Lipidated IL-22 Alone or Combined with Immunomodulatory Agents Improves Disease Endpoints and Promotes Mucosal Healing in a Mouse Model of Chronic Dextran Sodium Sulfate-Induced Colitis.

Background: IL-22 facilitates mucosal healing by directly inducing epithelial regeneration and barrier integrity, which is essential for achieving remission and thereby treating inflammatory bowel disease.

Aims: Here, we evaluated efficacy of a novel lipidated IL-22 alone and in combination with immunomodulatory agents in addressing chronic dextran sodium sulfate (DSS)-induced colitis in mice and demonstrated action of IL-22 on mucosal healing.

Methods: Mice were treated with DSS, followed by various doses of lipidated IL-22, anti-TNF antibody, fingolimod, or anti-mouse α4β7 integrin antibody.

Gut virome-colonising genus is associated with ulcerative colitis pathogenesis and induces intestinal inflammation .

Objectives: Ulcerative colitis (UC) is a chronic inflammatory disorder of unknown aetiology. Gut virome dysbiosis is fundamental in UC progression, although its role in the early phases of the disease is far from fully understood. Therefore, we sought to investigate the role of a virome-associated protein encoded by the genus, the hepatitis B virus X protein (HBx), in UC aetiopathogenesis.

Relationships Between Intestinal Ultrasound Parameters and Histopathologic Findings in a Prospective Cohort of Patients With Crohn's Disease Undergoing Surgery.

Objectives: Recognition of intestinal lesions with substantial fibrosis is strategic for optimal management of patients with Crohn's disease (CD). We aimed to assess the relationships between intestinal ultrasound parameters and histopathologic findings in a prospective cohort of patients with CD undergoing surgery.

Methods: Seventeen consecutive adult CD patients with involvement of the terminal ileum or the sigmoid colon who underwent bowel resective surgeries were enrolled and performed intestinal ultrasound (IUS) within 30 days prior to surgery.

Revisiting fibrosis in inflammatory bowel disease: the gut thickens.

Intestinal fibrosis, which is usually the consequence of chronic inflammation, is a common complication of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. In the past few years, substantial advances have been made in the areas of pathogenesis, diagnosis and management of intestinal fibrosis. Of particular interest have been inflammation-independent mechanisms behind the gut fibrotic process, genetic and environmental risk factors (such as the role of the microbiota), and the generation of new in vitro and in vivo systems to study fibrogenesis in the gut.

The Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) framework.

Inflammatory bowel disease (IBD) is a class of chronic disorders whose etiogenesis is still unknown. Despite the high number of IBD-related omics studies, the RNA-sequencing data produced results that are hard to compare because of the experimental variability and different data analysis approaches. We here introduce the IBD Transcriptome and Metatranscriptome Meta-Analysis (TaMMA) framework, a comprehensive survey of publicly available IBD RNA-sequencing datasets.

Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer.

Background: Sphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information on whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap.

Methods: We screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N = 76].

The Role of Pro-Resolving Lipid Mediators in Colorectal Cancer-Associated Inflammation: Implications for Therapeutic Strategies.

Inflammation is a recognized hallmark of cancer that contributes to the development and progression of colorectal cancer (CRC). Anti-inflammatory drugs currently used for the treatment of CRC show many adverse side effects that prompted researchers to propose the polyunsaturated fatty acids-derived specialized pro-resolving mediators (SPMs) as promoters of resolution of cancer-associated inflammation. SPMs were found to inhibit the CRC-associated pro-inflammatory milieu via specific G-coupled protein receptors, although clinical data are still lacking.

The gut virome in inflammatory bowel disease pathogenesis: From metagenomics to novel therapeutic approaches.

The association of intestinal dysbiosis with the pathogenesis of inflammatory bowel disease has been well established. Besides bacteria, microbiota comprises yeasts, archaea, protists and viruses, neglected actors in inflammatory bowel disease-associated microbiota. In the past, a great limitation in studying microbiota composition was the low sensitivity of sequencing technologies and that few computational approaches were sufficient to thoroughly analyse the whole microbiome.

