The GI tract is the most exposed organ to proteases, both in physiological and pathophysiological conditions. For digestive purposes, the lumen of the upper GI tract contains large amounts of ...pancreatic proteases, but studies have also demonstrated increased proteolytic activity into mucosal tissues (both in the upper and lower GI tract), associated with pathological conditions. This review aims at outlining the evidences for dysregulated proteolytic homeostasis in GI diseases and the pathogenic mechanisms of increased proteolytic activity. The therapeutic potential of protease inhibition in GI diseases is discussed, with a particular focus on IBDs, functional GI disorders and colorectal cancer.
The transient receptor potential vanilloid-4 (TRPV4) belongs to a family of ion channels and can be activated by warm temperature, hypotonicity, cell swelling or lipid mediators of the arachidonic ...cascade. The metabolites or events responsible for TRPV4 activation are associated with inflammation, arguing in favor of a role for this receptor in inflammatory diseases. The first studies have focused their attention on the role of TRPV4 in neurons and endothelial cells but TRPV4 cellular distribution is widespread, particularly in the gastrointestinal tract. Herein, we review a number of studies demonstrating the expression of TRPV4 in the gut, the regulation of its expression and functions by inflammatory mediators in that organ and the consequences of TRPV4 activation or inhibition in the intestine. We further discuss the relevance of considering this receptor as a potential target for therapeutic development in inflammatory bowel diseases.
Proteases have been shown to signal to cells through the activation of a novel class of receptors coupled to G proteins: the protease-activated receptors (PARs). Those receptors are expressed in a ...wide range of cells, which ultimately are all involved in mechanisms of inflammation and pain. Numerous studies have considered the role of PARs in cells, organ systems or in vivo, highlighting the fact that PAR activation results in signs of inflammation. A growing body of evidences discussed here suggests that these receptors, and the proteases that activate them, interfere with inflammation and pain processes. Whether a role for PARs has been clearly defined in inflammatory and pain pathologies is discussed in this review. Further, the pros and cons for considering PARs as targets for the development of therapeutic options for the treatment of inflammation and pain are discussed.
Gastrointestinal biofilms in health and disease Motta, Jean-Paul; Wallace, John L; Buret, André G ...
Nature reviews. Gastroenterology & hepatology,
05/2021, Letnik:
18, Številka:
5
Journal Article
Recenzirano
Microorganisms colonize various ecological niches in the human habitat, as they do in nature. Predominant forms of multicellular communities called biofilms colonize human tissue surfaces. The ...gastrointestinal tract is home to a profusion of microorganisms with intertwined, but not identical, lifestyles: as isolated planktonic cells, as biofilms and in biofilm-dispersed form. It is therefore of major importance in understanding homeostatic and altered host-microorganism interactions to consider not only the planktonic lifestyle, but also biofilms and biofilm-dispersed forms. In this Review, we discuss the natural organization of microorganisms at gastrointestinal surfaces, stratification of microbiota taxonomy, biogeographical localization and trans-kingdom interactions occurring within the biofilm habitat. We also discuss existing models used to study biofilms. We assess the contribution of the host-mucosa biofilm relationship to gut homeostasis and to diseases. In addition, we describe how host factors can shape the organization, structure and composition of mucosal biofilms, and how biofilms themselves are implicated in a variety of homeostatic and pathological processes in the gut. Future studies characterizing biofilm nature, physical properties, composition and intrinsic communication could shed new light on gut physiology and lead to potential novel therapeutic options for gastrointestinal diseases.
Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivity characterized by a ...breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. Here we show that duodenal biopsies from patients with active CeD have increased proteolytic activity against gluten substrates that correlates with increased Proteobacteria abundance, including Pseudomonas. Using Pseudomonas aeruginosa producing elastase as a model, we show gluten-independent, PAR-2 mediated upregulation of inflammatory pathways in C57BL/6 mice without villus blunting. In mice expressing CeD risk genes, P. aeruginosa elastase synergizes with gluten to induce more severe inflammation that is associated with moderate villus blunting. These results demonstrate that proteases expressed by opportunistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen.
In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key ...role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α
β
or PAR
activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR
activation, whereas formers were protected from cytotoxicity through α
β
engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients.
