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Role of Environmental and Metabolic Factors in Inflammatory Bowel Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 21617

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Special Issue Editor

Prof. Dr. Giovanni Latella

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Guest Editor

Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
Interests: inflammatory bowel diseases; metabolism and proliferation of colorectal epithelium; intestinal fibrosis; microscopic colitis; celiac disease; colonic diverticular disease; colorectal cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As you well know, the human intestine can be affected by different forms of chronic inflammation with different degrees of severity and extent of lesions and clinical outcomes. These forms of inflammation range from low-grade inflammation of irritable bowel syndrome to mild/moderate mucosal inflammation of microscopic colitis and celiac disease, to more severe mucosal inflammation of ulcerative colitis and segmental colitis associated with diverticulosis (SCAD), and to transmural inflammation of Crohn's disease.

These intestinal inflammatory disorders are different, but they share several clinical and pathogenetic features: a likely noninfectious etiology, a close correlation with environmental factors (external and internal like microbiota) and metabolic factors (western lifestyles, overweight/obesity, and dietary factors), and an immune-mediated pathogenesis.

These intestinal disorders, while sharing many cellular and molecular mechanisms, have different clinical outcomes including remission/relapse/recurrence, the risk of developing intestinal fibrosis, and the risk of developing intestinal cancer. It is not yet clear whether the different clinical outcomes of these intestinal disorders are determined by external environmental factors and/or metabolic factors, or whether they depend on a different interaction between the gut microbiota and the local immune response. In particular, it is not clear whether external environmental factors and/or metabolic factors directly modulate the intestinal immune-inflammatory response or whether they do it indirectly by inducing changes in the gut microbiota. Clarifying such a complex relationship is crucial in order to establish more rational and effective treatments of these intestinal disorders that have a significant impact on the health-related quality of life.

In this context, we would like to invite original articles and reviews that focus on understanding the role of environmental and metabolic factors in inflammatory bowel disorders, in particular on the different cellular and molecular responses to these factors in these different intestinal disorders.

Prof. Dr. Giovanni Latella
Guest Editor

Manuscript Submission Information

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Keywords

Inflammatory bowel disease
IBD
Crohn’s disease
Ulcerative colitis
Segmental colitis associated with diverticulosis
SCAD
Microscopic colitis
Celiac disease
Eosinophilic gastroenteritis
Eosinophilic enteritis
Eosinophilic colitis
Mastocytic enterocolitis
Colonic diverticular disease
Irritable bowel syndrome
Gut microbiota
Environmental factors
Dietary habits
Dietary factors
Nutrients
Micronutrients
Allergens
Metabolic factors
Obesity
Metabolic syndrome
Diabetes mellitus

Published Papers (7 papers)

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Research

Jump to: Review

11 pages, 1729 KiB

Open AccessArticle

Efficient Attenuation of Dextran Sulfate Sodium-Induced Colitis by Oral Administration of 5,6-Dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic Acid in Mice

by Shinya Takenouchi, Daiki Imai, Tatsuro Nakamura and Takahisa Murata

Int. J. Mol. Sci. 2021, 22(17), 9295; https://doi.org/10.3390/ijms22179295 - 27 Aug 2021