Hyaluronan Accelerates Intestinal Mucosal Healing through Interaction with TSG-6.

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.

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

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).

Activation of the VEGFC/VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer.

Colorectal cancer is a major cause of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LV) and tumor-associated macrophages (TAM). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available regarding its role during primary colorectal cancer development. We found that both VEGFC and VEGFR3 were upregulated in human nonmetastatic colorectal cancer, with VEGFR3 expressed on both LVs and TAMs.

TNF-Stimulated Gene-6 Is a Key Regulator in Switching Stemness and Biological Properties of Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) are well established to have promising therapeutic properties. TNF-stimulated gene-6 (TSG-6), a potent tissue-protective and anti-inflammatory factor, has been demonstrated to be responsible for a significant part of the tissue-protecting properties mediated by MSCs. Nevertheless, current knowledge about the biological function of TSG-6 in MSCs is limited.

Lymphatic endothelium contributes to colorectal cancer growth via the soluble matrisome component GDF11.

Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with cancer cells and extracellular matrix. Here we provide the first evidence that CRC-associated lymphatic endothelium displays a distinct matrisome-associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics.

Metagenomic analysis of intestinal mucosa revealed a specific eukaryotic gut virome signature in early-diagnosed inflammatory bowel disease.

Intestinal dysbiosis is one of the causes underlying the pathogenesis of inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD). Besides bacteria, microbiota comprises both prokaryotic and eukaryotic viruses, that together compose the gut virome. Few works have defined the viral composition of stools, while the virome populating intestinal mucosae from early-diagnosed IBD patients has never been studied.

Can IL-23 be a good target for ulcerative colitis?

A considerable percentage of patients with ulcerative colitis (UC) do not respond to therapies, including anti-tumor necrosis factor (TNF) drugs and vedolizumab, or lose response over time. Hence the continuing need to find new therapeutic strategies and novel drugs to control this chronic debilitating disease. Increased levels of interleukin (IL)-23 and T helper (Th) 17 cell cytokines have been found in intestinal mucosa, plasma, and serum of patients with inflammatory bowel disease (IBD).

Actors and Factors in the Resolution of Intestinal Inflammation: Lipid Mediators As a New Approach to Therapy in Inflammatory Bowel Diseases.

In the last few decades, the pathogenesis of inflammatory bowel disease (IBD) in genetically predisposed subjects susceptible to specific environmental factors has been attributed to disturbance of both the immune and non-immune system and/or to the imbalanced interactions with microbes. However, increasing evidences support the idea that defects in pro-resolving pathways might strongly contribute to IBD onset. The resolution of inflammation is now recognized as a dynamic event coordinated by specialized pro-resolving lipid mediators (LMs), which dampen inflammation-sustaining events, such as angiogenesis, release of pro-inflammatory cytokines, clearance of apoptotic cells, and microorganisms.

TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice.

Background And Aims: Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis.

MFSD2A Promotes Endothelial Generation of Inflammation-Resolving Lipid Mediators and Reduces Colitis in Mice.

Background & Aims: Alterations in signaling pathways that regulate resolution of inflammation (resolving pathways) contribute to pathogenesis of ulcerative colitis (UC). The resolution process is regulated by lipid mediators, such as those derived from the ω-3 docosahexaenoic acid (DHA), whose esterified form is transported by the major facilitator superfamily domain containing 2A (MFSD2A) through the endothelium of brain, retina, and placenta. We investigated if and how MFSD2A regulates lipid metabolism of gut endothelial cells to promote resolution of intestinal inflammation.

PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue.

Background: In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological drugs, a significant proportion of patients is unaffected by or lose their response to these compounds, along with increased risks of infections and malignancies. For these reasons there is an urgent need to look for new pharmacological targets.

Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis.

Prolyl hydroxylase domain-containing proteins (PHDs) regulate the adaptation of cells to hypoxia. Pan-hydroxylase inhibition is protective in experimental colitis, in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved.

Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1.

The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation.