Orlaith B. Kelly

Ursodeoxycholic acid attenuates colonic epithelial secretory function.

•  Although diarrhoeal diseases represent a significant health and economic burden to society, therapeutic options remain limited. •  While several bile acids are known to stimulate epithelial Cl− secretion, the major driving force for fluid secretion in the intestine, the effects of ursodeoxycholic acid (UDCA) on epithelial transport function are not well described. •  We report that in contrast to other bile acids, UDCA exerts anti‐secretory actions on colonic epithelial cells in vitro. •  In contrast, in vivo administration of UDCA enhances epithelial secretory function, an affect we ascribe to being due to its bacterial metabolism to lithocholic acid. In keeping with this hypothesis, in vivo administration of a metabolically stable analogue of UDCA, 6α‐methyl‐UDCA, was anti‐secretory. •  Our findings reveal novel anti‐secretory actions of UDCA and suggest that metabolically stable analogues of bile acid may be useful for development as a new class of anti‐diarrhoeal drug.

The importance of microbiological investigations, medications and artificial feeding in diarrhoea evaluation.

BackgroundDiarrhoea in hospitalised patients is usually attributed to medications especially antibiotics, enteral tube feeding or enteropathogenic bacteria particularlyClostridium difficile.AimsThe aim of this study was to evaluate the investigations performed on patients who developed diarrhoea during their stay in an acute general hospital.MethodOver 18 working days, an unselected group of adult inpatients who developed diarrhoea following their admission to hospital were reviewed. Symptoms, medications, nutritional support and any investigations performed were assessed.ResultsEighty-one patients developed diarrhoea. Forty-nine (60%) were receiving antibiotics prior to the development of symptoms, 30 (37%) were being enterally tube fed, 14 (17%) had positive stool forClostridium difficile A and B toxin and 3 (4%) had salmonella species positive stool.ConclusionThe majority of cases of diarrhoea were related to medications and enteral tube feeding. A small but significant number did develop bacterial infections. In contrast to some suggested guidelines, when investigating hospital acquired diarrhoea, it is considered worthwhile to perform microbiological stool examinations.

Chronic regulation of colonic epithelial secretory function by activation of G protein-coupled receptors.

Background  Enteric neurotransmitters that act at G protein‐coupled receptors (GPCRs) are well known to acutely promote epithelial Cl− and fluid secretion. Here we examined if acute GPCR activation might have more long‐term consequences for epithelial secretory function.

Su1405 The Safety of Biologic Use in the Pregnant IBD Patient: Analysis of Patient Characteristics, Pregnancy and Neonatal Outcomes

Background: TNF alpha inhibitors are being increasingly used in IBD in women of fertile age. Studies to date have been mainly limited to case reports and case series with the largest observational cohort from 50 centres in the US. We aimed to prospectively assess the use of anti TNF treatment during pregnancy in a large European cohort. Methods: This was an observational cohort study addressing a 5 year period between 2008-2013. Female patients with IBD who had undergone anti-TNF treatment during pregnancy were identified using the IBD databases of 2 tertiary referral centres for IBD in Dublin. Patient characteristics including disease activity scores, duration, site and concomitant medications were recorded. Pregnancy outcomes including mode of delivery, miscarriage, ante and postnatal complications, age at conception and need for escalation of IBD treatment during pregnancy were also assessed. Neonatal outcomes including low birth weight, pre-term delivery, NICU stays or perinatal infection and timing of vaccines were also recorded. Data were analysed using t testing, contingency and logistic regression analyses. Results: From an IBD population of over 2,500 patients, 31 individual females who underwent anti -TNF treatment during pregnancy from 2008-2013 were identified with a total of 36 pregnancies. Median disease duration at time of pregnancy was 12 years (IQR 3-17). 85% had Crohns Disease, 15% Ulcerative Colitis. Median Harvey Bradshaw Index pre-pregnancy was 4.5 (IQR 2-13). Median Mayo score was 1 (IQR 0-3). 57.3% received infliximab, 38% adalimumab, 4.7% certolizimab. 53.8% were on concomitant immunemodulators. The majority of patients stopped biologic treatment at the start of the third trimester. 67% had treatment reinstated in the postpartum period. Median age at conception was 30.5 (IQR 25-35). 19% had previous miscarriages. 92% had successful term pregnancies. 22% required escalation of treatment during pregnancy. 19.3% had a pregnancy complication including emergency section. 16% neonates had a low birth weight with 2 preterm deliveries and one case of NICU stay for meconium ileus. No perinatal infections were reported. 20%mothers breastfed. The majority of mothers delayed live vaccination of their children. Interestingly, there was a significant independent association between disease activity at time of conception and low birthweight (p < 0.01). There was no association between adverse outcomes or neonatal infections and anti-TNF use noted in this cohort.Conclusion: Disease control at time of conception and through pregnancy should be the main goal of treatment in this patient cohort and the use of TNF alpha antagonists to achieve this appears to warranted to improve pregnancy outcomes though definitive safety has yet to be proven.

