterogeneity has been detected in many loci/genes, such as NOD2/CARD15, TNFSF15 and human leukocyte antigen, contributing to the risk of IBD. Thus, although common pathways exist between Westerners and Asians in the development of IBD, their significance may differ for individual pathways. Although genetic studies are not universally applicable in the clinical field, they may be useful for diagnosing and categorizing IBD, predicting therapeutic responses and toxicity to drugs, and assessing prognosis by risk modeling, thereby enabling precision medicine for individual patients. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

14 pages, 459 KiB

Open AccessReview

Controlling Gut Inflammation by Restoring Anti-Inflammatory Pathways in Inflammatory Bowel Disease

by Paolo Giuffrida, Sara Cococcia, Mariangela Delliponti, Marco Vincenzo Lenti and Antonio Di Sabatino

Cells 2019, 8(5), 397; https://doi.org/10.3390/cells8050397 - 30 Apr 2019

Cited by 28 | Viewed by 8082

Abstract

Inflammatory bowel disease (IBD) is caused by a dysregulated immune response against normal components of the intestinal microflora combined with defective functioning of anti-inflammatory pathways. Currently, all therapies approved for IBD manipulate the immune system by inhibiting pro-inflammatory mechanisms, such as tumor necrosis [...] Read more.

Inflammatory bowel disease (IBD) is caused by a dysregulated immune response against normal components of the intestinal microflora combined with defective functioning of anti-inflammatory pathways. Currently, all therapies approved for IBD manipulate the immune system by inhibiting pro-inflammatory mechanisms, such as tumor necrosis factor-α, gut-homing α₄β₇ integrin, interleukin-12/interleukin-23, and Janus kinases. However, some IBD patients are non-responders to these drugs, which are also associated with serious side effects. Thus, it has been hypothesized that therapies aimed at restoring anti-inflammatory signals, by exploiting the tolerogenic potential of cytokines (interleukin-10, transforming growth factor-β, granulocyte macrophage colony-stimulating factor), immune cells (regulatory T cells, tolerogenic dendritic cells), or mesenchymal stem cells, might offer promising results in terms of clinical efficacy with fewer side effects. In this review, we provide new insights into putative novel treatments aimed at restoring anti-inflammatory signaling pathways in IBD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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15 pages, 1324 KiB

Open AccessReview

The Resolution of Intestinal Inflammation: The Peace-Keeper’s Perspective

by Sara Onali, Agnese Favale and Massimo C Fantini

Cells 2019, 8(4), 344; https://doi.org/10.3390/cells8040344 - 11 Apr 2019

Cited by 15 | Viewed by 5001

Abstract

The uncontrolled activation of the immune system toward antigens contained in the gut lumen in genetically predisposed subjects is believed to be the leading cause of inflammatory bowel disease (IBD). Two not mutually exclusive hypotheses can explain the pathogenic process leading to IBD. [...] Read more.

The uncontrolled activation of the immune system toward antigens contained in the gut lumen in genetically predisposed subjects is believed to be the leading cause of inflammatory bowel disease (IBD). Two not mutually exclusive hypotheses can explain the pathogenic process leading to IBD. The first and mostly explored hypothesis states that the loss of tolerance toward gut microbiota antigens generates an aberrant inflammatory response that is perpetuated by continuous and unavoidable exposure to the triggering antigens. However, the discovery that the resolution of inflammation is not the mere consequence of clearing inflammatory triggers and diluting pro-inflammatory factors, but rather an active process in which molecular and cellular elements are involved, implies that a defect in the pro-resolving mechanisms might cause chronic inflammation in different immune-mediated diseases, including IBD. Here we review data on pro-resolving and counter-regulatory mechanisms involved in the resolution of inflammation, aiming to identify their possible involvement in the pathogenesis of IBD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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24 pages, 2766 KiB

Open AccessReview

Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease—Focusing on Intestinal Barrier Function

by Ida Schoultz and Åsa V. Keita

Cells 2019, 8(2), 193; https://doi.org/10.3390/cells8020193 - 22 Feb 2019

Cited by 139 | Viewed by 11659

Abstract

The human gut relies on several cellular and molecular mechanisms to allow for an intact and dynamical intestinal barrier. Normally, only small amounts of luminal content pass the mucosa, however, if the control is broken it can lead to enhanced passage, which might [...] Read more.

The human gut relies on several cellular and molecular mechanisms to allow for an intact and dynamical intestinal barrier. Normally, only small amounts of luminal content pass the mucosa, however, if the control is broken it can lead to enhanced passage, which might damage the mucosa, leading to pathological conditions, such as inflammatory bowel disease (IBD). It is well established that genetic, environmental, and immunological factors all contribute in the pathogenesis of IBD, and a disturbed intestinal barrier function has become a hallmark of the disease. Genetical studies support the involvement of intestinal barrier as several susceptibility genes for IBD encode proteins with key functions in gut barrier and homeostasis. IBD patients are associated with loss in bacterial diversity and shifts in the microbiota, with a possible link to local inflammation. Furthermore, alterations of immune cells and several neuro-immune signaling pathways in the lamina propria have been demonstrated. An inappropriate immune activation might lead to mucosal inflammation, with elevated secretion of pro-inflammatory cytokines that can affect the epithelium and promote a leakier barrier. This review will focus on the main cells and molecular mechanisms in IBD and how these can be targeted in order to improve intestinal barrier function and reduce inflammation. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Inflammatory Bowel Diseases (IBD))

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