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Background: With advances in technology, there is an emerging concern that inequalities exist in provision and diabetes outcomes in areas of greater deprivation. We assess the relationship between socio‐economic status and deprivation with access to diabetes technology and their outcomes in adults with type 1 diabetes. Methods: Retrospective, observational analysis of adults attending a tertiary centre, comprising three urban hospitals in the UK. Socio‐economic deprivation was assessed by the English Indices of Deprivation 2019. Data analysis was performed using one‐way ANOVAs and chi‐squared tests. Results: In total, 1631 adults aged 44 ± 15 years and 758 (47%) women were included, with 391 (24%) using continuous subcutaneous insulin infusion, 312 (19%) using real‐time continuous glucose monitoring and 558 (34%) using intermittently scanned continuous glucose monitoring. The highest use of diabetes technology was in the least deprived quintile compared to the most deprived quintile (67% vs. 45%, respectively; p < 0.001). HbA1c outcomes were available in 400 participants; no association with deprivation was observed (p = 0.872). Participation in structured education was almost twice as high from the most deprived to the least deprived groups (23% vs. 43%; p < 0.001). Adults with white or mixed ethnicity were more likely to use technology compared to black ethnicity (60% vs. 40%; p < 0.001). Conclusions: Adults living in the most deprived quintile had less technology use. Irrespective of socio‐economic status or ethnicity, glycaemia was positively affected in all groups. It is imperative that health disparities are further addressed. [ABSTRACT FROM AUTHOR]

Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non‐metabolizable analog of UDCA, 6‐methyl‐UDCA (6‐MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation. Bile acids were administered daily to C57Bl6 mice by intraperitoneal injection. Colonic inflammation, induced by addition of DSS (2.5%) to the drinking water, was measured as disease activity index (DAI) and histological score. Epithelial permeability and apoptosis were assessed by measuring FITC‐dextran uptake and caspase‐3 cleavage, respectively. Cecal bile acids were measured by HPLC‐MS/MS. UDCA and LCA, but not 6‐MUDCA, were protective against DSS‐induced increases in epithelial permeability and colonic inflammation. Furthermore, UDCA and LCA inhibited colonic epithelial caspase‐3 cleavage both in DSS‐treated mice and in an in vitro model of cytokine‐induced epithelial injury. HPLC‐MS/MS analysis revealed UDCA administration to increase colonic LCA levels, whereas LCA administration did not alter UDCA levels. UDCA, and its primary metabolite, LCA, protect against intestinal inflammation in vivo, at least in part, by inhibition of epithelial apoptosis and promotion of barrier function. These data suggest that clinical trials of UDCA in IBD patients are warranted. [ABSTRACT FROM AUTHOR]

R5992 --> 582.3 --> Introduction and Aims: The intestinal epithelium forms the interface between the body and the luminal contents, facilitating fluid and electrolyte transport, while also acting as a barrier to harmful pathogens. Dysregulation of barrier and transport function is associated with the pathogenesis of a number of conditions, including chronic diarrhoeal and inflammatory bowel diseases (IBD). Previous studies from ours, and other laboratories, have identified the nuclear bile acid receptor, farnesoid x receptor (FXR), as an excellent target for the development of new anti‐diarrhoeal and anti‐inflammatory therapeutics. Polyunsaturated fatty acids (PUFAs), such as alpha‐linolenic acid (ALA), are a group of bioactive phytochemicals, which have been shown in other systems to modulate FXR activity. PUFAs are also thought to be ligands for another group of nuclear receptors, known as the peroxisome proliferator‐activated receptors (PPARs), which have been recently shown to modulate FXR expression. Here, we set out to investigate a possible