Thinking outside the box: a review of gastrointestinal symptoms and complications in cystic fibrosis

Yule, A; Sills, D.; Smith, Sherie; Spiller, Robin C.; Smyth, Alan

doi:10.1080/17476348.2023.2228194

Cited by 4 publications

(6 citation statements)

References 142 publications

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“…Because of its recent cloning and characterization as a Ca 2+- dependent anion channel [ 30 ], the focus was on TMEM16a since its discovery [ 31 ]. Now, since patients with severe CF mostly survive into adulthood because of better treatment options for their recurrent pulmonary infections and the ensuing lung destruction, the intestinal manifestations of cystic fibrosis have recently moved into the focus [ 32 , 33 , 34 , 35 ]. As mentioned in the introduction, the data obtained in mice, in human intestinal cell lines of cancer origin, and, to a very small extent, in patient biopsies, are controversial [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

The Anion Channel TMEM16a/Ano1 Modulates CFTR Activity, but Does Not Function as an Apical Anion Channel in Colonic Epithelium from Cystic Fibrosis Patients and Healthy Individuals

Salari,

Xiu,

Amiri

et al. 2023

IJMS

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Studies in human colonic cell lines and murine intestine suggest the presence of a Ca2+-activated anion channel, presumably TMEM16a. Is there a potential for fluid secretion in patients with severe cystic fibrosis transmembrane conductance regulator (CFTR) mutations by activating this alternative pathway? Two-dimensional nondifferentiated colonoid–myofibroblast cocultures resembling transit amplifying/progenitor (TA/PE) cells, as well as differentiated monolayer (DM) cultures resembling near-surface cells, were established from both healthy controls (HLs) and patients with severe functional defects in the CFTR gene (PwCF). F508del mutant and CFTR knockout (null) mice ileal and colonic mucosa was also studied. HL TA/PE monolayers displayed a robust short-circuit current response (ΔIeq) to UTP (100 µM), forskolin (Fsk, 10 µM) and carbachol (CCH, 100 µM), while ΔIeq was much smaller in differentiated monolayers. The selective TMEM16a inhibitor Ani9 (up to 30 µM) did not alter the response to luminal UTP, significantly decreased Fsk-induced ΔIeq, and significantly increased CCH-induced ΔIeq in HL TA/PE colonoid monolayers. The PwCF TA/PE and the PwCF differentiated monolayers displayed negligible agonist-induced ΔIeq, without a significant effect of Ani9. When TMEM16a was localized in intracellular structures, a staining in the apical membrane was not detected. TMEM16a is highly expressed in human colonoid monolayers resembling transit amplifying cells of the colonic cryptal neck zone, from both HL and PwCF. While it may play a role in modulating agonist-induced CFTR-mediated anion currents, it is not localized in the apical membrane, and it has no function as an apical anion channel in cystic fibrosis (CF) and healthy human colonic epithelium.

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Section: Discussionmentioning

confidence: 99%

The Anion Channel TMEM16a/Ano1 Modulates CFTR Activity, but Does Not Function as an Apical Anion Channel in Colonic Epithelium from Cystic Fibrosis Patients and Healthy Individuals

Salari,

Xiu,

Amiri

et al. 2023

IJMS

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“…Children should have age‐appropriate weight gain and growth, and adults should maintain their baseline weight. Poor weight gain or weight loss, particularly in the setting of the malabsorptive symptoms noted above, should be considered when assessing the adequacy and efficacy of EPI treatment 95,98–100 …”

Section: Pathophysiology Of the Cf Gi Tractmentioning

confidence: 99%

“…In severe cases of constipation, DIOS can occur, especially in cases in which there is inadequate treatment of EPI with PERT, with subsequent fat malabsorption occurring as a result. DIOS presents with an acute onset of symptoms with complete or partial obstruction of the bowel often requiring high doses of osmotic laxatives (polyethylene glycol) and, in severe cases, Gastrografin (Bracco Diagnostics) enemas and hospitalization for bowel clean out are needed 100 . If these medical interventions are unsuccessful at clearing the obstruction, surgical intervention is necessary.…”

Section: Pathophysiology Of the Cf Gi Tractmentioning

confidence: 99%

“…Poor weight gain or weight loss, particularly in the setting of the malabsorptive symptoms noted above, should be considered when assessing the adequacy and efficacy of EPI treatment 95,[98][99][100]…”

Section: Tests For Fat Malabsorptionmentioning

confidence: 99%

“…DIOS presents with an acute onset of symptoms with complete or partial obstruction of the bowel often requiring high doses of osmotic laxatives (polyethylene glycol) and, in severe cases, Gastrografin (Bracco Diagnostics) enemas and hospitalization for bowel clean out are needed. 100 If these medical interventions are unsuccessful at clearing the obstruction, surgical intervention is necessary. An estimated 21% of the CF population could be experiencing GI-related complications because of EPI-related fat malabsorption.…”

Section: Physical Symptomsmentioning

confidence: 99%

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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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Gastrointestinal complications of cystic fibrosis

Ng,

Prayle

2024

Paediatrics and Child Health

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Thinking outside the box: a review of gastrointestinal symptoms and complications in cystic fibrosis

Cited by 4 publications

References 142 publications

The Anion Channel TMEM16a/Ano1 Modulates CFTR Activity, but Does Not Function as an Apical Anion Channel in Colonic Epithelium from Cystic Fibrosis Patients and Healthy Individuals

The Anion Channel TMEM16a/Ano1 Modulates CFTR Activity, but Does Not Function as an Apical Anion Channel in Colonic Epithelium from Cystic Fibrosis Patients and Healthy Individuals

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

Gastrointestinal complications of cystic fibrosis

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