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• W2805318313 abstract "Biennially, a group of around 200 researchers interested in various facets of gastrointestinal science convenes at the FASEB Science Research Conference (SRC) on the Gastrointestinal Tract. The meeting was most recently held in its 17th iteration in the summer of 2017, in Steamboat Springs, Colorado. The conference has developed an excellent reputation not only for the outstanding level of scientific discourse that it promotes, but also the opportunities it affords to nurture the careers of recent entrants to the field and to ensure that they can network with senior figures working in their area. For 5 days in a beautiful and relaxed setting, attendees enjoy oral and poster sessions, communal meals, outdoor activities and unique social events that have cemented loyalty to the meeting. Indeed, the most recent conference was sold out and a number of prospective participants could not be accommodated from the substantial waiting list. Many individuals have attended the meeting for more than two decades, and many, including the author, consider it one of the most formative influences in their career development as an “enteroscientist”. The Journal of Physiology has been happy to be a repeat sponsor of the conference, which has allowed us to showcase The Journal as a venue keenly interested in attracting more submissions in the area of alimentary physiology. In addition, we have invited a number of speakers from the conference to submit short review articles that summarize the subject matter of their talks as well as related work from the literature. These articles serve as a record for participants and provide insights to some of the most exciting areas of current gastrointestinal research for a broader audience. This issue of The Journal gathers five such compact reviews from distinguished speakers across various areas of the meeting's programme. While the topics of the articles are distinct, they illustrate some common themes that represent the state of the art in gastrointestinal physiology and pathophysiology. First of all, there is a focus on inflammation, injury and repair, and the negative consequences (such as metaplasia and malignant transformation) that can result if such cycles are repeated too often. Second, the articles emphasize new insights into the complex crosstalk between the intestinal epithelium, mucosal immune system and the microbiota, and the importance of this crosstalk for homeostasis in a system that is buffeted daily by external influences. Finally, there is discussion of novel, non-canonical signalling roles expressed by systems previously recognized for other functions, such as cell adhesion molecules or molecular sensors of hypoxia. Meyer and Goldenring (2018) describe how they have mapped the signalling cascade linking epithelial damage in the stomach to the development of intestinal-type gastric cancer. A common metaplastic response to gastric injury, often triggered by the loss of parietal cells, is the emergence of so-called “SPEM” – spasmolytic polypeptide-expressing metaplasia. Such cells arise from the transdifferentiation of chief cells in the gastric glands. Initially, the presence of SPEM lineages, which secrete mucus and express trefoil factors, can be considered an appropriate adaptation that protects the epithelium from further injury. Indeed, SPEM lineages are present at the healing margins of gastric ulcers and promote repair of the epithelium. However, in the setting of chronic inflammation, the presence of SPEM may be a double-edged sword, by setting the stage for further transformation and ultimately dysplasia. By using various genetically engineered mouse models, the authors have developed a scheme whereby SPEM formation is initiated when damaged epithelial cells release the alarmin, interleukin 33 (IL-33). This cytokine, in turn, activates type II innate lymphoid cells to secrete IL-13, which is an important trigger for transdifferentiation of chief cells into SPEM. IL-13 also triggers the recruitment and alternative activation of macrophages, themselves a source of IL-33 and important for tissue remodelling and repair. Thus, an amplifying loop that initially promotes homeostasis may over-drive the metaplastic process in the setting of chronic inflammation, predisposing ultimately to the development of cancer. Meyer and Goldenring (2018) also raise intriguing parallels between the disease process they have modelled in the stomach and other conditions that likely involve the transdifferentiation of zymogenic cells in other organs, such as in the pancreas or salivary glands. Innate mucosal immune responses are also at the centre of the contribution of Goethel and colleagues (Goethel et al. 2018), although in this case the associated disease state is that of inflammatory bowel disease (IBD). Genome-wide association studies have uncovered a plethora of genes in which polymorphisms increase susceptibility to IBD, but the strongest association uncovered to date is that between the intracellular immune sensor, NOD2, and Crohn's disease. Activation of NOD2 by microbial or damage-related signals engages both inflammatory and mitotic signalling pathways. It is also implicated in the control of adaptive immune responses, autophagy and gut barrier function, and in shaping the microbiota. As the authors point out, a major challenge to the mucosal immune system is to appropriately downregulate its response to the commensal microbiota while retaining the ability to respond to pathogenic threats. In this scenario, dysregulation of immune sensing mechanisms such as NOD2 can readily be understood to lead to chronic inflammation, particularly in the context of knowledge that IBD (and animal models thereof) depend on the presence of luminal bacteria. However, studies of intestinal inflammation in mice lacking NOD2 have often been discordant. The review attempts to reconcile the conflicting conclusions drawn from these