role for ALA in regulating farnesoid x receptor signalling in colonic epithelial cells. Methods: T84 human colonic epithelial cells were cultured as polarised monolayers on permeable supports and treated bilaterally with alpha‐linolenic acid (ALA) (100 µM) for 1 – 24 hours, in the presence or absence of the FXR agonist, GW4064 (5 µM), or the PPARg antagonist, GW9662 (20 µM). Levels of FXR, FGF19, an index of FXR activation, and ANGPTL4, a PPAR target gene, were measured by qRT‐PCR, western blotting, or ELISA. Results: Treatment of T84 cells with ALA increased FXR expression in a time dependent fashion. Maximal effects of ALA occurred after 6 hrs when increases in FXR mRNA and protein were 8.65 ± 0.80 fold (n = 4; p < 0.01) and 4.44 ± 0.85 fold (n = 4) of untreated controls, respectively. Moreover, treatment of the cells with ALA potentiated GW4064‐induced expression of the FXR target gene, FGF‐19, at both mRNA and protein levels by 2.66 ± 0.56 (n = 4) and 5.52 ± 1.52 (n = 6), respectively. The effects of ALA on FXR expression and activity were mimicked by the PPARg agonist, rosiglitazone (1 mM). Treatment with ALA also significantly increased mRNA expression of the PPAR target gene, ANGPTL4, by 56.69 ± 5.7 (n = 4; p < 0.01), while the PPARg antagonist, GW9662 (20 µM; 1 hr), inhibited ALA‐induced FXR mRNA expression by 0.44 ± 0.12 fold (n =4) and protein by 0.23 ± 0.06 fold (n = 3). Conclusion: The dietary PUFA, ALA, regulates colonic epithelial FXR expression through mechanisms that involve activation of PPARγ. By virtue of their ability to upregulate FXR expression and activity, PUFAs, such as ALA, have excellent potential for development as FXR‐targeted nutraceuticals for the treatment and prevention of intestinal disease. [ABSTRACT FROM AUTHOR]

R4543 --> 582.2 --> Introduction: Bile acids classically known for their roles in dietary fat absorption are now recognized as hormones critical to regulating intestinal and metabolic function, including mucosal immune responses, epithelial proliferation/apoptosis, and transepithelial transport and barrier function. Downregulation of the nuclear bile acid receptor, farnesoid X receptor (FXR), in intestinal epithelium occurs in inflammatory bowel disease and colorectal cancer, whereas FXR activation prevents disease progression in pre‐clinical models. Thus strategies to upregulate epithelial FXR expression have been proposed to treat such conditions. Previous studies suggest that some plant‐derived phytochemicals have the capacity to modulate FXR activity. Plant sources have been reported to contain such phytochemicals, which are proposed to modulate FXR. Aim: The aim of the current study was to investigate the potential for developing plant extracts, rich in FXR‐modulating phytochemicals, as a novel nutraceutical‐based approach to treat and prevent intestinal diseases. Methods: T84 human colonic epithelial cells and primary cultures of murine colonic epithelial enteroids were employed to examine the effects of a common‐dietary phytochemical, denoted here as KFS1, and a KFS1‐rich plant extract on FXR expression and signaling in vitro. Ex vivo studies were carried out on human colonic tissue obtained during endoscopy with ethical approval from Beaumont Hospital. In vivo studies in C57BL/6 mice were carried out and proximal colonic tissue were examined with ethical approval from the HPRA. Expression of FXR and FGF19/15, an established marker of FXR activation, was assessed by qRT‐PCR, ELISA and immunoblotting. Data are expressed as mean ± SEM for a series of n experiments. Results: KFS1 treatment (5 µM; 24hrs) increased FXR mRNA and protein expression in T84 cells by 4.2 ± 0.4 (p<0.05; n = 4) and 1.7 ± 0.1 fold (p<0.05; n = 7) respectively. KFS1 also enhanced FGF19 protein expression in response to the FXR agonist GW4064 (5 µM), by 4.1 ± 0.5 fold (p<0.001; n = 7). Similarly KFS1 upregulated FXR expression by 2.1 ± 0.4 fold in human biopsies (p<0.05; n = 6). Oral KFS1 administration to mice had a tendency to upregulate colonic epithelial FXR signaling in