Cited by 4 | Viewed by 1691

Abstract

5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid (5,6-DiHETE) is an eicosapentaenoic acid-derived newly discovered bioactive anti-inflammatory lipid mediator having diverse functions. Here, we assessed the potential of orally administered 5,6-DiHETE in promoting healing of dextran sulfate sodium (DSS)-induced colitis in mice. We measured the plasma concentrations of 5,6-DiHETE in untreated mice before and 0.5, 1, 3, and 6 h after its oral administration (150 or 600 μg/kg) in mice. Mice developed colitis by DSS (2% in drinking water for 4 days), and 5,6-DiHETE (150 or 600 μg/kg/day) was orally administered from day 9 to 14. Next, the faecal hardness and bleeding were assessed, and the dissected colons on day 14 via H&E staining. The plasma concentration of 5,6-DiHETE reached 25.05 or 44.79 ng/mL 0.5 h after the administration of 150 or 600 μg/kg, respectively, followed by a gradual decrease. The half-life of 5,6-DiHETE was estimated to be 1.25–1.63 h. Diarrhoea deteriorated after day 3 and peaked on day 5, followed by a gradual recovery. Histological assessment on day 14 showed DSS-mediated granulocyte infiltration, mucosal erosion, submucosal edema, and cryptal abscesses in mice. Oral administration of 150 or 600 μg/kg/day of 5,6-DiHETE accelerated the recovery from the DSS-induced diarrhoea and significantly ameliorated colon inflammation. The therapeutic effect of 600 μg/kg/day 5,6-DiHETE was slightly stronger than that by 150 μg/kg/day. Our study reveals attenuation of DSS-induced colitis in mice by the oral administration of 5,6-DiHETE dose-dependently, thereby suggesting a therapeutic potential of 5,6-DiHETE for inflammatory bowel disease. Full article

(This article belongs to the Special Issue Role of Environmental and Metabolic Factors in Inflammatory Bowel Disorders)

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15 pages, 6809 KiB

Open AccessArticle

Prolonged Chronic Consumption of a High Fat with Sucrose Diet Alters the Morphology of the Small Intestine

by Roberta Sferra, Simona Pompili, Alfredo Cappariello, Eugenio Gaudio, Giovanni Latella and Antonella Vetuschi

Int. J. Mol. Sci. 2021, 22(14), 7280; https://doi.org/10.3390/ijms22147280 - 6 Jul 2021

Cited by 10 | Viewed by 2802

Abstract

(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body’s health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat. Full article

(This article belongs to the Special Issue Role of Environmental and Metabolic Factors in Inflammatory Bowel Disorders)

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19 pages, 2408 KiB

Open AccessArticle

Crohn’s Disease Increases the Mesothelial Properties of Adipocyte Progenitors in the Creeping Fat

by Ana Madeira, Carolina Serena, Miriam Ejarque, Elsa Maymó-Masip, Monica Millan, M. Carmen Navarro-Ruiz, Rocío Guzmán-Ruiz, María M. Malagón, Eloy Espin, Marc Martí, Margarita Menacho, Ana Megía, Joan Vendrell and Sonia Fernández-Veledo

Int. J. Mol. Sci. 2021, 22(8), 4292; https://doi.org/10.3390/ijms22084292 - 20 Apr 2021

Cited by 6 | Viewed by 2939

Abstract

Our understanding of the interplay between human adipose tissue and the immune system is limited. The mesothelium, an immunologically active structure, emerged as a source of visceral adipose tissue. After investigating the mesothelial properties of human visceral and subcutaneous adipose tissue and their progenitors, we explored whether the dysfunctional obese and Crohn’s disease environments influence the mesothelial/mesenchymal properties of their adipocyte precursors, as well as their ability to mount an immune response. Using a tandem transcriptomic/proteomic approach, we evaluated the mesothelial and mesenchymal expression profiles in adipose tissue, both in subjects covering a wide range of body-mass indexes and in Crohn’s disease patients. We also isolated adipose tissue precursors (adipose-derived stem cells, ASCs) to assess their mesothelial/mesenchymal properties, as well as their antigen-presenting features. Human visceral tissue presented a mesothelial phenotype not detected in the subcutaneous fat. Only ASCs from mesenteric adipose tissue, named creeping fat, had a significantly higher expression of the hallmark mesothelial genes mesothelin (MSLN) and Wilms’ tumor suppressor gene 1 (WT1), supporting a mesothelial nature of these cells. Both lean and Crohn’s disease visceral ASCs expressed equivalent surface percentages of the antigen-presenting molecules human leucocyte antigen—DR isotype (HLA-DR) and CD86. However, lean-derived ASCs were predominantly HLA-DR ^dim, whereas in Crohn’s disease, the HLA-DR ^bright subpopulation was increased 3.2-fold. Importantly, the mesothelial-enriched Crohn’s disease precursors activated CD4⁺ T-lymphocytes. Our study evidences a mesothelial signature in the creeping fat of Crohn’s disease patients and its progenitor cells, the latter being able to present antigens and orchestrate an immune response. Full article

