Genetic analyses of celiac disease in a Spanish population confirm association with CELIAC3 but not with CELIAC4

[EN] Genetic predisposition to celiac disease (CD) is determined primarily by the human leukocyte antigen (HLA) genes (CELIAC1 region; 6p21), although many loci are involved in disease susceptibility. First, we have analysed a large series of CD patients from the Spanish Mediterranean region who had previously been characterised for the HLA complex. We have investigated how relevant regions contribute to CD susceptibility: CELIAC3 (CD28/CTLA4/ICOS region on 2q33) and CELIAC4 (19p13) as well as the tumour necrosis factor alpha (TNF-alpha) and the linfotoxin loci by case-control and association analyses. We highlight the association with the +49*A allele of cytotoxic T-lymphocyte-associated antigen 4 locus (P = 0.01), and the -308*A of TNF-alpha locus (P = 0.0008) in DQ2 individuals, although an independent role for TNF-alpha as risk factor has not been proven. Moreover, we do not confirm the association with the CELIAC4 region polymorphisms described in other populations.We are grateful for the kind collaboration of patients and families and Asociación de Celíacos de la Comunidad Valenciana (ACECOVA). This work was supported by the Fondo de Investigacio¿n Sanitaria (grant PI02573) and by the CSIC Intramural Frontiers Project (PROFICEL). ED holds a fellowship from the Fundacio¿n La Fe. English text revised by F. BarracloughCapilla, A.; Donat, E.; Planelles, D.; Espinós-Armero, CÁ.; Ribes-Koninckx, C.; Palau, F. (2007). Genetic analyses of celiac disease in a Spanish population confirm association with CELIAC3 but not with CELIAC4. Tissue Antigens. 70(4):324-329. https://doi.org/10.1111/j.1399-0039.2007.00899.x32432970

A first approach for an evidence-based in vitro digestion method to adjust pancreatic enzyme replacement therapy in cystic fibrosis

[EN] Background Patients with cystic fibrosis have to take enzymatic supplements to allow for food digestion. However, an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy (PERT) is inexistent, and lipid content of meals is used as a rough criterion. Objective In this study, an in vitro digestion model was set up to determine the theoretical optimal dose (TOD) of enzymatic supplement for a selection of foods, which is the dose that allows for maximum lipolysis extent. Methods A static in vitro digestion model was applied to simulate digestion of eight foods covering a wide range of lipid contents. First, the dose of the enzymatic supplement was fixed at 2000 lipase units per gram of fat (LU/g fat) using intestinal pH and bile salt concentration as variables. Second, intestinal pH and bile salt concentrations were fixed and the variable was the dose of the enzymatic supplement. Lipolysis extent was determined by measuring the free fatty acids released from initial triglycerides content of foods after digestion. Results in terms of percentage of lipolysis extent were fitted into a linear-mixed segmented model and the deducted equations were used to predict the TOD to reach 90% of lipolysis in every food. In addition, the effect of intestinal pH and bile salt concentration were investigated. Results The predictive equations obtained for the assessed foods showed that lipolysis was not only dependent on the dose of the enzyme supplement or the lipid content. Moreover, intestinal pH and bile salt concentration had significant effects on lipolysis. Therefore an evidence-based model can be developed taking into account these variables. Conclusions Depending on food characteristics, a specific TOD should be assigned to achieve an optimal digestion extent. This work represents a first step towards an evidence-based method for PERT dosing, which will be applied in an in vivo setting to validate its efficacy.This work was fully funded by the European Union and the Horizon 2020 Research and Innovation Framework Programme (PHC-26-2014 call Self management of health and disease: citizen engagement and mHealth) under grant number 643806.Calvo-Lerma, J.; Fornes-Ferrer, V.; Peinado Pardo, I.; Heredia Gutiérrez, AB.; Ribes-Koninckx C.; Andrés Grau, AM. (2019). A first approach for an evidence-based in vitro digestion method to adjust pancreatic enzyme replacement therapy in cystic fibrosis. PLoS ONE. 14(2):1-14. https://doi.org/10.1371/journal.pone.0212459S114142Lesmes, U., & McClements, D. J. (2012). Controlling lipid digestibility: Response of lipid droplets coated by β-lactoglobulin-dextran Maillard conjugates to simulated gastrointestinal conditions. Food Hydrocolloids, 26(1), 221-230. doi:10.1016/j.foodhyd.2011.05.011Humbert, L., Rainteau, D., Tuvignon, N., Wolf, C., Seksik, P., Laugier, R., & Carrière, F. (2018). Postprandial bile acid levels in intestine and plasma reveal altered biliary circulation in chronic pancreatitis patients. Journal of Lipid Research, 59(11), 2202-2213. doi:10.1194/jlr.m084830Lamothe, S., Azimy, N., Bazinet, L., Couillard, C., & Britten, M. (2014). Interaction of green tea polyphenols with dairy matrices in a simulated gastrointestinal environment. Food Funct., 5(10), 2621-2631. doi:10.1039/c4fo00203bMuggeo, V. & Muggeo, V. M. R. Segmented mixed models with random changepoints in R Working paper (2016)