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites ...are increased in abundance in IBS and are implicated in the alteration of sensation to mechanical stimuli, which is defined as visceral hypersensitivity. We sought to quantify PUFA metabolites in patients with IBS and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increased abundance of 5-oxoeicosatetraenoic acid (5-oxoETE) only in biopsies taken from patients with IBS with predominant constipation (IBS-C). Local administration of 5-oxoETE to mice induced somatic and visceral hypersensitivity to mechanical stimuli without causing tissue inflammation. We found that 5-oxoETE directly acted on both human and mouse sensory neurons as shown by lumbar splanchnic nerve recordings and Ca
imaging of dorsal root ganglion (DRG) neurons. We showed that 5-oxoETE selectively stimulated nonpeptidergic, isolectin B4 (IB4)-positive DRG neurons through a phospholipase C (PLC)- and pertussis toxin-dependent mechanism, suggesting that the effect was mediated by a G protein-coupled receptor (GPCR). The MAS-related GPCR D (Mrgprd) was found in mouse colonic DRG afferents and was identified as being implicated in the noxious effects of 5-oxoETE. Together, these data suggest that 5-oxoETE, a potential biomarker of IBS-C, induces somatic and visceral hyperalgesia without inflammation in an Mrgprd-dependent manner. Thus, 5-oxoETE may play a pivotal role in the abdominal pain associated with IBS-C.
Interstitial cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic inflammatory disease characterized by visceral pain and voiding symptoms. IC/BPS is still an unsolved enigma with ineffective ...diagnosis criteria and treatment. A main limitation in IC/BPS understanding is the lack of appropriate preclinical model. Cyclophosphamide (CYP) is commonly used as an experimental model for IC/BPS in rodent. However, the proposed models are very aggressive, contrasting with what occurs in clinic, and often associated with severe toxicity and high mortality rate. In addition, visceral pain, the hallmark symptom of IC/BPS, has been validated in only few of them. In this study, we developed a chronic model of CYP-induced IC/BPS in female rat. In our protocol, no severe weight loss occurred and the survival rate was 100%. In accordance to human pathology, chronic CYP-injected rats developed severe painful behavior whereas only sparse inflammation was observed. Inflammatory response was characterized by bladder edema and focal urothelial damage but absence of massive infiltrate. This chronic model showed persistent symptoms indicative for a central sensitization mechanism. We further demonstrate that CYP-induced chronic visceral pain was significantly reduced by curative treatment with clinically relevant compounds (gabapentin, ibuprofen, and Ialuril ®). We therefore developed and validated a rat model of chronic cystitis that shares strong similarity with human non-ulcerative IC/BPS features without overtly affecting the animal health. This model will thus provide mechanistic insights of the disease and help to evaluate therapeutic agents for IC/BPS.
Many studies have demonstrated the involvement of proteases in gut physiology and pathophysiology over the recent years. Among them, thrombin has appeared for a long time as an old player only ...involved in blood clotting upon tissue injury. The fact that thrombin receptors (Protease-Activated Receptors-1 and -4) are expressed and functional in almost all cell types of the gut, contributing to barrier, immune or motility functions, suggested that thrombin could actually be at the crossroad of intestinal physiology. Recent work has unraveled the constitutive release of active thrombin by intestinal epithelial cells, opening new research avenues on the role of thrombin in the gut. These roles are considered in the present review, as well as the regulation of thrombin in the gut. The potential of thrombin as a target for treatments of intestinal pathologies is also discussed here.
•Physiology and Pathophysiology of Thrombin in the Intestine.•Thrombin: a Gut protease with pleiotropic mechanisms.•Thrombin is a major signal to microbiota and in inflammatory bowel diseases.
Quiescent phases of inflammatory bowel disease (IBD) are often accompanied by chronic abdominal pain. Although the transient receptor potential vanilloid 1 (TRPV1) ion channel has been postulated as ...an important mediator of visceral hypersensitivity, its functional role in postinflammatory pain remains elusive. This study aimed at establishing the role of TRPV1 in the peripheral sensitization underlying chronic visceral pain in the context of colitis. Wild-type and TRPV1-deficient mice were separated into three groups (control, acute colitis, and recovery), and experimental colitis was induced by oral administration of dextran sulfate sodium (DSS). Recovery mice showed increased chemically and mechanically evoked visceral hypersensitivity 5 wk post-DSS discontinuation, at which point inflammation had completely resolved. Significant changes in nonevoked pain-related behaviors could also be observed in these animals, indicative of persistent discomfort. These behavioral changes correlated with elevated colonic levels of substance P (SP) and TRPV1 in recovery mice, thus leading to the hypothesis that SP could sensitize TRPV1 function. In vitro experiments revealed that prolonged exposure to SP could indeed sensitize capsaicin-evoked currents in both cultured neurons and TRPV1-transfected human embryonic kidney (HEK) cells, a mechanism that involved TRPV1 ubiquitination and subsequent accumulation at the plasma membrane. Importantly, although TRPV1-deficient animals experienced similar disease severity and pain as wild-type mice in the acute phase of colitis, TRPV1 deletion prevented the development of postinflammatory visceral hypersensitivity and pain-associated behaviors. Collectively, our results suggest that chronic exposure of colon-innervating primary afferents to SP could sensitize TRPV1 and thus participate in the establishment of persistent abdominal pain following acute inflammation.
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