Multiple Pathogenic Roles of Microvasculature in Inflammatory Bowel Disease: A Jack of All Trades

Several studies have shown alterations in vascular anatomy and physiology in inflammatory bowel disease (IBD). These findings, together with the observed upregulation of the mediators of angiogenesis in IBD patients, suggest that angiogenesis possibly contributes to the initiation and perpetuation of IBD. There is considerable evidence of an interrelationship between the mechanisms of angiogenesis and chronic inflammation in IBD. The increased expression of endothelial junction adhesion molecules found in IBD patients indicates the presence of active angiogenesis. Evidence that angiogenesis is involved in IBD was also obtained from animal models of colitis, most notably from studies of angiogenesis inhibition. Serum levels of vascular endothelial growth factor (VEGF) correlate with disease activity in human IBD and fall with the use of steroids, thalidomide, or infliximab. Pharmacological inhibition of angiogenesis, therefore, has the potential to be a therapeutic strategy in IBD. This review outlines the evidence that the rate of angiogenesis is increased in the inflamed intestine in IBD and proposes lines for future research in this field.

Although the human inflammatory bowel diseases (IBDs), Crohn’s disease (CD), and ulcerative colitis (UC) are well-known inflammatory disorders that are characterized by progressive destructive inflammation in the gastrointestinal tract, their etiology and promulgating factors remain a mystery. Recently, vasculopathy is being implicated in these disease processes in an increasing number of studies. Chronically inflamed IBD microvessels have demonstrated significant alterations in microvascular physiology and function compared with vessels from healthy and uninvolved IBD intestine. The microcirculation and its endothelial lining play a central role in the initiation and perpetuation of the inflammatory process, and investigation into human IBD has demonstrated an important role for the endothelium in both normal mucosal immunity as well as the dysregulated chronic inflammation characterizing IBD. Chronically inflamed IBD microvessels demonstrate an enhanced capacity to adhere leukocytes after inflammatory activation and have alterations in selective leukocyte recruitment compared with uninvolved areas of bowel. In addition to the role of the vasculature in leukocyte recruitment, both forms of IBD are characterized by refractory mucosal damage and ulceration with an impaired capacity to heal. Previous work has demonstrated an abnormal, remodeled vascular architecture characterized by stenotic microvessels in chronically inflamed CD and UC lesions. This would suggest chronic ischemia in the IBD gut. Human in vivo investigation has demonstrated a significant decrease in mucosal intestinal microvascular perfusion in chronic IBD gut inflammation. Significantly impaired endothelial-dependent microvascular vasorelaxation in chronically inflamed CD and UC bowel has been defined recently. In this work we review the role of the microvasculature in human chronic intestinal inflammation in IBD, our present understanding of the vasculature in disease etiopathogenesis, and the emerging IBD therapies, target the vasculature.

The precise aetiology of chronic inflammatory bowel disease (IBD) has remained elusive despite many years of investigation. Both Crohn’s disease and ulcerative colitis are characterised by chronic inflammation of the...

Unique Role of Junctional Adhesion Molecule-A in Maintaining Mucosal Homeostasis in Inflammatory Bowel Disease

Mend Your Fences: The Epithelial Barrier and its Relationship With Mucosal Immunity in Inflammatory Bowel Disease.

Crohn’s disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. “Humanized” mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.

Angiogenesis is the growth of new blood vessels. In the two major forms of inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis, robust angiogenesis exists, and its blockade may have therapeutic potential, as shown in animal models of experimental intestinal inflammation. While abundant literature is available on the positive regulators of intestinal pathological angiogenesis, e.g. VEGF, b-FGF, IL-8, CD40 and CD40L, almost no data exist on negative regulators. Thrombospondin-1 is a negative regulator of angiogenesis, and it plays a new role in IBD-associated angiogenesis. In addition, recombinant thrombospondin-1 may inhibit pathological angiogenesis and may offer a new therapeutic approach to intestinal inflammation.

Translational Inhibition of Colonic Epithelial Heat Shock Proteins by IFN-γ and TNF-α in Intestinal Inflammation

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation and impaired epithelial barrier function. Emerging evidence highlights the critical role of vascular remodeling and angiogenesis in IBD pathogenesis. This review explores the intricate relationship between blood vessels and the intestinal epithelial barrier, emphasizing how aberrant vascularization contributes to barrier dysfunction and disease progression. In IBD, excessive angiogenesis is driven by hypoxia, immune cell infiltration, and pro-inflammatory cytokines, further perpetuating inflammation and tissue damage. Key angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietins, and platelet-derived growth factor (PDGF), are upregulated in IBD, promoting pathological vessel formation. These newly formed vessels are often immature and hyperpermeable, exacerbating leukocyte recruitment and inflammatory responses. Given the pivotal role of angiogenesis in IBD, anti-angiogenic therapies have emerged as a potential therapeutic strategy. Preclinical and clinical studies targeting VEGF and other angiogenic pathways have shown promise in reducing inflammation and promoting mucosal healing. This review summarizes current knowledge on vascular-epithelial interactions in IBD, the mechanisms driving pathological angiogenesis, and the therapeutic potential of anti-angiogenic approaches, providing insights for future research and treatment development.

SummaryInterleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23-independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3+ cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.

This month in gastroenterology

Quality Is as Important as the Quantity: Role of Mucin Glycosylation on Intestinal Barrier Function

Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis (UC), are complex disorders characterized by chronic, local and systemic inflammation and spontaneously relapsing course. The causes of these diseases are unknown, however they display genetic and environmental components and appear to be immunologically mediated in part by enteric microbiota [1]. The immune system cells activation may lead to activation of plasma proteolytic cascades [1,2], as well as to release of inflammatory mediators in inflamed intestine. There are convincing evidences that IBD are diseases of immunological hyperresponsiveness within the mucosa. Immunological reactions may be directed against luminal bacteria and their products normally present in the intestine [2]. Both innate and adaptive immune response play a role in IBD pathogenesis and possibly in etiology. Autacoids, a local hormones e.g., histamine, serotonin, kinins, angiotensin, eicosanoids, neurotensin, nitric oxide, endothelins may be produced and act locally in IBD – inflamed intestine, and play a role inflammatory response, and progression in both Crohn’s disease and UC. A role of eicosanoids and nitric oxide in IBD was relatively well delineated. Much less attention has been paid to other autacoids, although a significance of the intestinal tissue kallikrein – kinin system in IBD has been investigated in the late 1990s – 2000s. Histamine, serotonin and kinins are vasodilator autacoids which as part of the humoral defense system participate in the inflammatory response. Enterochromaffin cellwhich are present in the mucosa of all regions of the gut except the oesophagus, contain most of the body’s serotonin (5-HT). Derived serotonin (5-HT) express toll-like receptors and thus may detect microorganisms [3,4]. Enterochromaffin cell 5-HT also appears to contribute to the initiation of intestinal inflammation, at least in the animal models. Mice that lack the 5-HT transporter (SERT; SERTKO mice), which inactivates 5-HT, are sensitive to experimentally induced colitis especially in animals with interleukin (IL)-10 deletion [5,6]. Histamine as a proinflammatory mediator is selectively located in the granules of human mast cells and basophils and released from these cells upon degranulation. It was shown that the number of mast cells and mast cells tryptase expression (a marker of mast cell degranulation are increased in colonic mucosa and submucosa in experimental and human IBD [7]. Interestingly, mast cells originated from the resected colon of active Crohn’s disease or UC released more histamine than those from normal colon after stimulation with colon-derived murine epithelial cell-associated compounds [8]. Knutson et al. found that the histamine secretion was increased in patients with Crohn’s disease compared with normal controls, and the secretion of histamine was related to disease activity, indicating strongly that degranulation of mast cells was involved in active Crohn’s disease [9]. A significance kinins in human IBD is still underestimated although in animal IBD models kinins have been documented in part to mediate intestinal and systemic inflammation. Tissue kallikrein cleaves kininogens to release kinins. The importance of intestinal tissue kallikrein (ITK) in the intestine mainly depends upon the secretion of active enzyme in the presence of kininogens, especially low molecular weight kininogen (LK), with subsequent kinins generation. It should be noted that in mild insults, kinins may play a salutary role recruiting to the extravascular milieu proteases, acute phase proteins, and neutrophils. In severe inflammation, however, kinins amplifies the inflammatory cascade, and contributes to tissue destruction. In late 1990s we have focused our attention on the ITK-kinin system in IBD. To study the localization of ITK and its naturally occurring serine protein inhibitor (SERPIN), kallistatin, in IBD we first focused in our models of rats enterocolitis induced by proteoglycan-polysaccharide (PG-APS) closely resembling Crohn’s disease [10]. We showed that the normal location of ITK was the goblet cells and that substantial amounts of ITK were present in the macrophages of the granuloma found in the submucosa, suggesting that ITK is present at the site of inflammation. In addition, ITK was found to be lower in the supernatant from in vitro cultures of inflamed intestine. This combination suggested secretion of ITK during inflammation.

