CFTR dysregulation drives active selection of the gut microbiome

Meeker, Stacey; Mears, Kevin S; Sangwan, Naseer; Brittnacher, M.; Weiss, Eli; Treuting, Piper M.; Tolley, Nicholas; Pope, Charles E.; Hager, Kyle R.; Vo, Anh T.; Paik, Ji-Sun; Frevert, Charles W.; Hayden, Hillary S.; Hoffman, Lucas R.; Miller, Samuel I.; Hajjar, Adeline M.

doi:10.1371/journal.ppat.1008251

Cited by 64 publications

(85 citation statements)

References 48 publications

(71 reference statements)

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“…Preclinical animal models are a prerequisite to test therapeutic strategies targeting the gut microbiomes of CF patients. To date, almost all CF animal gut microbiome studies have used mice [ 16 , 17 , 18 ]. Interestingly, loss of functional CFTR in CF mice is associated with significant decreases in GI bacterial community richness, evenness, and diversity, and reduced relative abundance of putative protective species in some reports [ 16 ], but not in others [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Intestinal Dysbiosis in Young Cystic Fibrosis Rabbits

Bouhamdan

Hou

Zhang

et al. 2021

JPM

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Individuals with cystic fibrosis (CF) often experience gastrointestinal (GI) abnormalities. In recent years, the intestinal microbiome has been postulated as a contributor to the development of CF-associated GI complications, hence representing a potential therapeutic target for treatment. We recently developed a rabbit model of CF, which is shown to manifest many human patient-like pathological changes, including intestinal obstruction. Here, we investigated the feces microbiome in young CF rabbits in the absence of antibiotics treatment. Stool samples were collected from seven- to nine-week-old CF rabbits (n = 7) and age-matched wild-type (WT) rabbits (n = 6). Microbiomes were investigated by iTag sequencing of 16S rRNA genes, and functional profiles were predicted using PICRUSt. Consistent with reports of those in pediatric CF patients, the fecal microbiomes of CF rabbits are of lower richness and diversity than that of WT rabbits, with a marked taxonomic and inferred functional dysbiosis. Our work identified a new CF animal model with the manifestation of intestinal dysbiosis phenotype. This model system may facilitate the research and development of novel treatments for CF-associated gastrointestinal diseases.

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Section: Discussionmentioning

confidence: 99%

Intestinal Dysbiosis in Young Cystic Fibrosis Rabbits

Bouhamdan

Hou

Zhang

et al. 2021

JPM

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“…The intestinal tract involvement in CF begins during fetal life and is noted in most patients [ 2 , 32 ]. Associated common GI symptoms in CF include abdominal pain, bloating, distention, steatorrhea, poor weight gain, and constipation [ 2 , 33 ]. CFTR is expressed in intestinal epithelial cells, and its dysfunction in CF results in defective CFTR protein, which leads to various physiological and biochemical imbalances.…”

Section: Gut Dysbiosis In Cystic Fibrosismentioning

confidence: 99%

“…These include thick and inspissated mucus due to chloride channel dysfunction, defective bicarbonate secretion altering the intestinal pH milieu, prolonged intestinal transit, pancreatic insufficiency, enhanced intestinal inflammation, and altered immune mechanisms with an impaired intestinal barrier function [ 9 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] ( Table 2 ). Clinically, the GI symptoms in CF are mainly related to obstruction, malabsorption, and inflammation [ 2 , 33 ]. The changes in the GI ecosystem result in an early and chronic state of gut dysbiosis.…”

Section: Gut Dysbiosis In Cystic Fibrosismentioning

confidence: 99%

Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis

et al. 2021

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Cystic fibrosis (CF) is the most common lethal, multisystemic genetic disorder in Caucasians. Mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein are responsible for impairment of epithelial anionic transport, leading to impaired fluid regulation and pH imbalance across multiple organs. Gastrointestinal (GI) manifestations in CF may begin in utero and continue throughout the life, resulting in a chronic state of an altered intestinal milieu. Inherent dysfunction of CFTR leads to dysbiosis of the gut. This state of dysbiosis is further perpetuated by acquired factors such as use of antibiotics for recurrent pulmonary exacerbations. Since the gastrointestinal microbiome and their metabolites play a vital role in nutrition, metabolic, inflammatory, and immune functions, the gut dysbiosis will in turn impact various manifestations of CF—both GI and extra-GI. This review focuses on the consequences of gut dysbiosis and its metabolic implications on CF disease and possible ways to restore homeostasis.

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“…Lynch et al demonstrated that changes in CF and non-CF mouse microbiome under antibiotics were greater than the pre-treatment difference between the two types of mice [65]. Germ-free animals [66] or animals under different diets [67] are other ways to explore microbiome function. Finally, animal models can explore the gut-lung axis or specific microbial interactions identified as pathophysiologically critical by -omics studies [68].…”

Section: Animal Modelsmentioning

confidence: 99%

“…A close relationship was demonstrated between cftr genotype and microbiome constitution [66]. CF mice initially germ-free and transplanted with fecal microbiota from non-CF mice had a different microbiological profile than non-CF controls [66]. However, the exact mechanisms of microorganism selection by genotype are unknown.…”

Section: Influence Of Cftr Mutation On Pulmotypes and Enterotypesmentioning

confidence: 99%

The Microbiome in Cystic Fibrosis Pulmonary Disease

Françoise

Héry-Arnaud

2020

Genes

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Cystic fibrosis (CF) is a genetic disease with mutational changes leading to profound dysbiosis, both pulmonary and intestinal, from a very young age. This dysbiosis plays an important role in clinical manifestations, particularly in the lungs, affected by chronic infection. The range of microbiological tools has recently been enriched by metagenomics based on next-generation sequencing (NGS). Currently applied essentially in a gene-targeted manner, metagenomics has enabled very exhaustive description of bacterial communities in the CF lung niche and, to a lesser extent, the fungi. Aided by progress in bioinformatics, this now makes it possible to envisage shotgun sequencing and opens the door to other areas of the microbial world, the virome, and the archaeome, for which almost everything remains to be described in cystic fibrosis. Paradoxically, applying NGS in microbiology has seen a rebirth of bacterial culture, but in an extended manner (culturomics), which has proved to be a perfectly complementary approach to NGS. Animal models have also proved indispensable for validating microbiome pathophysiological hypotheses. Description of pathological microbiomes and correlation with clinical status and therapeutics (antibiotic therapy, cystic fibrosis transmembrane conductance regulator (CFTR) modulators) revealed the richness of microbiome data, enabling description of predictive and follow-up biomarkers. Although monogenic, CF is a multifactorial disease, and both genotype and microbiome profiles are crucial interconnected factors in disease progression. Microbiome-genome interactions are thus important to decipher.

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CFTR dysregulation drives active selection of the gut microbiome

Cited by 64 publications

References 48 publications

Intestinal Dysbiosis in Young Cystic Fibrosis Rabbits

Intestinal Dysbiosis in Young Cystic Fibrosis Rabbits

Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis

The Microbiome in Cystic Fibrosis Pulmonary Disease

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