(This article belongs to the Special Issue Role of Environmental and Metabolic Factors in Inflammatory Bowel Disorders)

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14 pages, 3157 KiB

Open AccessArticle

Modeling Intestinal Epithelial Response to Interferon-γ in Induced Pluripotent Stem Cell-Derived Human Intestinal Organoids

by Michael J. Workman, Elissa Troisi, Stephan R. Targan, Clive N. Svendsen and Robert J. Barrett

Int. J. Mol. Sci. 2021, 22(1), 288; https://doi.org/10.3390/ijms22010288 - 30 Dec 2020

Cited by 10 | Viewed by 3385

Abstract

Human intestinal organoids (HIOs) are increasingly being used to model intestinal responses to various stimuli, yet few studies have confirmed the fidelity of this modeling system. Given that the interferon-gamma (IFN-γ) response has been well characterized in various other cell types, our goal was to characterize the response to IFN-γ in HIOs derived from induced pluripotent stem cells (iPSCs). To achieve this, iPSCs were directed to form HIOs and subsequently treated with IFN-γ. Our results demonstrate that IFN-γ phosphorylates STAT1 but has little effect on the expression or localization of tight and adherens junction proteins in HIOs. However, transcriptomic profiling by microarray revealed numerous upregulated genes such as IDO1, GBP1, CXCL9, CXCL10 and CXCL11, which have previously been shown to be upregulated in other cell types in response to IFN-γ. Notably, “Response to Interferon Gamma” was determined to be one of the most significantly upregulated gene sets in IFN-γ-treated HIOs using gene set enrichment analysis. Interestingly, similar genes and pathways were upregulated in publicly available datasets contrasting the gene expression of in vivo biopsy tissue from patients with IBD against healthy controls. These data confirm that the iPSC-derived HIO modeling system represents an appropriate platform to evaluate the effects of various stimuli and specific environmental factors responsible for the alterations in the intestinal epithelium seen in various gastrointestinal conditions such as inflammatory bowel disease. Full article

(This article belongs to the Special Issue Role of Environmental and Metabolic Factors in Inflammatory Bowel Disorders)

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Review

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16 pages, 918 KiB

Open AccessReview

The Multiple Faces of Integrin–ECM Interactions in Inflammatory Bowel Disease

by Valentina Garlatti, Sara Lovisa, Silvio Danese and Stefania Vetrano

Int. J. Mol. Sci. 2021, 22(19), 10439; https://doi.org/10.3390/ijms221910439 - 28 Sep 2021

Cited by 5 | Viewed by 3171

Abstract

Inflammatory Bowel Disease (IBD) comprises a series of chronic and relapsing intestinal diseases, with Crohn’s disease and ulcerative colitis being the most common. The abundant and uncontrolled deposition of extracellular matrix, namely fibrosis, is one of the major hallmarks of IBD and is responsible for the progressive narrowing and closure of the intestine, defined as stenosis. Although fibrosis is usually considered the product of chronic inflammation, the substantial failure of anti-inflammatory therapies to target and reduce fibrosis in IBD suggests that fibrosis might be sustained in an inflammation-independent manner. Pharmacological therapies targeting integrins have recently shown great promise in the treatment of IBD. The efficacy of these therapies mainly relies on their capacity to target the integrin-mediated recruitment and functionality of the immune cells at the damage site. However, by nature, integrins also act as mechanosensitive molecules involved in the intracellular transduction of signals and modifications originating from the extracellular matrix. Therefore, understanding integrin signaling in the context of IBD may offer important insights into mechanisms of matrix remodeling, which are uncoupled from inflammation and could underlie the onset and persistency of intestinal fibrosis. In this review, we present the currently available knowledge on the role of integrins in the etiopathogenesis of IBD, highlighting their role in the context of immune-dependent and independent mechanisms. Full article

