Project description:Background: A recently developed animal model of the genetic disease is the cystic fibrosis (CF) rat, which similar to other animal models of CF exhibits a lethal intestinal phenotype. To begin characterizing the CF rat intestinal phenotype, we investigated global gene expression in the CF rat small intestine. Methods: Total RNA was extracted from full thickness of the entire small intestines of wild type (WT) and CF rats just before weaning. Results: There were 890 genes with significantly different expression levels (1.2-fold cutoff) comparing CF to wild type (WT), including 485 genes increased and 405 decreased in the CF intestine. The major pathways associated with these changes were inflammation, lipid metabolism, cytochrome P450-mediated degradative pathways, and cell growth/death. Comparison of the rat RNA-Seq dataset to earlier microarray analysis using a CFTR knockout mouse showed significant overlap with the CF rat small intestine. Conclusions: The small intestine of the new CF rat model exhibits numerous alterations in gene expression similar to other animal models of CF which indicate this will be an additional new model to study the gut effects CF.
Project description:This study aimed to compare – at a multi-omics level, inflammation, protease abundance and activity, microbiome, and proteome in sputum samples from patients with cystic fibrosis (CF, n=38) or chronic obstructive pulmonary disease (COPD, n=18) and healthy controls (n=10) to identify shared and unique pathways between these respiratory conditions. Sputum analysis revealed elevated inflammatory cell counts in both CF and COPD patients, with neutrophils being the dominant cell type. Key inflammatory markers, including IL-1β, TNF-α, TGF-β1, IL-8, and LTB4, were increased in both disease groups, with the highest levels observed in CF. Conversely, COPD patients exhibited higher levels of IL-5, IL-6, and IL-10. Microbiome analysis showed distinct clusters for each group, with CF patients often characterized by a preponderance of Pseudomonas. Hierarchical clustering unveiled robust interdependencies between microbiome parameters and inflammation, a richer and more diverse microbiome was associated with a healthier microbial community. This study uncovered significant disparities in inflammation, microbiome composition, and proteome profiles among CF, COPD, and healthy control cohorts. Neutrophilic inflammation and protease activity emerged as common factors in both diseases highlighting proteases as good targets for both indications, while distinct microbial signatures were identified. These findings offer valuable insights into the underlying mechanisms of CF and COPD and may inform future clinical strategies.
Project description:Rationale: We recently demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves lung ventilation and airway mucus plugging determined by multiple-breath washout and magnetic resonance imaging in CF patients with at least one F508del allele. However, effects of ELX/TEZ/IVA on viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. Objectives: To examine the effects of ELX/TEZ/IVA on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged 12 years and older. Methods: In this prospective observational study, we determined sputum rheology, microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ELX/TEZ/IVA. Measurements and Main Results: CF patients with at least one F508del allele and healthy controls were enrolled in this study. ELX/TEZ/IVA improved the elastic and viscous modulus of CF sputum. Further, ELX/TEZ/IVA improved the microbiome α-diversity and decreased the relative abundance of Pseudomonas aeruginosa (P<0.05) in CF sputum. ELX/TEZ/IVA also reduced IL-8 and free NE activity, and shifted the CF sputum proteome towards healthy. Conclusions: Our data demonstrate that ELX/TEZ/IVA improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele, however, without reaching levels close to healthy.
Project description:In this study, we investigated whether miRNA deregulation might underlie the functional abnormalities of cystic fibrosis (CF) macrophages. To this aim we performed miRNA profiling in macrophages from CF and non-CF macrophages. This led to the identification of a panel of differentially expressed miRNAs in CF macrophages compared to non-CF cells.
Project description:We explore whether a low-energy diet intervention for Metabolic dysfunction-associated steatohepatitis (MASH) improves liver disease by means of modulating the gut microbiome. 16 individuals were given a low-energy diet (880 kcal, consisting of bars, soups, and shakes) for 12 weeks, followed by a stepped re-introduction to whole for an additional 12 weeks. Stool samples were obtained at 0, 12, and 24 weeks for microbiome analysis. Fecal microbiome were measured using 16S rRNA gene sequencing. Positive control (Zymo DNA standard D6305) and negative control (PBS extraction) were included in the sequencing. We found that low-energy diet improved MASH disease without lasting alterations to the gut microbiome.