Cftr deletion in mouse epithelial and immune cells differentially influence the intestinal microbiota

Scull, Callie; Luo, Meng; Jennings, Scott; Taylor, Christopher M.; Wang, Guoshun

doi:10.1038/s42003-022-04101-5

Cited by 3 publications

(2 citation statements)

References 83 publications

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“…Animal models suggest that CFTR variants may contribute to intestinal epithelial cell dysfunction, leading to decreased intestinal pH as well as inherent immune dysfunction, which leads to an overabundance of bacteria with decreased flagella function 43 . PPI use may predispose pwCF to SIBO because of its inhibitory effect on gastric acid production combined with the inherent GI motility issues associated with CF 63,64 . In particular, small bowel dysmotility as seen in many pwCF may lead to the expansion of intestinal bacterial satellite taxa with resultant GI symptoms 65 .…”

Section: Pathophysiology Of the Cf Gi Tractmentioning

confidence: 99%

“…43 PPI use may predispose pwCF to SIBO because of its inhibitory effect on gastric acid production combined with the inherent GI motility issues associated with CF. 63,64 In particular, small bowel dysmotility as seen in many pwCF may lead to the expansion of intestinal bacterial satellite taxa with resultant GI symptoms. 65 Certain enteral antibiotics, such as rifaximin, can alleviate symptoms of SIBO in pwCF.…”

Section: Mucosal Inflammation Conditionsmentioning

confidence: 99%

See 1 more Smart Citation

Cystic fibrosis and fat malabsorption: Pathophysiology of the cystic fibrosis gastrointestinal tract and the impact of highly effective CFTR modulator therapy

McDonald,

Reid,

Pohl

et al. 2024

Nut in Clin Prac

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Cystic fibrosis (CF) is a progressive, genetic, multi‐organ disease affecting the respiratory, digestive, endocrine, and reproductive systems. CF can affect any aspect of the gastrointestinal (GI) tract, including the esophagus, stomach, small intestine, colon, pancreas, liver, and gall bladder. GI pathophysiology associated with CF results from CF membrane conductance regulator (CFTR) dysfunction. The majority of people with CF (pwCF) experience exocrine pancreatic insufficiency resulting in malabsorption of nutrients and malnutrition. Additionally, other factors can cause or worsen fat malabsorption, including the potential for short gut syndrome with a history of meconium ileus, hepatobiliary diseases, and disrupted intraluminal factors, such as inadequate bile salts, abnormal pH, intestinal microbiome changes, and small intestinal bacterial overgrowth. Signs and symptoms associated with fat malabsorption, such as abdominal pain, bloating, malodorous flatus, gastroesophageal reflux, nausea, anorexia, steatorrhea, constipation, and distal intestinal obstruction syndrome, are seen in pwCF despite the use of pancreatic enzyme replacement therapy. Given the association of poor nutrition status with lung function decline and increased mortality, aggressive nutrition support is essential in CF care to optimize growth in children and to achieve and maintain a healthy body mass index in adults. The introduction of highly effective CFTR modulator therapy and other advances in CF care have profoundly changed the course of CF management. However, GI symptoms in some pwCF may persist. The use of current knowledge of the pathophysiology of the CF GI tract as well as appropriate, individualized management of GI symptoms continue to be integral components of care for pwCF.

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Section: Pathophysiology Of the Cf Gi Tractmentioning

confidence: 99%

Section: Mucosal Inflammation Conditionsmentioning

confidence: 99%

Cystic fibrosis and fat malabsorption: Pathophysiology of the cystic fibrosis gastrointestinal tract and the impact of highly effective CFTR modulator therapy

McDonald,

Reid,

Pohl

et al. 2024

Nut in Clin Prac

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Fecal Dysbiosis and Inflammation in Intestinal-Specific Cftr Knockout Mice on Regimens Preventing Intestinal Obstruction

