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Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 40922

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Dr. Susanne M. Krug

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Institute of Clinical Physiology/Nutritional Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany
Interests: tricellulin: function, regulation, structure, and clinical impact; the interplay of the impaired tight junction and the subjacent immune cells in inflammation; the role of the tricellular tight junction in inflammatory bowel diseases; inflammatory bowel diseases: barrier defect via IL-13 and tricellulin; tricellular tight junction as a pathway for macromolecules; drug absorption enhancement by targeting the tricellular TJ; neuropathic pain resolution by nerve barrier sealing and netrin-1
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Dear Colleagues,

Inflammatory bowel disease (IBD) is an umbrella term describing chronic idiopathic relapsing and remitting gastrointestinal autoimmune diseases. The main disorders are ulcerative colitis and Crohn’s disease.

IBD has proven to be multifactorial as genetic factors in parallel with environmental, infectious, and immunologic factors have been identified. Dysregulation of transcellular and paracellular intestinal barriers as well as activation of mucosal immune responses are involved either by representing a consequence or a trigger of the pathological impairments.

Recent advances in IBD research have allowed the identification of new molecular predictive markers and development of innovative therapeutic concepts. Nevertheless, the etiological background of IBD remains poorly understood, and basic research with translational applications is cogently needed.

This Special Issue aims to gather knowledge of original research and review articles covering functional, ultrastructural, genetic, and molecular research to promote solving the complex puzzle of IBD with the goal on new targets for effective intervention.

Dr. Susanne M. Krug
Guest Editor

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Keywords

Pathogenesis of inflammatory bowel diseases (IBD)
Intestinal mucosal inflammation and healing
Epithelial barrier impairment and regulation
Mucosal immune cells
Cytokines and other molecules involved in IBD
Gut microbiota in IBD
Therapeutic developments in IBD

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

4 pages, 189 KiB

Open AccessEditorial

Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases

by Susanne M. Krug

Int. J. Mol. Sci. 2023, 24(17), 13389; https://doi.org/10.3390/ijms241713389 - 29 Aug 2023

Viewed by 852

Abstract

Inflammatory bowel disease (IBD) encompasses chronic idiopathic relapsing and remitting gastrointestinal autoimmune diseases characterized by chronic inflammatory disorders of complex etiology, posing clinical challenges due to their often therapy-refractory nature [...] Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

Research

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15 pages, 4993 KiB

Open AccessArticle

FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis

by Jenisha Ghimire, Rida Iftikhar, Harrison M. Penrose, Patricia Snarski, Emmanuelle Ruiz and Suzana D. Savkovic

Int. J. Mol. Sci. 2023, 24(11), 9730; https://doi.org/10.3390/ijms24119730 - 4 Jun 2023

Cited by 3 | Viewed by 2370

Abstract

Inflammatory bowel disease (IBD), characterized by infiltration of polymorphonuclear neutrophils (PMNs), increases the risk of colon cancer. PMN activation corresponds to the accumulation of intracellular Lipid Droplets (LDs). As increased LDs are negatively regulated by transcription factor Forkhead Box O3 (FOXO3), we aim to determine the significance of this regulatory network in PMN-mediated IBD and tumorigenesis. Affected tissue of IBD and colon cancer patients, colonic and infiltrated immune cells, have increased LDs’ coat protein, PLIN2. Mouse peritoneal PMNs with stimulated LDs and FOXO3 deficiency have elevated transmigratory activity. Transcriptomic analysis of these FOXO3-deficient PMNs showed differentially expressed genes (DEGs; FDR < 0.05) involved in metabolism, inflammation, and tumorigenesis. Upstream regulators of these DEGs, similar to colonic inflammation and dysplasia in mice, were linked to IBD and human colon cancer. Additionally, a transcriptional signature representing FOXO3-deficient PMNs (PMN-FOXO3₃₈₉) separated transcriptomes of affected tissue in IBD (p = 0.00018) and colon cancer (p = 0.0037) from control. Increased PMN-FOXO3₃₈₉ presence predicted colon cancer invasion (lymphovascular p = 0.015; vascular p = 0.046; perineural p = 0.03) and poor survival. Validated DEGs from PMN-FOXO3₃₈₉ (P2RX1, MGLL, MCAM, CDKN1A, RALBP1, CCPG1, PLA2G7) are involved in metabolism, inflammation, and tumorigenesis (p < 0.05). These findings highlight the significance of LDs and FOXO3-mediated PMN functions that promote colonic pathobiology. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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11 pages, 1298 KiB