Background and aims Inflammatory bowel disease (IBD) cause chronic relapsing-remitting inflammatory flares in the gastrointestinal tract, resulting in abdominal pain, diarrhea, and gut dysmotility in non-destructive collagenous and lymphocytic microscopic colitis. In addition, classic IBDs Crohn´s disease and ulcerative colitis cause bloody diarrhea and extraintestinal symptoms. Non-destructive IBDs seem to restrain an overt immune response that will damage the tissue and impair wound healing. Thus, I will work under the premise that non-destructive IBDs are undeveloped forms of classic IBDs. Methods First, I aim to deeply characterize and compare immune cells and their activation levels in all forms of IBD using “immunomics” (spectral/computational cytometry) and validate my previous finding of two subtypes of lymphocytic colitis. To identify the microbiota that adheres to intestinal epithelial cell (IEC) and therefore alter permeability, and induce collagen deposition, I will coculture IEC and fibroblasts in organ-on-a-chip platforms to mimic gut conditions, including microflow shear stress. I will stimulate chips with patient-derived microbiota-containing luminal content or homogenized biopsies and resections from collagenous colitis (characterized by pathogenic collagen position) and intestinal fibrosis (a major, irreversible IBD complication that increases mortality), respectively, and study using different sequencing techniques. Of note, collagenous colitis could resemble early stages of intestinal fibrosis. My third objective aims to test my previous observation that regulatory B-cells in collagenous colitis might be responsible of restricting overt inflammation. Anticipated impact I will adapt spectral cytometry panels to characterize the state of mucosal B- and plasma cells. The support of my host, the well-established IBD immunologist Assoc. Prof. David Bernardo at the Institute of Biomedicine and Molecular Genetics (Valladolid, Spain, h-index=33) and me as coordinator of the biobank for the European Microscopic Colitis Group, ensure the feasibility to complete my ambitious research agenda and make a great impact on IBD field to discover disease-specific biomarkers, pathomechanisms, and new druggable targets.

Inflammatory bowel disease (IBD) is a chronic disease involving multiple genes, and the current available targeted drugs for IBD only deliver moderate efficacy. Whether there is a single gene that systematically regulates IBD is not yet known. MiR-146a plays a pivotal role in repression of innate immunity, but its function in the intestinal inflammation is sort of controversy, and the genetic regulatory networks regulated by miR-146a in IBD has not been revealed. RT-qPCR was employed to detect the expression of miR-146a in IBD patients and in a mouse IBD model induced by dextran sulfate sodium (DSS), and then we generated a miR-146a knock-out mouse line with C57/Bl6N background. The disease activity index was scored in DSS-treated miR-146a deficiency mice and their wild type (WT) littermates. Bulk RNA-sequencing, RT-qPCR and immunostaining were done to illustrate the downstream genetic regulatory networks of miR-146a in flamed colon. Finally, the modified miR-146a mimics were used to treat DSS-induced IBD in miR-146a knock-out and WT IBD mice. We showed that the expression of miR-146a in the colon was elevated in dextran sulfate sodium (DSS)-induced IBD mice and patients with IBD. DSS induced dramatic body weight loss and more significant rectal bleeding, shorter colon length, and colitis in miR-146a knock-out mice than WT mice. The miR-146a mimics alleviated DSS-induced symptoms in both miR-146a-/- and WT mice. Further RNA sequencing illustrated that the deficiency of miR-146a de-repressed majority of DSS-induced IBD-related genes that cover multiple genetic regulatory networks in IBD, and supplementation with miR-146a mimics inhibited the expression of many IBD-related genes. Quantitative RT-PCR or immunostaining confirmed that Ccl3, Saa3, Csf3, Lcn2, Serpine1, Serpine2, MMP3, MMP8, MMP10, IL1A, IL1B, IL6, CXCL2, CXCL3, S100A8, S100A9, TRAF6, P65, p-P65, and IRAK1 were regulated by miR-146a in DSS induced IBD. Among them, MMP3, MMP10, IL6, IL1B, S100A8, S100A9, SERPINE1, CSF3, and IL1A were involved in the active stage of IBD in humans. Our date demonstrated that miR-146a acts as a top regulator in C57/BL6N mice to systematically repress multiple genetic regulatory networks involved in immune response of intestine to environment factors, and combinatory treatment with miR-146a-5p and miR-146a-3p mimics attenuates DSS-induced IBD in mice through down-regulating multiple genetic regulatory networks which were increased in colon tissue from IBD patients. Our findings suggests that miR-146a is a top inhibitor of IBD, and that miR-146a-5p and miR-146a-3p mimics might be potential drug for IBD.