Pathogenesis of Ulcerative Colitis: the role of Claudin-8 in epithelial barrier function and inflammation

Ulcerative colitis is a relapsing and remitting inflammatory bowel disease involving the large bowel. The current hypothesis on the pathogenesis of UC is that an abnormal innate immune response in genetically susceptible individuals, combined with environmental factors, result in excessive activation of the adaptive immune system within lamina propria. The role of abnormal barrier function is widely accepted. Using transcriptomic analysis of punch biopsies of patients with quiescent UC, CLDN8 was identified as grossly downregulated in the intestine. In this thesis, loss of Cldn8, a tight junction (TJ) molecule, was shown to result in reduced susceptibility of mice to DSS-induced colitis. Cldn8 knock out (Cldn98-KO) mice, had smaller increase in intestinal permeability to 3H-mannitol, reduced neutrophils and macrophages in inflammatory cell infiltrate in lamina propria during the early phase of inflammation. The inner layer of mucous is sterile in naïve Cldn8-KO and WT mice, and remains sterile after the animals have been exposed to DSS-water for 12 hours. Transcriptomic analysis between Cldn8-KO and WT mice did not reveal any significant differences between the two groups at different time points. After correction for multiple-testing, no differentially-expressed genes remained. These results suggest that downregulation of CLDN8 in patients with UC is a physiologic response by the intestine to increase local defences against luminal pathogens

Digital outpatient health solutions as a vehicle to improve healthcare sustainability—a United Kingdom focused policy and practice perspective

IntroductionIn the midst of a global climate emergency and with health care systems across the world facing extreme pressure, interest in digital approaches as a potential part-solution to these challenges has increased rapidly. The evidence base to support the role that digitalization can play in moving towards more sustainable models of healthcare is growing, as is the awareness of this key area of healthcare reform amongst policy makers, clinicians and the public.Method and ResultsIn this policy and practice review we explore four domains of healthcare sustainability-environmental, economic, and patient and clinician, delineating the potential impact that digitally enabled healthcare can have on each area. Real-world examples are provided to illustrate the impact individual digital interventions can have on each pillar of sustainability and demonstrate the scale of the potential benefits which can be achieved.DiscussionDigitally enabled healthcare solutions present an approach which offer numerous benefits, including environmental sustainability, economic benefits, and improved patient experience. There are also potential drawbacks such as the risk of digital exclusion and the need for integration with existing technology platforms. Overall, it is essential to strike a balance between the benefits and potential drawbacks of digital healthcare solutions to ensure that they are equitable, effective, and sustainable

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

BACKGROUND AND AIMS: ADAM (A Disintegrin And Metalloproteinase) is a family of peptidase proteins, which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like Decysin-1 (ADAMDEC1) a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn's disease patients has provided evidence of a potential role in bowel inflammation. METHODS: Adamdec1(-/-) mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium The clinical response was monitored. RESULTS: The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1β secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia. CONCLUSION: In summary, Adamdec1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn's disease

Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease

BACKGROUND: Evidence suggests an important role for gut-microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes in gut bacteria and the development of joint inflammation is missing. Here, we address whether there are changes to the gut environment and how they contribute to arthritis pathogenesis. METHODS: We analyzed changes in markers of gut permeability, damage, and inflammation in peripheral blood and serum of RA patients. Serum, intestines, and lymphoid organs isolated from K/BxN mice with spontaneous arthritis or from wild-type, genetically modified interleukin (IL)-10R(−/−)or claudin-8(−/−)mice with induced arthritis were analyzed by immunofluorescence/histology, ELISA, and flow cytometry. FINDINGS: RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity. Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ)(+)and decreases in IL-10(+)intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. Mechanistically, both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. We show that exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. Claudin-8(−/−)mice with constitutively increased gut permeability also develop worse joint disease. Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. CONCLUSIONS: We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA. FUNDING: Funded by Versus Arthritis (21140 and 21257) and UKRI/MRC (MR/T000910/1)