Serenella Bertasi

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Allelic Variants Relate to Shifts in Faecal Microbiota of Cystic Fibrosis Patients

Introduction In this study we investigated the effects of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene variants on the composition of faecal microbiota, in patients affected by Cystic Fibrosis (CF). CFTR mutations (F508del is the most common) lead to a decreased secretion of chloride/water, and to mucus sticky secretions, in pancreas, respiratory and gastrointestinal tracts. Intestinal manifestations are underestimated in CF, leading to ileum meconium at birth, or small bowel bacterial overgrowth in adult age. Methods Thirty-six CF patients, fasting and under no-antibiotic treatment, were CFTR genotyped on both alleles. Faecal samples were subjected to molecular microbial profiling through Temporal Temperature Gradient Electrophoresis and species-specific PCR. Ecological parameters and multivariate algorithms were employed to find out if CFTR variants could be related to the microbiota structure. Results Patients were classified by two different criteria: 1) presence/absence of F508del mutation; 2) disease severity in heterozygous and homozygous F508del patients. We found that homozygous-F508del and severe CF patients exhibited an enhanced dysbiotic faecal microbiota composition, even within the CF cohort itself, with higher biodiversity and evenness. We also found, by species-specific PCR, that potentially harmful species (Escherichia coli and Eubacterium biforme) were abundant in homozygous-F508del and severe CF patients, while beneficial species (Faecalibacterium prausnitzii, Bifidobacterium spp., and Eubacterium limosum) were reduced. Conclusions This is the first report that establishes a link among CFTR variants and shifts in faecal microbiota, opening the way to studies that perceive CF as a ‘systemic disease’, linking the lung and the gut in a joined axis.

Effect of a medium dose of ursodeoxycholic acid with or without taurine supplementation on the nutritional status of patients with cystic fibrosis: a randomized, placebo-controlled, crossover trial

Ursodeoxycholic acid administration has been reported to improve cholestasis and inflammatory activity in primary biliary cirrhosis and, in an uncontrolled study, also in young adults with cystic fibrosis (CF) and chronic cholestasis. As an improvement in nutritional status was also observed in these young adult patients, we investigated whether the administration of a medium dose of ursodeoxycholic acid ameliorates the nutritional status of malnourished young adult CF patients with chronic liver disease. The study included 51 patients (27 male patients and 24 female patients; age range, 8–32 years; median, 14) with body mass percentiles < 90%. Patients were randomly assigned to receive either ursodeoxycholic acid (10–12 mg/kg/day) alone or with taurine (18–22 mg/kg/day). Patients were followed in a crossover fashion within each group; 6 months of treatment was randomly alternated with 6 months of placebo. Nine patients dropped out before concluding the study. Liver function tests, nutritional status, and coefficients of fat absorption were determined at entry and after each 6 months of placebo or treatment. Nutritional status and fat absorption were not significantly modified by either treatment. Liver function tests improved after ursodeoxycholic acid administration only in patients with concomitant chronic liver disease. Our findings indicate that 6 months of therapy with a medium dose of ursodeoxycholic acid, either alone or with taurine, does not improve the nutritional status of young malnourished CF patients. Higher doses given for longer periods might be worth investigating.

Slow-release insulin in cystic fibrosis patients with glucose intolerance: A randomized clinical trial

Minicucci L, Haupt M, Casciaro R, De Alessandri A, Bagnasco F, Lucidi V, Notarnicola S, Lorini R, Bertasi S, Raia V, Cialdella P, Haupt R. Slow‐release insulin in cystic fibrosis patients with glucose intolerance: a randomized clinical trial.

A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis.

Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype-phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype-phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype-phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway.

WS9.5 The role of daily physical activity on exercise performance in adults with cystic fibrosis

WS9.5 The role of daily physical activity on exercise performance in adults with cystic fibrosis D. Savi1, M. Di Paolo2, N.J. Simmonds3, T. Perelli1, M. Varchetta1, S. Bertasi1, G. Cimino1, P. Troiani1, V. D’Alù1, S. Quattrucci1, S. Cucchiara1, P. Palange2. 1Sapienza University of Rome, Department of Pediatrics and Pediatric Neurology, Cystic Fibrosis Center, Rome, Italy; 2Sapienza University of Rome, Department of Public Health and Infectious Diseases, Rome, Italy; 3Royal Brompton Hospital and Imperial College, Department of Cystic Fibrosis, London, United Kingdom

307 Kidney transplantation after lung transplantation in cystic fibrosis patients

Objectives: Long term survival after lung transplantation has significantly improved during the last 10 years. On the other hand, complications have increased. Renal diseases, most probably related to the immunosuppression therapy and cystic fibrosis therapy such as antibiotic threrapy, are important complications during the followup. Methods: During the period November 1996 up to now 84 lung transplantation recipients with with cystic fibrosis (40 males) followed in our center according to a pre-established follow-up protocol for Tx patients: During the follow-up period all patients developed renal complications. The mean time of occurrence after lung transplantation was 12 months. All patients have reduced immunosuppression therapy during the follow-up period (in 10 patient Tacrolimus was changed to Rapamycin) Three patients (2 females) developed severe renal complications after 8, 10, 13 years after lung transplantation, and underwent kidney transplantation. Two pts are alive after 4 and 1 year after renal transplantation with good pulmonary function (FEV1 65% and 85% predicted) normal creatinine serum level and good creatinine clereance. One pt (female) died after 1 year after renal transplantation due to bronchiolitis obliterans syndrome. Conclusion: Renal diseases after lung transplantation are an important complication; A multidisciplinary approach is needed since the beginning of the followup, in order to obtain precocious diagnosis and establish an adequate therapy. Kidney transplantation for our opinion is a good opportunity in pts with severe renal complication. 308 Temporal bone pneumatization in adult patients with cystic fibrosis M.C. Berkhout1, C.J. van Rooden2, R.C. Aalbers3, E. Rijntjes3, L.H. el Bouazzaoui1, H.G.M. Heijerman1. 1Haga Teaching Hospital, Pulmonary Diseases, The Hague, Netherlands; 2Haga Teaching Hospital, Radiology, The Hague, Netherlands; 3Haga Teaching Hospital, Otorhinolaryngology, The Hague, Netherlands