(This article belongs to the Special Issue Role of Environmental and Metabolic Factors in Inflammatory Bowel Disorders)

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24 pages, 744 KiB

Open AccessReview

Gut Microbiota and Dietary Factors as Modulators of the Mucus Layer in Inflammatory Bowel Disease

by Samuel Fernández-Tomé, Lorena Ortega Moreno, María Chaparro and Javier P. Gisbert

Int. J. Mol. Sci. 2021, 22(19), 10224; https://doi.org/10.3390/ijms221910224 - 23 Sep 2021

Cited by 13 | Viewed by 4087

Abstract

The gastrointestinal tract is optimized to efficiently absorb nutrients and provide a competent barrier against a variety of lumen environmental compounds. Different regulatory mechanisms jointly collaborate to maintain intestinal homeostasis, but alterations in these mechanisms lead to a dysfunctional gastrointestinal barrier and are associated to several inflammatory conditions usually found in chronic pathologies such as inflammatory bowel disease (IBD). The gastrointestinal mucus, mostly composed of mucin glycoproteins, covers the epithelium and plays an essential role in digestive and barrier functions. However, its regulation is very dynamic and is still poorly understood. This review presents some aspects concerning the role of mucus in gut health and its alterations in IBD. In addition, the impact of gut microbiota and dietary compounds as environmental factors modulating the mucus layer is addressed. To date, studies have evidenced the impact of the three-way interplay between the microbiome, diet and the mucus layer on the gut barrier, host immune system and IBD. This review emphasizes the need to address current limitations on this topic, especially regarding the design of robust human trials and highlights the potential interest of improving our understanding of the regulation of the intestinal mucus barrier in IBD. Full article

(This article belongs to the Special Issue Role of Environmental and Metabolic Factors in Inflammatory Bowel Disorders)

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18 pages, 1200 KiB

Open AccessReview

Adipokine-Modulated Immunological Homeostasis Shapes the Pathophysiology of Inflammatory Bowel Disease

by Yi-Wen Tsai, Shin-Huei Fu, Jia-Ling Dong, Ming-Wei Chien, Yu-Wen Liu, Chao-Yuan Hsu and Huey-Kang Sytwu

Int. J. Mol. Sci. 2020, 21(24), 9564; https://doi.org/10.3390/ijms21249564 - 15 Dec 2020

Cited by 10 | Viewed by 2825

Abstract

Inflammatory colon diseases, which are a global health concern, include a variety of gastrointestinal tract disorders, such as inflammatory bowel disease and colon cancer. The pathogenesis of these colon disorders involves immune alterations with the pronounced infiltration of innate and adaptive immune cells into the intestines and the augmented expression of mucosal pro-inflammatory cytokines stimulated by commensal microbiota. Epidemiological studies during the past half century have shown that the proportion of obese people in a population is associated with the incidence and pathogenesis of gastrointestinal tract disorders. The advancement of understanding of the immunological basis of colon disease has shown that adipocyte-derived biologically active substances (adipokines) modulate the role of innate and adaptive immune cells in the progress of intestinal inflammation. The biomedical significance in immunological homeostasis of adipokines, including adiponectin, leptin, apelin and resistin, is clear. In this review, we highlight the existing literature on the effect and contribution of adipokines to the regulation of immunological homeostasis in inflammatory colon diseases and discuss their crucial roles in disease etiology and pathogenesis, as well as the implications of these results for new therapies in these disorders. Full article

(This article belongs to the Special Issue Role of Environmental and Metabolic Factors in Inflammatory Bowel Disorders)

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