A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families known to be produced by the microbiome have a profound impact on the balance between health and disease 1-9. Considering the diversity of the human microbiome, numbering over 40,000 operational taxonomic units 10 , the impact of the microbiome on the chemistry of an entire animal remains underexplored. In this study, mass spectrometry informatics and data visualization approaches 11-13 were used to provide an assessment of the impacts of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free (GF) and specific pathogen Reprints and/or permissions can be provided by R. Quinn or P.C. Dorrestein.
Over 70% of patients with cystic fibrosis have the DeltaF508 mutation. This protein is a partially functional chloride (Cl-) channel that is prematurely degraded in the endoplasmic reticulum. Specific members of the flavonoid class of compounds have been shown to increase Cl- conductance of wild-type and DeltaF508 cystic fibrosis transmembrane regulator (CFTR). Although flavonoid effects on CFTR processing are unknown, evidence of effects on heat shock proteins, specifically those that have been shown to interact with CFTR, led us to believe that there would be an effect on CFTR processing through modulation of CFTR-chaperone interactions. We sought to determine (i) the effect of apigenin, genistein, kaempferol, and quercetin on CFTR processing in IB3-1 cells (F508/W1282X) and (ii) whether sequential treatment with 4-phenylbutyrate (4-PBA) to increase CFTR processing and flavonoid to directly stimulate CFTR would increase Cl- conductance. Our results show no significant effect on CFTR processing as measured by immunoblotting with 1 microM or 5 microM of apigenin, genistein, kaempferol, or quercetin. However, despite no effect on CFTR processing as determined by immunoblot, immunofluorescence demonstrated a favorable change in the intracellular distribution of CFTR with 24 h treatments of apigenin, kaempferol, and genistein. Furthermore, we observed an increase in Cl- conductance as measured by Cl- efflux in cells that were treated for 24 h with 4-PBA and then assayed with forskolin and 1 microM or 5 microM genistein, and also with cells treated for 24 h with either 4-PBA, 5 microM apigenin, or 1 microM quercetin. Thus, a combination of chronic treatment with 4-PBA or select flavonoids, followed by acute flavonoid exposure, may be beneficial in cystic fibrosis.
Exocrine pancreatic insufficiency (EPI), which leads to malabsorption and poor weight gain, is seen in 85% of patients with cystic fibrosis (CF). EPI is treated with pancreatic enzyme replacement therapy taken with each meal. The highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator, ivacaftor, restores CFTR function in patients with responsive mutations. It is a widely held view that EPI in CF is irreversible due to the complete destruction of pancreatic ducts and acinar cells. We describe three pediatric CF patients with EPI who were started on ivacaftor, and subsequently showed evidence of restored exocrine pancreatic function with clinical and biochemical parameters.
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