Open AccessCommunication

Analysis of Circulating Food Antigen-Specific T-Cells in Celiac Disease and Inflammatory Bowel Disease

by Yasmina Rodríguez-Sillke, Michael Schumann, Donata Lissner, Federica Branchi, Fabian Proft, Ulrich Steinhoff, Britta Siegmund and Rainer Glauben

Int. J. Mol. Sci. 2023, 24(9), 8153; https://doi.org/10.3390/ijms24098153 - 2 May 2023

Cited by 3 | Viewed by 2288

Abstract

To demonstrate and analyze the specific T-cell response following barrier disruption and antigen translocation, circulating food antigen-specific effector T-cells isolated from peripheral blood were analyzed in patients suffering from celiac disease (CeD) as well as inflammatory bowel disease (IBD). We applied the antigen-reactive T-cell enrichment (ARTE) technique allowing for phenotypical and functional flow cytometric analyses of rare nutritional antigen-specific T-cells, including the celiac disease-causing gliadin (gluten). For CeD, patient groups, including treatment-refractory cases, differ significantly from healthy controls. Even symptom-free patients on a gluten-free diet were distinguishable from healthy controls, without being previously challenged with gluten. Moreover, frequency and phenotype of nutritional antigen-specific T-cells of IBD patients directly correlated to the presence of small intestinal inflammation. Specifically, the frequency of antigen specific T-cells as well as pro-inflammatory cytokines was increased in patients with active CeD or Crohn’s disease, respectively. These results suggest active small intestinal inflammation as key for the development of a peripheral food antigen-specific T-cell response in Crohn’s disease and celiac disease. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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18 pages, 6287 KiB

Open AccessArticle

Bacterial Lysate from the Multi-Strain Probiotic SLAB51 Triggers Adaptative Responses to Hypoxia in Human Caco-2 Intestinal Epithelial Cells under Normoxic Conditions and Attenuates LPS-Induced Inflammatory Response

by Francesca Lombardi, Francesca Rosaria Augello, Paola Palumbo, Laura Bonfili, Serena Artone, Serena Altamura, Jenna Marie Sheldon, Giovanni Latella, Maria Grazia Cifone, Anna Maria Eleuteri and Benedetta Cinque

Int. J. Mol. Sci. 2023, 24(9), 8134; https://doi.org/10.3390/ijms24098134 - 2 May 2023

Cited by 5 | Viewed by 3608

Abstract

Hypoxia-inducible factor-1α (HIF-1α), a central player in maintaining gut-microbiota homeostasis, plays a pivotal role in inducing adaptive mechanisms to hypoxia and is negatively regulated by prolyl hydroxylase 2 (PHD2). HIF-1α is stabilized through PI3K/AKT signaling regardless of oxygen levels. Considering the crucial role of the HIF pathway in intestinal mucosal physiology and its relationships with gut microbiota, this study aimed to evaluate the ability of the lysate from the multi-strain probiotic formulation SLAB51 to affect the HIF pathway in a model of in vitro human intestinal epithelium (intestinal epithelial cells, IECs) and to protect from lipopolysaccharide (LPS) challenge. The exposure of IECs to SLAB51 lysate under normoxic conditions led to a dose-dependent increase in HIF-1α protein levels, which was associated with higher glycolytic metabolism and L-lactate production. Probiotic lysate significantly reduced PHD2 levels and HIF-1α hydroxylation, thus leading to HIF-1α stabilization. The ability of SLAB51 lysate to increase HIF-1α levels was also associated with the activation of the PI3K/AKT pathway and with the inhibition of NF-κB, nitric oxide synthase 2 (NOS2), and IL-1β increase elicited by LPS treatment. Our results suggest that the probiotic treatment, by stabilizing HIF-1α, can protect from an LPS-induced inflammatory response through a mechanism involving PI3K/AKT signaling. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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19 pages, 4231 KiB

Open AccessArticle

Development of an Inflammation-Triggered In Vitro “Leaky Gut” Model Using Caco-2/HT29-MTX-E12 Combined with Macrophage-like THP-1 Cells or Primary Human-Derived Macrophages

by Nguyen Phan Khoi Le, Markus Jörg Altenburger and Evelyn Lamy

Int. J. Mol. Sci. 2023, 24(8), 7427; https://doi.org/10.3390/ijms24087427 - 18 Apr 2023

