Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

IntroductionExtracellular matrix turnover, a ubiquitous dynamic biological process, can be diverted to fibrosis. The latter can affect the intestine as a serious complication of Inflammatory Bowel Diseases (IBD) and is resistant to current pharmacological interventions. It embosses the need for out-of-the-box approaches to identify and target molecular mechanisms of fibrosis.Methods and resultsIn this study, a novel mRNA sequencing dataset of 22 pairs of intestinal biopsies from the terminal ileum (TI) and the sigmoid of 7 patients with Crohn’s disease, 6 with ulcerative colitis and 9 control individuals (CI) served as a validation cohort of a core fibrotic transcriptomic signature (FIBSig), This signature, which was identified in publicly available data (839 samples from patients and healthy individuals) of 5 fibrotic disorders affecting different organs (GI tract, lung, skin, liver, kidney), encompasses 241 genes and the functional pathways which derive from their interactome. These genes were used in further bioinformatics co-expression analyses to elucidate the site-specific molecular background of intestinal fibrosis highlighting their involvement, particularly in the terminal ileum. We also confirmed different transcriptomic profiles of the sigmoid and terminal ileum in our validation cohort. Combining the results of these analyses we highlight 21 core hub genes within a larger single co-expression module, highly enriched in the terminal ileum of CD patients. Further pathway analysis revealed known and novel inflammation-regulated, fibrogenic pathways operating in the TI, such as IL-13 signaling and pyroptosis, respectively.DiscussionThese findings provide a rationale for the increased incidence of fibrosis at the terminal ileum of CD patients and highlight operating pathways in intestinal fibrosis for future evaluation with mechanistic and translational studies