vivo and increased FXR expression and GW4064‐induced FGF15 by 2.3 ± 0.2 (p<0.01; n = 4) and 2.2 ± 0.1 fold (p<0.01; n = 4) in murine colonic enteroids. Finally a methanolic KFS1‐rich plant extract, denoted QE1, verified by LC/MS to contain KFS1, increased FXR protein expression in vitro by 1.8 ± 0.2 fold (p<0.05; n = 5) and enhanced GW4064‐induced FGF19 protein by 1.9 ± 0.1 fold (p<0.01; n = 9). Conclusion: Our data demonstrate that KFS1‐containing plant extracts modulate expression and activity of FXR in the intestinal epithelium. Given the critical role of FXR in maintenance of gut health and metabolic function, such extracts have significant therapeutic and commercial potential to be developed as a novel first‐in‐class "FXR‐targeted nutraceutical" for treatment and prevention of common intestinal disorders. [ABSTRACT FROM AUTHOR]

R6019 --> 731.7 --> Introduction and Aims: CFTR, a Cl‐ channel important in regulating intestinal fluid and electrolyte secretion, is implicated in the pathogenesis of a number of intestinal disorders. We have previously shown that bile acids, acting via the nuclear receptor, farnesoid X receptor (FXR), inhibit colonic epithelial CFTR expression. Dietary phytochemicals have been reported to have the capacity to modulate FXR signalling. Here, we set out to investigate mechanisms underlying FXR regulation of CFTR expression, and the potential for therapeutically targeting the receptor with dietary phytochemicals. Methods: Monolayers of T84 colonic epithelial cells were treated with the FXR agonist, GW4064 (5 µM) in the absence or presence of a plant phytochemical, designated here as KFS1 (5 µM). mRNA and protein expression were measured by qPCR and Western blotting. FXR binding to the CFTR promoter was investigated by chromatin immunoprecipitation (ChIP). Electrophysiological studies of T84cells were conducted in Ussing chambers. Studies on human and murine enteroids were carried out with ethical approval from Johns Hopkins University School of Medicine Institutional Review Board and the Institutional Review Board of the University of California San Diego, respectively. Results: Treatment of T84 monolayers with GW4064 downregulated CFTR mRNA to 0.51 ± 0.06 fold after 12 hrs (n = 12; p < 0.001) and protein levels to 0.28 ± 0.06 fold after 48 hrs, compared to controls (n = 8; p < 0.001). Studies in Ussing chambers showed that GW4064 treatment for 48 hrs inhibited Cl‐ secretory responses to the Ca2+‐ and cAMP‐dependent agonists, carbachol (CCh; 100mM) and forskolin (FSK; 10mM), by 79.9 ± 7.5 % and 74.2 ± 8.9 %, respectively. Transcriptomic analysis of human colonic enteroids revealed FXR to be robustly expressed in secretory (crypt‐like) cells and that its activation also induced CFTR downregulation. FXR activation did not alter expression or phosphorylation of the p65 subunit of NF‐κB, or inhibit its translocation to the nucleus. ChIP‐qPCR analysis appears to show enhanced binding of FXR to the CFTR promoter upon GW4064 treatment. The phytochemical, KFS1 (5 mM; 24hrs), upregulated FXR mRNA and protein expression in T84 cells and enhanced GW4064‐induced downregulation of CFTR mRNA by 0.28 ± 0.05 fold (n = 8; p <0.01) and protein by 0.25 ± 0.11 fold (n = 4) after 24 hours. Similarly, KFS1 significantly upregulated FXR mRNA expression in murine colonic epithelial enteroids (2.3 ± 0.2; n = 4; p < 0.01) and enhanced GW4064‐induced downregulation of CFTR mRNA by 0.5 ± 0.1 fold (n = 4; p < 0.05) compared to GW4064 alone. Finally, KFS1 enhanced FXR inhibition of agonist‐induced Cl‐ secretory responses across T84 cells mounted in Ussing chambers. Conclusion: FXR regulates colonic epithelial CFTR expression and function by a mechanism which appears to involve direct binding of FXR to the CFTR promoter. By virtue of their ability to upregulate FXR expression, and thereby enhance its antisecretory actions, plant extracts containing KFS1 have excellent potential to be developed as FXR‐targeted nutraceuticals for the treatment and prevention of intestinal disease. [ABSTRACT FROM AUTHOR]