Su1616 The Inappropriate Prescription of Proton Pump Inhibitor Therapy in a Hospital Setting

BACKGROUNDS AND AIMS: Proton-pump inhibitor is more effective for gastric acid control in Asian than Western population possible because of high prevalence of poor metabolizing CYP2C19 genotype in Asian people. The aim of this study was to evaluate the effect of low dose intravenous (IV) bolus vs. standard recommended dose continuous IV infusion of omeprazole in Thai healthy volunteers with extensive metabolizing CYP2C19 genotype. METHODS: 8 healthy subjects (age 30±6yr, 5 F, BMI 24±3 kg/m2) with extensive metabolizing CYP2C19 genotype were randomized to receive either omeprazole 80mg IV bolus followed by 40 mg IV bolus every 12 hr or omeprazole 80mg IV bolus followed by 8mg/ hr continuous infusion for 48 hr. The gastric pH was monitored by a pH catheter with a data logger (DIGITRAPPER pH 400, Medtronic A/S) for 2 days during the omeprazole treatment peroids. The gastric pH sensor was positioned at 10 cm below the lower esophageal sphincter located by esophageal manometry. All subjects were allowed to consume 3 standard meals/day. RESULTS : The mean gastric pH for IV bolus was significantly lower than continuous infusion only on day 1 [6.2±1.0 vs. 7.1±0.6 (p 6 for IV bolus was also significantly lower compared to continuous infusion only on day 1(66.2±22.7% vs. 84.7±17.3%)(p 6 for the entire 48-hr study was significantly lower for IV bolus compared to continuous infusion (69.9±12.6% vs. 83.0±13.8%, p 24 had similar intragastric pH during both IV bolus and IV continuous infusion of omeprazole (IV bolus, BMI 24: 6.4±0.9 vs. 6.3±0.4) (continuous drip; 7.1±0.3 vs. 6.8±0.6)(p>0.05). CONCLUSION: Continuous IV infusion of standard recommended dose of omeprazole provided better gastric acid control compared to lower dose IV bolus only during the first day but not on the second day. Although the continuous IV infusion was more effective both standard dose continuous IV infusion and low dose IV bolus omeprazole was effective for gastric pH control in Thai healthy volunteers with extensive metabolizing CYP2C19 genotypes. The better gastric acid control compared to those reported in healthy volunteers in Western countries suggests the role of other factor(s), beside the CYP2C19 genotype, on gastric acid inhibition effect of IV omeprazole.

Ursodeoxycholic Acid Stimulates CA2+ Influx and Exerts Antisecretory Actions in Colonic Epithelial Cells

Background Previously, we have shown that ursodeoxycholic acid (UDCA) exerts antisecretory effects In Vitro and thus may represent a novel therapeutic target in treating intestinal disorders associated with diarrhea. These antisecretory effects are mediated by inhibition of basolateral Na+/K+-ATPase pumps and K+ currents, key components of the Clsecretory pathway. Here, we aimed to further elucidate molecular mechanisms underlying the antisecretory actions of UDCA. Methods Clsecretion was measured as changes in short-circuit current (Isc) across voltage-clamped T84 cell monolayers. Intracellular Ca2+ was measured by fluorescence imaging and cAMP using a commercially available assay. Results As previously reported, UDCA inhibited secretory responses to both Ca2+and cAMP-dependent agonists in T84cells. Antisecretory effects of UDCA were very rapid in onset being apparent within 1 minute of addition. Apical addition of TUDCA, the taurine conjugated, membrane-impermeable derivative of UDCA, reduced CCh-induced secretory responses to 60 ± 10.9% of controls, suggesting the bile acid exerts its effects through interactions with the membrane, rather than intracellularly. Even though it did not stimulate secretory responses, UDCA (50 μM) rapidly elevated intracellular levels of Ca2+ (ΔF340/380 = 0.2995 ± 0.04) in T84 cells (n = 12). UDCA also inhibited subsequent Ca2+ mobilization responses to CCh by 63 ± 0.573% compared to controls (n = 10, p < 0.01). Removal of Ca2+ from the extracellular bathing solution abolished UDCA-induced Ca2+ elevations (n = 5, p < 0.01) but had minimal effects on CCh-induced peak Ca2+ responses. UDCA did not alter FSK-induced elevations in intracellular cAMP levels. Conclusion: These data suggest that UDCA elevates intracellular Ca2+ in colonic epithelial cells through an interaction with the cell membrane and stimulation of Ca2+influx. In contrast to the well-described prosecretory actions of Ca2+ released from intracellular stores, influx of extracellular Ca2+ induced by UDCA appears to be antisecretory. These data provide intriguing new insights into the mechanisms by which UDCA exerts antisecretory actions in the colon.