A research of the motility of the stomach on diabetic patients

Background: Although it is apparent that gastrointestinal motor function is commonly disturbed in diabetes, the risk factors for its development, as well as its clinical consequences, remain controversial and poorly defined. Particularly, it is uncertain whether diabetic gastroparesis can be predicted based on clinical, demogaphic, or biochemical variables. The prevalence of upper gut dysmotility in patients with diabetes has been subject to debate for several years. Aims: After taken the aforementioned into account, the aim was to investigate the prevalence of delayed gastric emptying in a relatively large cohort of unselected patients and to examine the effect of domperidone on the rate of gastric emptying among these patients. This study also tested the hypothesis that some of the motor abnormalities observed in diabetic gastroparesis may be caused by elevations in plasma glucose levels irrespective of the concomitant presence of a visceral neuropathy. The other objective or this study was to define the predictors (determinants) of delayed gastric emptying in patients with diabetes. Research Design and Methods: The study group comprised 48 outpatients with diabetes mellitus (24 female, 24 male; age 16-71 years) and 14 asymptomatic healthy subjects (7 female, 7 male, age 28-59 years). Diabetics underwent upper endoscopy as a part of the diagnostic workup, in order to exclude lesions that can induce delay of gastric emptying. Helicobacter pylori was evaluated in each patient by rapid urease test (CLO test). Hp-positive diabetics received 10 days of Hp eradication regimen (omeprazole 20mg bid, amoxicillin 1000mg bid and clarithromycin 500mg bid). Patients who were symptomatic or presented with clear endoscopic findings followed a monthly treatment with PPIs (omeprazole 20mg bid). The gastric emptying of a standard mixed (solid/liquid) meal was evaluated using the paracetamol absorption method in patients with diabetes mellitus and in asymptomatic healthy subjects. Gastric emptying results were compared with a range established in healthy individuals. If gastric emptying was prolonged, a prokinetic agent was administered for a monthly duration (domperidone 10mg qid) and gastric emptying was reassessed with the paracetamol absorption method. Results: Diabetic patients had significantly delayed gastric emptying compared with controls (Mann-Whitney test: p=0,001). Of the 48 patients, gastric emptying was delayed in 31 (65%) patients. Hyperglycemia (?175mg/dl) induced prolonged gastric emptying (p=0,003)). There were no significant relationships between the gastric emptying results and age, gender and duration of the disease. A total of 29 (60,4%) diabetics had upper gastrointestinal symptoms. Upper abdominal pain and dyspepsia were the most common symptoms, occurring in 15 (31%) patients. There was a trend for a relationship between symptoms, delayed gastric emptying, plasma glucose levels and gender. Of the 48 patients, upper gastrointestinal endoscopic lesions were found in 28 (58,3%) patients. Endoscopic findings were correlated well (p=0,0001) with upper gastrointestinal symptoms. H. pylori infected 66,7% of the patients (32 out of 48). No significant differences were found between gender age and duration of diabetes with regard to infection status among diabetics. Moreover, significant difference was found between infected and uninfected asymptomatic diabetic patients (p=0,0001) with regard to endoscopic findings. Domperidone failed to improve gastric emptying in patients with diabetic gastroparesis (p=0,6) and this has been attributed to hyperglycemia. On the other hand, the administration of domperidone provided significant (66%) improvement in the upper gastrointestinal symptoms. Conclusions: Our study demonstrates that gastric emptying is often (65%) retarded in diabetic patients. Hyperglycemia disturbs gastric motility as this condition has been shown to delay gastric motor function in diabetics. Age, gender and duration of diabetes are not predictive of delayed gastric emptying. Gastrointestinal symptoms correlate weakly with measurements of gastric emptying. Prevalence of helicobacter infection was found to be significantly higher in diabetics than in general population. Finally, domperidone had no effect on gastric emptying and this appears to be due to hyperglycemia.Εισαγωγή: Μολονότι είναι γενικά αποδεκτό ότι ο Σακχαρώδης Διαβήτης (ΣΔ) προκαλεί συχνά δυσλειτουργία του γαστρεντερικού συστήματος, οι παράγοντες κινδύνου για την ανάπτυξή της καθώς και οι κλινικές συνέπειες αυτής παραμένουν αμφιλεγόμενες και μη επαρκώς διευκρινισμένες. Ειδικότερα είναι αβέβαιο εάν η διαβητική γαστροπάρεση μπορεί να προβλεφθεί με βάση κλινικές, δημογραφικές ή βιοχημικές πραμέτρους. Η συχνότητα εμφάνισης διαταραγμένης κινητικότητας του ανώτερου πεπτικού σε διαβητικούς ασθενείς αποτελεί σημείο επιστημονικής διαμάχης εδώ και αρκετά χρόνια. Σκοπός: Λαμβάνοντας υπόψη τα παραπάνω, σκοπός της μελέτης ήταν η διερεύνηση της συχνότητας εμφάνισης βραδείας γαστρικής κένωσης σε ένα σχετικά μεγάλο δείγμα διαβητικών ασθενών και η εξέταση της επίδρασης της δομπεριδόνης στην γαστρική κένωση των παραπάνω ασθενών.Ακόμη η παρούσα μελέτη εξέτασε την υπόθεση ότι τα αυξημένα επίπεδα γλυκόζης στο αίμα μπορεί να ευθύνονται για την διαβητική γαστροπάρεση, άσχετα με την ταυτόχρονη συνύπαρξη αυτόνομης νευροπάθειας. Υλικό και Μέθοδος: Η ομάδα μελέτης αποτελούνταν από 48 διαβητικούς των εξωτερικών ιατρείων (24 άνδρες, 24 γυναίκες, εύρος ηλικίας 16-71 έτη) και 14 ασυμπτωματικούς υγιείς μάρτυρες (7 άνδρες, 7 γυναίκες, εύρος ηλικίας 28-59 έτη). Οι διαβητικοί υποβλήθηκαν σε ενδοσκόπηση του ανώτερου πεπτικού, προκειμένου να διαγνωσθούν βλάβες που προκαλούν βραδεία γαστρική κένωση. Η διάγνωση της λοίμωξης με Helicobacter pylori ( Hp) γινόταν με την ταχεία δοκιμασία ουρεάσης (CLO test). Οι Hp-θετικοί ασθενείς ελάμβαναν αγωγή εκρίζωσης του Hp (ομεπραζόλη 20mg δις ημερησίως, αμοξυκιλλίνη 1000mg δις ημερησίως και κλαριθρομυκίνη 500mg δις ημερησίως) διάρκειας δέκα ημερών. Oι ασθενείς με συμπτώματα από το ανώτερο πεπτικό ή με ενδοσκοπικά ευρήματα ακολουθούσαν μηνιαία αγωγή με αναστολείς της αντλίας πρωτονίων (ομεπραζόλη 20mg δις ημερησίως). H ταχύτητα γαστρικής κένωσης ενός πρότυπου μεικτού (στερεάς/υγρής φάσης) γεύματος μετρήθηκε με την μέθοδο απορρόφησης παρακεταμόλης σε διαβητικούς ασθενείς και σε ασυμπτωματικούς υγιείς μάρτυρες. Τα αποτελέσματα της γαστρικής κένωσης εκτιμήθηκαν με βάση τις τιμές που προέκυψαν από τους υγιείς μάρτυρες. Εφόσον διαπιστωνόταν βραδεία γαστρική κένωση, χορηγούνταν προκινητικός παράγοντας (δομπεριδόνη 10mg τέσσερις φορές ημερησίως) για διάστημα μηνός και στη συνέχεια γινόταν επανεκτίμηση του αποτελέσματος με την μέθοδο απορρόφησης παρακεταμόλης