Young¹,

Woode²,

Williams³

et al. 2023

Preprint

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Chronic intestinal inflammation is a poorly understood manifestation of Cystic Fibrosis (CF), which may be refractory to ion channel CFTR modulator therapy. People with CF exhibit intestinal dysbiosis which has potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia and in the leukocyte population. Here, we investigate the contribution of intestinal epithelial-specific loss of Cftr (iCftr KO) to dysbiosis and inflammation in mice treated with either of two anti-obstructive dietary regimens necessary to maintain CF mouse models (PEG laxative or a liquid diet, LiqD). Feces collected from iCftr KO mice and their wildtype (WT) sex-matched littermates were used to measure fecal calprotectin and to perform 16S rRNA sequencing to characterize the gut microbiome. Fecal calprotectin was elevated in iCftr KO relative to WT samples of mice consuming either PEG or LiqD. PEG iCftr KO mice did not show a change in α-diversity versus WT but demonstrated a significant difference in microbial composition (β-diversity) with increases in phylumProteobacteria, familyPeptostreptococcaceae, four genera ofClostridiaincludingC. innocuum, and mucolytic genusAkkermansia. Fecal microbiome analysis of LiqD iCftr KO mice showed both decreased α-diversity and differences in microbial composition with increases inProteobacteriafamilyEnterobacteriaceae,FirmicutesfamiliesClostridiaceaeandPeptostreptococcaceae, and enrichment ofClostridium perfringens,C. innocuum,C. difficile, mucolyticRuminococcus gnavus, and reduction ofAkkermansia. It was concluded that epithelial-specific loss of Cftr is a major driver of CF intestinal dysbiosis and inflammation with significant similarities to previous studies of global Cftr KO mice.

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Fecal dysbiosis and inflammation in intestinal-specific Cftr knockout mice on regimens preventing intestinal obstruction

Young,

Woode,

Williams

et al. 2024

Physiological Genomics

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Chronic intestinal inflammation is a poorly understood manifestation of Cystic Fibrosis (CF), which may be refractory to ion channel CFTR modulator therapy. People with CF exhibit intestinal dysbiosis which has potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia and in the leukocyte population. Here, we investigate the contribution of intestinal epithelial-specific loss of Cftr (iCftr KO) to dysbiosis and inflammation in mice treated with either of two anti-obstructive dietary regimens necessary to maintain CF mouse models (PEG laxative or a liquid diet, LiqD). Feces collected from iCftr KO mice and their wildtype (WT) sex-matched littermates were used to measure fecal calprotectin and to perform 16S rRNA sequencing to characterize the gut microbiome. Fecal calprotectin was elevated in iCftr KO relative to WT samples of mice consuming either PEG or LiqD. PEG iCftr KO mice did not show a change in a-diversity versus WT but demonstrated a significant difference in microbial composition (b-diversity) with increases in phylum Proteobacteria, family Peptostreptococcaceae, four genera of Clostridia including C. innocuum, and mucolytic genus Akkermansia. Fecal microbiome analysis of LiqD iCftr KO mice showed both decreased a-diversity and differences in microbial composition with increases in Proteobacteria family Enterobacteriaceae, Firmicutes families Clostridiaceae and Peptostreptococcaceae, and enrichment of Clostridium perfringens, C. innocuum, C. difficile, mucolytic Ruminococcus gnavus, and reduction of Akkermansia. It was concluded that epithelial-specific loss of Cftr is a major driver of CF intestinal dysbiosis and inflammation with significant similarities to previous studies of global Cftr KO mice.

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Cftr deletion in mouse epithelial and immune cells differentially influence the intestinal microbiota

Cited by 3 publications

References 83 publications

Cystic fibrosis and fat malabsorption: Pathophysiology of the cystic fibrosis gastrointestinal tract and the impact of highly effective CFTR modulator therapy

Cystic fibrosis and fat malabsorption: Pathophysiology of the cystic fibrosis gastrointestinal tract and the impact of highly effective CFTR modulator therapy

Fecal Dysbiosis and Inflammation in Intestinal-Specific Cftr Knockout Mice on Regimens Preventing Intestinal Obstruction

Fecal dysbiosis and inflammation in intestinal-specific Cftr knockout mice on regimens preventing intestinal obstruction

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