Association between faecal pH and fat absorption in children with cystic fibrosis on a controlled diet and enzyme supplements dose

[EN] Background Despite treatment with pancreatic enzyme replacement therapy (PERT), patients with cystic fibrosis (CF) can still suffer from fat malabsorption. A cause could be low intestinal pH disabling PERT. The aim of this study was to assess the association between faecal pH (as intestinal pH surrogate) and coefficient of fat absorption (CFA). Additionally, faecal free fatty acids (FFAs) were quantified to determine the amount of digested, but unabsorbed fat. Methods In a 24-h pilot study, CF patients followed a standardised diet with fixed PERT doses, corresponding to theoretical optimal doses determined by an in vitro digestion model. Study variables were faecal pH, fat and FFA excretion, CFA and transit time. Linear mixed regression models were applied to explore associations. Results In 43 patients, median (1st, 3rd quartile) faecal pH and CFA were 6.1% (5.8, 6.4) and 90% (84, 94), and they were positively associated (p < 0.001). An inverse relationship was found between faecal pH and total fat excretion (p < 0.01), as well as total FFA (p = 0.048). Higher faecal pH was associated with longer intestinal transit time (p = 0.049) and the use of proton pump inhibitors (p = 0.009). Conclusions Although the clinical significance of faecal pH is not fully defined, its usefulness as a surrogate biomarker for intestinal pH should be further explored. Impact Faecal pH is a physiological parameter that may be related to intestinal pH and may provide important physiopathological information on CF-related pancreatic insufficiency. Faecal pH is correlated with fat absorption, and this may explain why pancreatic enzyme replacement therapy is not effective in all patients with malabsorption related to CF. Use of proton pump inhibitors is associated to higher values of faecal pH. Faecal pH could be used as a surrogate biomarker to routinely monitor the efficacy of pancreatic enzyme replacement therapy in clinical practice. Strategies to increase intestinal pH in children with cystic fibrosis should be targeted.We acknowledge the support of the MyCyFAPP Project consortium. We especially thank the participation and the effort of the patients involved in the study and their families. This work was fully funded by the European Union and the Horizon 2020 Research and Innovation Framework Programme (PHC-26-2014 call Self management of health and disease: citizen engagement and mHealth) under grant number 643806.Calvo-Lerma, J.; Roca-Llorens, M.; Boon, M.; Colombo, C.; De Koning, B.; Fornés-Ferrer, V.; Masip, E.... (2021). Association between faecal pH and fat absorption in children with cystic fibrosis on a controlled diet and enzyme supplements dose. Pediatric Research. 89(1):205-210. https://doi.org/10.1038/s41390-020-0860-3S205210891Turck, D. et al. ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin. Nutr. 35, 557–577 (2016).Borowitz, D., Baker, R. 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