Addition of senna improves quality of colonoscopy preparation with magnesium citrate

AIM: To prospectively investigate the effectiveness and patient’s tolerance of two low-cost bowel cleansing preparation protocols based on magnesium citrate only or the combination of magnesium citrate and senna

Primary hepatic gastrinoma: Report of a case and review of literature

Primary hepatic gastrinoma is a very rare ectopic gastrinoma with less than 20 cases reported worldwide. We report the case of a patient with hypergastrinemia who was subjected to exhaustive preoperative and intraoperative imaging and also careful surgical exploration of the duodenum and pancreas which failed initially to identify the primary tumour. Eventually the patient was subjected to left liver lobectomy, as a small palpable lesion was noted intraoperatively. The diagnosis of gastrinoma requires a high index of clinical suspicion and the flawless cooperation of many specialties

The Probiotic Strains Bifidοbacterium lactis, Lactobacillus acidophilus, Lactiplantibacillus plantarum and Saccharomyces boulardii Regulate Wound Healing and Chemokine Responses in Human Intestinal Subepithelial Myofibroblasts

Bifidobacterium lactis, Lactobacillus acidophilus, Lactiplantibacillus plantarum and Saccharomyces boulardii are common probiotic supplements. Colonic subepithelial myofibroblasts (cSEMFs) are actively involved in mucosal wound healing and inflammation. cSEMFs, isolated from healthy individuals, were stimulated with 102 or 104 cfu/mL of these probiotic strains alone and in combination, and their effect on chemokine and wound healing factor expression was assessed by qRT-PCR, ELISA and Sircol Assay, and on cSEMFs migration, by Wound Healing Assay. These strains remained viable and altered cSEMFs’ inflammatory and wound healing behavior, depending on the strain and concentration. cSEMFs treated with a combination of the four probiotics had a moderate, but statistically significant, increase in the mRNA and/or protein expression of chemokines CXCL1, CXCL2, CXCL4, CXCL8, CXCL10, CCL2 and CCL5, and healing factors, collagen type I and III, fibronectin and tissue factor. In contrast, when each strain was administered alone, different effects were observed, with greater increase or decrease in chemokine and healing factor expression, which was balanced by the mixture. Overall, this study highlights that the use of multiple probiotic strains can potentially alert the gut mucosal immune system and promote wound healing, having a better effect on mucosal immunity than the use of single probiotics

Endothelin-1 Signaling Promotes Fibrosis In Vitro in a Bronchopulmonary Dysplasia Model by Activating the Extrinsic Coagulation Cascade

Neonatal respiratory distress syndrome can progress to bronchopulmonary dysplasia (BPD), a serious pulmonary fibrotic disorder. Given the involvement of the extrinsic coagulation cascade in animal models of lung fibrosis, we examined its role in BPD. We observed a higher number of neutrophils expressing tissue factor (TF) in bronchoalveolar lavage fluid (BALF) from infants with BPD than from those with uncomplicated respiratory distress syndrome together with a parallel decrease in TF and connective tissue growth factor (CTGF) in BALF supernatants during the disease course. The involvement of coagulation in the fibrotic process associated with BPD was further evaluated by treating primary human colonic myofibroblasts with BALF supernatants from infants with BPD. These human colonic myofibroblasts demonstrated an enhanced C5a- and thrombin-dependent migration. Moreover, they expressed TF in an endothelin-1-dependent manner, with subsequent activation of the extrinsic coagulation cascade and CTGF production mediated by protease-activator receptor-1 signaling. These data provide a novel mechanism for the development of BPD and indicate that endothelin-1 signaling contributes to fibrosis by upregulating a TF/thrombin amplification loop responsible for CTGF production, and offer novel and specific therapeutic targets for pulmonary fibrotic disease. The Journal of Immunology, 2011, 186: 6568-6575