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      Impact of CFTR modulation with Ivacaftor on Gut Microbiota and Intestinal Inflammation

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          Abstract

          Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Next to progressive airway disease, CF is also associated with intestinal inflammation and dysbiosis. Ivacaftor, a CFTR potentiator, has improved pulmonary and nutritional status but its effects on the intestinal microbiota and inflammation are unclear. Hence, we assessed the changes on the intestinal microbial communities (16S rRNA variable 3 gene region) and inflammatory markers (calprotectin and M2-pyruvate kinase [M2-PK]) in 16 CF individuals (8 children and 8 adults) before and after (median 6.1 months) ivacaftor. Stool calprotectin significantly decreased following ivacaftor (median [IQR]: 154.4 [102.1–284.2] vs. 87.5 [19.5–190.2] mg/kg, P = 0.03). There was a significant increase in Akkermansia with ivacaftor. Increased abundance of Akkermansia was associated with normal stool M2-PK concentrations, and decreased abundances of Enterobacteriaceae correlated with decreased stool calprotectin concentrations. In summary, changes in the gut microbiome and decrease in intestinal inflammation was associated with Ivacaftor treatment among individuals with CF carrying at least one gating CFTR mutation. Thus, CFTR-modifying therapy may adequately improve the aberrant pathophysiology and milieu of the CF gut to favor a more healthy microbiota, which in turn reduces intestinal inflammation.

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          Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice

          Recent evidence indicates that the gut microbiota plays a key role in the pathophysiology of obesity. Indeed, diet-induced obesity (DIO) has been associated to substantial changes in gut microbiota composition in rodent models. In the context of obesity, enhanced adiposity is accompanied by low-grade inflammation of this tissue but the exact link with gut microbial community remains unknown. In this report, we studied the consequences of high-fat diet (HFD) administration on metabolic parameters and gut microbiota composition over different periods of time. We found that Akkermansia muciniphila abundance was strongly and negatively affected by age and HFD feeding and to a lower extend Bilophila wadsworthia was the only taxa following an opposite trend. Different approaches, including multifactorial analysis, showed that these changes in Akkermansia muciniphila were robustly correlated with the expression of lipid metabolism and inflammation markers in adipose tissue, as well as several circulating parameters (i.e., glucose, insulin, triglycerides, leptin) from DIO mice. Thus, our data shows the existence of a link between gut Akkermansia muciniphila abundance and adipose tissue homeostasis on the onset of obesity, thus reinforcing the beneficial role of this bacterium on metabolism.
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            Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study.

            Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown.
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              Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin.

              MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca(2+) it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. The MUC2-N aggregates were dissolved by removing Ca(2+) and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion.
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                Author and article information

                Contributors
                keith.ooi@unsw.edu.au
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                13 December 2018
                13 December 2018
                2018
                : 8
                : 17834
                Affiliations
                [1 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, School of Women’s and Children’s Health, Medicine, , The University of New South Wales, ; Sydney, NSW Australia
                [2 ]ISNI 0000 0001 1282 788X, GRID grid.414009.8, Molecular and Integrative Cystic Fibrosis (miCF) Research Centre, , Sydney Children’s Hospital, ; Randwick, NSW Australia
                [3 ]ISNI 0000 0001 1282 788X, GRID grid.414009.8, Department of Gastroenterology, , Sydney Children’s Hospital, ; Randwick, NSW Australia
                [4 ]ISNI 0000 0004 1936 8227, GRID grid.25073.33, Department of Medicine, , McMaster University, Hamilton, ; Ontario, Canada
                [5 ]ISNI 0000 0004 1936 8227, GRID grid.25073.33, Department of Biochemistry & Biomedical Sciences, , McMaster University, ; Hamilton, ON Canada
                [6 ]ISNI 0000 0004 1936 8227, GRID grid.25073.33, Farncombe Family Digestive Health Research Institute, , McMaster University, ; Hamilton, ON Canada
                [7 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Department of Paediatrics, Division of Gastroenterology, , Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ; Ontario, Canada
                [8 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Translational Medicine, Research Institute, , The Hospital for Sick Children, Toronto, ; Ontario, Canada
                Author information
                http://orcid.org/0000-0001-7111-0926
                http://orcid.org/0000-0002-0936-1828
                Article
                36364
                10.1038/s41598-018-36364-6
                6292911
                30546102
                56e00c29-9eea-4f8c-93f2-0b0ab093b5bd
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 June 2018
                : 9 November 2018
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