Intestinal bile acid malabsorption in cystic fibrosis.

O'Brien, S.; Mulcahy, H.; Fenlon, Helen M.; O'Broin, A; Casey, Michael; Burke, Anne; FitzGerald, M. X.; Hegarty, John E.

doi:10.1136/gut.34.8.1137

Cited by 84 publications

(68 citation statements)

References 21 publications

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“…Small intestine bacterial overgrowth has been found in 30 to 40% of CF patients by breath testing techniques (23,30), but the cause is unknown. The normal small intestine has low numbers of bacteria, and there are several mechanisms that play roles in minimizing microbial colonization (for a review, see reference 39).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of the small intestine in humans with CF reported an increase in mononuclear cells in the duodenum (34) and increases in luminal albumin, immunoglobulins, eosinophil cationic protein, neutrophil elastase, interleukin-1␤, and interleukin-8, which suggest increased epithelial permeability and inflammation (40). The cause of intestinal inflammation in humans with CF is not known, but 30 to 40% of CF patients have been reported to have microbial overgrowth in the small intestine (23,30).…”

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confidence: 99%

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Bacterial Overgrowth in the Cystic Fibrosis Transmembrane Conductance Regulator Null Mouse Small Intestine

2004

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We recently reported the inflammation of the cystic fibrosis (CF) mouse small intestine, and we hypothesized bacterial overgrowth as a possible cause. Quantitative PCR of bacterial 16S genomic DNA in the CF mouse small intestine revealed an increase of greater than 40-fold compared to controls. Sequencing of 16S PCR products and Gram staining showed that the majority of bacteria in the CF mouse intestine were gram negative. Bacteria were observed to colonize the mucus that accumulates in the intestinal lumen of mice with CF. Impaired Paneth cell defenses were suggested by observation of partially dispersed Paneth granules in the mucus plugs of CF mouse intestinal crypts, and this mucus was strongly immunoreactive for Paneth cell bactericidal products. The role of bacterial overgrowth in intestinal inflammation in CF was tested by treating mice with oral antibiotics (ciprofloxacin and metronidazole) for 3 weeks, which reduced bacterial load in the CF mouse small intestine over 400-fold. Antibiotic treatment decreased the expression of the inflammationrelated genes mast cell protease 2, leucine-rich ␣2 glycoprotein/leucine-rich high endothelial venule glycoprotein, suppressor of cytokine signaling 3, hematopoietic cell transcript 1, and resistin-like molecule ␤/found in inflammatory zone 2, all of which were no longer expressed at levels significantly different from control levels. The reduction of intestinal bacteria also significantly improved the growth of CF mice but had no effect on the growth of wild-type mice. These data suggest that bacterial overgrowth in the CF mouse small intestine has a role in inflammation and contributes to the failure to thrive in this mouse model of CF.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Bacterial Overgrowth in the Cystic Fibrosis Transmembrane Conductance Regulator Null Mouse Small Intestine

2004

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“…Clinically significant CF liver disease rarely develops de novo in patients over age 18 (Bhardwaj et al 2009). Even in CF patients without clinical liver disease there is fecal loss of bile acids (O'Brien et al 1993), which can lead to poor micelle formation, contributing to fat and vitamin malabsorption. However, in CF mice fecal loss of bile salts does not appear to affect fat absorption (reviewed in Wouthuyzen-Bakker et al 2011).…”

Section: Clinical Consequences Of Cf In the Intestinementioning

confidence: 99%

The Cystic Fibrosis Intestine

Lisle

Borowitz

2013

Cold Spring Harbor Perspectives in Medicine

175

203

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“…Here, ASBT fulfils an important function in the salvage of BS, and a defect in ileal BS absorption may underlie the high BS loss observed in CF (22,40). CFTR constitutes the major Cl Ϫ conductance pathway in the apical membrane of crypt cells, required for intestinal electrolyte and fluid secretion.…”

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confidence: 99%

Activation of CFTR by ASBT-mediated bile salt absorption

Bijvelds¹,

Jorna²,

Verkade³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal ileum might also modulate intestinal fluid secretion. Taurocholate (TC) induced a biphasic rise in the short circuit current across ileal tissue, reflecting transepithelial electrogenic ion transport. This response was sensitive to bumetanide and largely abrogated in Cftr-null mice, indicating that it predominantly reflects CFTR-mediated Cl−secretion. The residual response in Cftr-null mice could be attributed to electrogenic ASBT activity, as it matched the TC-coupled absorptive Na+flux. TC-evoked Cl−secretion required ASBT-mediated TC uptake, because it was blocked by a selective ASBT inhibitor and was restricted to the distal ileum. Suppression of neurotransmitter or prostaglandin release, blocking of the histamine H1receptor, or pretreatment with 5-hydroxytryptamine did not abrogate the TC response, suggesting that neurocrine or immune mediators of Cl−secretion are not involved. Responses to TC were retained after carbachol treatment and after permeabilization of the basolateral membrane with nystatin, indicating that BS modulate CFTR channel gating rather than the driving force for Cl−exit. TC-induced Cl−secretion was maintained in cGMP-dependent protein kinase II-deficient mice and only partially inhibited by the cAMP-dependent protein kinase inhibitor H89, suggesting a mechanism of CFTR activation different from cAMP or cGMP signaling. We conclude that active BS absorption in the ileum triggers CFTR activation and, consequently, local salt and water secretion, which may serve to prevent intestinal obstruction in the postprandial state.

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Intestinal bile acid malabsorption in cystic fibrosis.

Abstract: This study aimed at examining the mechanisms

Cited by 84 publications

References 21 publications

Bacterial Overgrowth in the Cystic Fibrosis Transmembrane Conductance Regulator Null Mouse Small Intestine

Bacterial Overgrowth in the Cystic Fibrosis Transmembrane Conductance Regulator Null Mouse Small Intestine

The Cystic Fibrosis Intestine

Activation of CFTR by ASBT-mediated bile salt absorption

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