studies, and identifies a path forward to fully understand the precise contribution(s) of NOD2 to the pathogenesis of IBD. Epithelial responses to injury, including in the setting of IBD, form the subject matter of the article penned by Yulis and coworkers (Yulis et al. 2018). The authors have catalogued many intriguing ways in which adhesion molecules in the cadherin family not only contribute to epithelial barrier integrity, but also may regulate other cellular homeostatic events, such as proliferation, differentiation or apoptosis. For example, cadherins may modulate proliferation either by directly engaging (and thereby sequestering) intracellular binding partners such as β-catenin, or by binding to growth factor receptors and thereby modulating their interactions with downstream signalling effectors. There also appear to be several distinct classes of cadherin-mediated signalling pathways, including those that do or do not depend on the adhesive functions of the molecules. As an example of the latter, exposure of intestinal epithelial cells to inflammatory cytokines promotes the proteolytic cleavage of the extracellular domain of the desmosomal cadherin, Dsc-2. The soluble fragment so released can not only interrupt cell adhesion, but also bind directly to growth factor receptors and trigger proliferation. The article also comments on intriguing data that implicate desmoglein signalling in the pathogenesis of eosinophilic oesophagitis. There is also emerging evidence that the intracellular fragment of cadherins released when they are acted upon by proteinases may exhibit independent signalling properties, which likely will be an active area of investigation. It should be stressed, moreover, that Yulis and co-authors also emphasize the commonalities of cadherin-mediated signalling across a variety of tissue types beyond the intestine, including in the skin and in various non-intestinal cancers, as well as during embryonic development. Overall, the article illuminates the fact that the full repertoire of signalling capabilities of the diverse cadherin family is only beginning to be understood, and further exploration of this area will undoubtedly yield important new insights into a variety of disease mechanisms. Kennel et al. (2018) also emphasize non-canonical signalling events linked to molecules that initially were identified as mediators of responses to hypoxia, focusing particularly on one such molecule, prolyl hydroxylase-1 (PHD-1). PHD-1 and related hydroxylases active on the hypoxia-inducible factor (HIF) classically confer the hypoxia sensitivity of HIF, which in turn can then activate appropriate transcriptional responses to adapt to a relative lack of molecular oxygen. However, it has become apparent that not only can PHD-1 and related proteins be regulated by factors other than, or in addition to, molecular oxygen, but they may also target proteins other than HIF, including the master inflammatory regulator, NF-κB. As such, PHD-1 has recently been identified as a possible therapeutic target in a variety of diseases, including IBD and various cancers. Moreover, as for the cadherin effects discussed above, the article by Kennel et al. (2018) identifies many additional systems and diseases beyond the gastrointestinal system where non-canonical PHD-1 activity may play a critical role, further enhancing its potential as a profitable means whereby disease states can be interrupted. Nevertheless, there remains much work still to be done, particularly in the area of developing isoform-specific PHD inhibitors that might harness the benefits of reducing the activity of PHD-1 without running the risk of off-target effects on other HIF hydrolases. Finally, Mims and Grisham (2018) supply an update on various strategies that can be used to reconstitute mouse models with a humanized immune system. There has been significant recent attention to the fact that therapeutic strategies uncovered in mice, discussed here in the context of diseases where the splanchnic circulation is interrupted, have often been disappointingly lacking in efficacy when translated to the setting of human patients. As Mims and Grisham describe, there is a growing concern that these failures relate to the significant differences that exist between the immune systems of mice and humans. This provides the impetus for the development of so-called “humanized mice” via adoptive transfer of human lymphoid or progenitor cells to immunodeficient murine recipients. The authors summarize a number of strategies that have been employed to generate these novel models and how they are being used to study the pathophysiology of splanchnic organ inflammation, including food allergies and IBD. In particular, they highlight the key discovery that elimination of the murine IL-2 receptor common γ chain has permitted the long-term engraftment of human haemato-lymphoid cells. Either peripheral blood mononuclear cells, haematopoietic stem cells, or bone marrow, liver and thymus cells can be transferred to suitably prepared recipients, resulting in mice that are reconstituted with a smaller or larger collection of human immune cell subsets. The value of each model depends on the specific research question being asked and/or disease state to be modelled. Nevertheless, there remain limitations of the overall humanized mice approach and possible pathways to circumvent these are also discussed. In total, therefore, this collection of review articles illuminates several novel aspects of gastrointestinal physiology and pathophysiology as well as strategies to study these phenomena. We are grateful to the speakers from the 2017 FASEB SRC on the GI tract for taking the time to share their elegant work, as well as that of others in the field, with our readership. None declared." @default.
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• W2805318313 title "New frontiers in gastrointestinal physiology and pathophysiology" @default.
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