Cited by 12 | Viewed by 4623

Abstract

The “leaky gut” syndrome describes a damaged (leaky) intestinal mucosa and is considered a serious contributor to numerous chronic diseases. Chronic inflammatory bowel diseases (IBD) are particularly associated with the “leaky gut” syndrome, but also allergies, autoimmune diseases or neurological disorders. We developed a complex in vitro inflammation-triggered triple-culture model using 21-day-differentiated human intestinal Caco-2 epithelial cells and HT29-MTX-E12 mucus-producing goblet cells (90:10 ratio) in close contact with differentiated human macrophage-like THP-1 cells or primary monocyte-derived macrophages from human peripheral blood. Upon an inflammatory stimulus, the characteristics of a “leaky gut” became evident: a significant loss of intestinal cell integrity in terms of decreased transepithelial/transendothelial electrical resistance (TEER), as well as a loss of tight junction proteins. The cell permeability for FITC-dextran 4 kDa was then increased, and key pro-inflammatory cytokines, including TNF-alpha and IL-6, were substantially released. Whereas in the M1 macrophage-like THP-1 co-culture model, we could not detect the release of IL-23, which plays a crucial regulatory role in IBD, this cytokine was clearly detected when using primary human M1 macrophages instead. In conclusion, we provide an advanced human in vitro model that could be useful for screening and evaluating therapeutic drugs for IBD treatment, including potential IL-23 inhibitors. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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21 pages, 9339 KiB

Open AccessArticle

Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing

by Leonie Wittner, Lukas Wagener, Jakob J. Wiese, Iris Stolzer, Susanne M. Krug, Elisabeth Naschberger, Rene Jackstadt, Rudi Beyaert, Raja Atreya, Anja A. Kühl, Gregor Sturm, Miguel Gonzalez-Acera, Jay V. Patankar, Christoph Becker, Britta Siegmund, Zlatko Trajanoski, Beate Winner, Markus F. Neurath, Michael Schumann and Claudia Günther

Int. J. Mol. Sci. 2023, 24(8), 7402; https://doi.org/10.3390/ijms24087402 - 17 Apr 2023

Cited by 3 | Viewed by 3081

Abstract

The paracaspase MALT1 is a crucial regulator of immune responses in various cellular contexts. Recently, there is increasing evidence suggesting that MALT1 might represent a novel key player in mucosal inflammation. However, the molecular mechanisms underlying this process and the targeted cell population remain unclear. In this study, we investigate the role of MALT1 proteolytic activity in the context of mucosal inflammation. We demonstrate a significant enrichment of MALT1 gene and protein expression in colonic epithelial cells of UC patients, as well as in the context of experimental colitis. Mechanistically we demonstrate that MALT1 protease function inhibits ferroptosis, a form of iron-dependent cell death, upstream of NF-κB signaling, which can promote inflammation and tissue damage in IBD. We further show that MALT1 activity contributes to STAT3 signaling, which is essential for the regeneration of the intestinal epithelium after injury. In summary, our data strongly suggests that the protease function of MALT1 plays a critical role in the regulation of immune and inflammatory responses, as well as mucosal healing. Understanding the mechanisms by which MALT1 protease function regulates these processes may offer novel therapeutic targets for the treatment of IBD and other inflammatory diseases. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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22 pages, 6415 KiB

Open AccessArticle

Identification of Novel Core Genes Involved in Malignant Transformation of Inflamed Colon Tissue Using a Computational Biology Approach and Verification in Murine Models

by Andrey V. Markov, Innokenty A. Savin, Marina A. Zenkova and Aleksandra V. Sen’kova

Int. J. Mol. Sci. 2023, 24(5), 4311; https://doi.org/10.3390/ijms24054311 - 21 Feb 2023

Cited by 5 | Viewed by 2432

Abstract

Inflammatory bowel disease (IBD) is a complex and multifactorial systemic disorder of the gastrointestinal tract and is strongly associated with the development of colorectal cancer. Despite extensive studies of IBD pathogenesis, the molecular mechanism of colitis-driven tumorigenesis is not yet fully understood. In the current animal-based study, we report a comprehensive bioinformatics analysis of multiple transcriptomics datasets from the colon tissue of mice with acute colitis and colitis-associated cancer (CAC). We performed intersection of differentially expressed genes (DEGs), their functional annotation, reconstruction, and topology analysis of gene association networks, which, when combined with the text mining approach, revealed that a set of key overexpressed genes involved in the regulation of colitis (C3, Tyrobp, Mmp3, Mmp9, Timp1) and CAC (Timp1, Adam8, Mmp7, Mmp13) occupied hub positions within explored colitis- and CAC-related regulomes. Further validation of obtained data in murine models of dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS-stimulated CAC fully confirmed the association of revealed hub genes with inflammatory and malignant lesions of colon tissue and demonstrated that genes encoding matrix metalloproteinases (acute colitis: Mmp3, Mmp9; CAC: Mmp7, Mmp13) can be used as a novel prognostic signature for colorectal neoplasia in IBD. Finally, using publicly available transcriptomics data, translational bridge interconnecting of listed colitis/CAC-associated core genes with the pathogenesis of ulcerative colitis, Crohn’s disease, and colorectal cancer in humans was identified. Taken together, a set of key genes playing a core function in colon inflammation and CAC was revealed, which can serve both as promising molecular markers and therapeutic targets to control IBD and IBD-associated colorectal neoplasia. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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14 pages, 2663 KiB

Open AccessArticle

Natural NADH and FAD Autofluorescence as Label-Free Biomarkers for Discriminating Subtypes and Functional States of Immune Cells

by Sarah Lemire, Oana-Maria Thoma, Lucas Kreiss, Simon Völkl, Oliver Friedrich, Markus F. Neurath, Sebastian Schürmann and Maximilian J. Waldner

Int. J. Mol. Sci. 2022, 23(4), 2338; https://doi.org/10.3390/ijms23042338 - 20 Feb 2022

Cited by 17 | Viewed by 3384

Abstract

Immune cell activity is a major factor for disease progression in inflammatory bowel diseases (IBD). Classifying the type and functional state of immune cells is therefore crucial in clinical diagnostics of IBD. Label-free optical technologies exploiting NADH and FAD autofluorescence, such as multiphoton microscopy, have been used to describe tissue morphology in healthy and inflamed colon samples. Nevertheless, a strategy for the identification of single immune cell subtypes within the tissue is yet to be developed. This work aims to initiate an understanding of autofluorescence changes depending on immune cell type and activation state. For this, NADH and FAD autofluorescence signals of different murine immune cell subtypes under native conditions, as well as upon in vitro stimulation and cell death, have been evaluated. Autofluorescence was assessed using flow cytometry and multiphoton microscopy. Our results reveal significantly increased NADH and FAD signals in innate immune cells compared to adaptive immune cells. This allowed identification of relative amounts of neutrophils and CD4+ T cells in mixed cell suspensions, by using NADH signals as a differentiation marker. Furthermore, in vitro stimulation significantly increased NADH and FAD autofluorescence in adaptive immune cells and macrophages. Cell death induced a significant drop in NADH autofluorescence, while FAD signals were hardly affected. Taken together, these results demonstrate the value of autofluorescence as a tool to characterize immune cells in different functional states, paving the way to the label-free clinical classification of IBD in the future. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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Review

Jump to: Editorial, Research

13 pages, 1414 KiB

Open AccessReview

Claudin Barriers on the Brink: How Conflicting Tissue and Cellular Priorities Drive IBD Pathogenesis

by Christopher T. Capaldo

Int. J. Mol. Sci. 2023, 24(10), 8562; https://doi.org/10.3390/ijms24108562 - 10 May 2023

Cited by 14 | Viewed by 2889

Abstract

Inflammatory bowel diseases (IBDs) are characterized by acute or chronic recurring inflammation of the intestinal mucosa, often with increasing severity over time. Life-long morbidities and diminishing quality of life for IBD patients compel a search for a better understanding of the molecular contributors to disease progression. One unifying feature of IBDs is the failure of the gut to form an effective barrier, a core role for intercellular complexes called tight junctions. In this review, the claudin family of tight junction proteins are discussed as they are a fundamental component of intestinal barriers. Importantly, claudin expression and/or protein localization is altered in IBD, leading to the supposition that intestinal barrier dysfunction exacerbates immune hyperactivity and disease. Claudins are a large family of transmembrane structural proteins that constrain the passage of ions, water, or substances between cells. However, growing evidence suggests non-canonical claudin functions during mucosal homeostasis and healing after injury. Therefore, whether claudins participate in adaptive or pathological IBD responses remains an open question. By reviewing current studies, the possibility is assessed that with claudins, a jack-of-all-trades is master of none. Potentially, a robust claudin barrier and wound restitution involve conflicting biophysical phenomena, exposing barrier vulnerabilities and a tissue-wide frailty during healing in IBD. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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15 pages, 351 KiB

Open AccessReview

Intestinal Behcet’s Disease: A Review of the Immune Mechanism and Present and Potential Biological Agents

by Kun He, Xiaxiao Yan and Dong Wu

Int. J. Mol. Sci. 2023, 24(9), 8176; https://doi.org/10.3390/ijms24098176 - 3 May 2023

Cited by 6 | Viewed by 3241

Abstract

Behcet’s disease (BD) is a chronic and recurrent systemic vasculitis involving almost all organs and tissues. Intestinal BD is defined as BD with predominant gastrointestinal involvement, presenting severe complications such as massive gastrointestinal hemorrhage, perforation, and obstruction in some cases. To some extent, intestinal BD is classified as a member of inflammatory bowel disease (IBD), as it has a lot in common with classical IBD including Crohn’s disease (CD) and ulcerative colitis (UC). Certainly, the underlying pathogenesis is not the same and dysregulation of immune function is believed to be one of the main pathogeneses in intestinal BD, although the etiology has not been clear up to now. Biological agents are an emerging category of pharmaceuticals for various diseases, including inflammatory diseases and cancers, in recent decades. Based on the deep understanding of the immune mechanism of intestinal BD, biological agents targeting potential pathogenic cells, cytokines and pathways are optimized options. Recently, the adoption of biological agents such as anti-tumor necrosis factor agents has allowed for the effective treatment of patients with refractory intestinal BD who show poor response to conventional medications and are faced with the risk of surgical treatment. In this review, we have tried to summarize the immune mechanism and present potential biological agents of intestinal BD. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

15 pages, 1008 KiB

Open AccessReview

Role of Muscarinic Acetylcholine Receptors in Intestinal Epithelial Homeostasis: Insights for the Treatment of Inflammatory Bowel Disease

by Junsuke Uwada, Hitomi Nakazawa, Ikunobu Muramatsu, Takayoshi Masuoka and Takashi Yazawa

Int. J. Mol. Sci. 2023, 24(7), 6508; https://doi.org/10.3390/ijms24076508 - 30 Mar 2023

Cited by 11 | Viewed by 6420

Abstract

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is an intestinal disorder that causes prolonged inflammation of the gastrointestinal tract. Currently, the etiology of IBD is not fully understood and treatments are insufficient to completely cure the disease. In addition to absorbing essential nutrients, intestinal epithelial cells prevent the entry of foreign antigens (micro-organisms and undigested food) through mucus secretion and epithelial barrier formation. Disruption of the intestinal epithelial homeostasis exacerbates inflammation. Thus, the maintenance and reinforcement of epithelial function may have therapeutic benefits in the treatment of IBD. Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors for acetylcholine that are expressed in intestinal epithelial cells. Recent studies have revealed the role of mAChRs in the maintenance of intestinal epithelial homeostasis. The importance of non-neuronal acetylcholine in mAChR activation in epithelial cells has also been recognized. This review aimed to summarize recent advances in research on mAChRs for intestinal epithelial homeostasis and the involvement of non-neuronal acetylcholine systems, and highlight their potential as targets for IBD therapy. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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29 pages, 2049 KiB

Open AccessReview

Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases

by Nathalie Britzen-Laurent, Carl Weidinger and Michael Stürzl

Int. J. Mol. Sci. 2023, 24(6), 5517; https://doi.org/10.3390/ijms24065517 - 14 Mar 2023

Cited by 23 | Viewed by 3521

Abstract

Inflammatory bowel diseases (IBDs) consist of a group of chronic inflammatory disorders with a complex etiology, which represent a clinical challenge due to their often therapy-refractory nature. In IBD, inflammation of the intestinal mucosa is characterized by strong and sustained leukocyte infiltration, resulting in the loss of epithelial barrier function and subsequent tissue destruction. This is accompanied by the activation and the massive remodeling of mucosal micro-vessels. The role of the gut vasculature in the induction and perpetuation of mucosal inflammation is receiving increasing recognition. While the vascular barrier is considered to offer protection against bacterial translocation and sepsis after the breakdown of the epithelial barrier, endothelium activation and angiogenesis are thought to promote inflammation. The present review examines the respective pathological contributions of the different phenotypical changes observed in the microvascular endothelium during IBD, and provides an overview of potential vessel-specific targeted therapy options for the treatment of IBD. Full article

(This article belongs to the Special Issue Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases)

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