Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases

Duboc, Henri; Rajca, Sylvie; Rainteau, Dominique; Benarous, David; Maubert, Marie-Anne; Quervain, Elodie; Thomas, G.; Barbu, Véronique; Humbert, Lydie; Despras, Guillaume; Bridonneau, Chantal; Dumetz, Fabien; Grill, Jean-Pierre; Masliah, J.; Beaugerie, Laurent; Cosnes, Jacques; Chazouillères, Olivier; Poupon, Raoul; Wolf, Claude; Mallet, Jean‐Maurice; Langella, Philippe; Trugnan, Germain; Sokol, Harry; Seksik, Philippe

doi:10.1136/gutjnl-2012-302578

Cited by 672 publications

(693 citation statements)

References 55 publications

(46 reference statements)

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“…In particular, fecal dysbiosis in IBD was linked with dysmetabolism of bile salts, characterized by decreased levels of secondary bile acids. 10 Although these secondary bile acids show anti-inflammatory effects on epithelial cells in vitro, 10 they vary in hydrophobicity and cytotoxicity. Although hydrophobic bile acids have the potential to damage cell membranes, hydrophilic bile acids possess cytoprotective properties.…”

Section: Dss-induced Colitismentioning

confidence: 99%

“…9 Recently, decreased concentrations of secondary bile salts have been found in fecal samples of patients with IBD. 10 Whereas the severity of colitis in mice is correlated with hydrophobicity of fecal bile acids, 9 the more hydrophilic bile acids exhibit anti-inflammatory effects on epithelial cells in vitro. [11][12][13] A secondary and hydrophilic bile salt that has long been studied for its potent cytoprotective properties is tauroursodeoxycholic acid (TUDCA), which is the taurine-coupled conjugate of ursodeoxycholic acid, a drug that is routinely used for the treatment of primary biliary cirrhosis and to some extent of primary sclerosing cholangitis.…”

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confidence: 99%

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Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Laukens

Devisscher

Bossche

et al. 2014

Laboratory Investigation

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Ulcerative colitis (UC) is characterized by increased epithelial cell death and subsequent breakdown of the intestinal epithelial barrier, which perpetuates chronic intestinal inflammation. Since fecal bile acid dysmetabolism is associated with UC and tauroursodeoxycholic acid (TUDCA) has been shown to improve murine colitis, we evaluated the effect of TUDCA on intestinal epithelial cell death in a mouse model of UC-like barrier dysfunction elicited by dextran sulfate sodium (DSS). We identified the prevention of colonic caspase-3 induction, a key proapoptotic marker which was also over-activated in UC, as the earliest event resulting in a clear clinical benefit. Whereas vehicle-treated mice showed a cumulative mortality of 40%, all TUDCA-treated mice survived the DSS experiment during a 14-day follow-up period. In line with a barrier protective effect, TUDCA decreased bacterial translocation to the spleen and stimulated mucin production. Similarly, TUDCA inhibited lipopolysaccharide-induced intestinal permeability and associated enterocyte apoptosis. The anti-apoptotic effect was confirmed in vitro by a dose-dependent inhibition of both receptor-dependent (using tumor necrosis factor and Fas ligand) and receptor-independent (staurosporine) caspase-3 induction in HT29 colonic epithelial cells. These data imply that caspase-3 activation is an early marker of colitis that is prevented by TUDCA treatment. These data, together with the previously reported beneficial effect in colitis, suggest that TUDCA could be an add-on strategy to current immunosuppressive treatment of UC patients.

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Section: Dss-induced Colitismentioning

confidence: 99%

mentioning

confidence: 99%

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Laukens

Devisscher

Bossche

et al. 2014

Laboratory Investigation

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“…[15][16][17] Within the past decade, LC-MS has been heavily utilized for the separation and detection of BAs in human and animal model biofluid samples. 9,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] The most comprehensive of these methods have a relatively long analytical cycle (> 30 minutes), precluding rapid sample analysis. 21,25,28,30,34 On the other hand, the most rapid methods (< 10 minutes) have limited BA coverage.…”

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confidence: 99%

“…19,33 The majority of separations have analytical times greater than 20 minutes and intermediate level of BA species coverage (ranging from 11 to 32 species monitored). 9,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Very few LC-MS methods report coverage of tertiary BAs such as sulfate conjugates which have recently been implicated in the important role of the gut microbiota in human metabolism. 9,32,[34][35][36] The analytical foundation of these methods is reversed-phase separation utilizing a C 18 stationary phase, which is suitable for retention and separation of the diverse range of hydrophobicity present among BAs.…”

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confidence: 99%

Bile Acid Profiling and Quantification in Biofluids Using Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry

et al. 2015

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Bile acids are important end products of cholesterol metabolism. While they have been identified as key factors in lipid emulsification and absorption due to their detergent properties, bile acids have also been shown to act as signaling molecules and intermediates between the host and the gut microbiota. To further the investigation of bile acid functions in humans, an advanced platform for high throughput analysis is essential. Herein, we describe the development and application of a 15 min UPLC procedure for the separation of bile acid species from human biofluid samples requiring minimal sample preparation. High resolution time-of-flight mass spectrometry was applied for profiling applications, elucidating rich bile acid profiles in both normal and disease state plasma. In parallel, a second mode of detection was developed utilizing tandem mass spectrometry for sensitive and quantitative targeted analysis of 145 bile acid (BA) species including primary, secondary, and tertiary bile acids. The latter system was validated by testing the linearity (lower limit of quantification, LLOQ, 0.25?10 nM and upper limit of quantification, ULOQ, 2.5?5 ?M), precision (?6.5%), and accuracy (81.2?118.9%) on inter- and intraday analysis achieving good recovery of bile acids (serum/plasma 88% and urine 93%). The ultra performance liquid chromatography?mass spectrometry (UPLC-MS)/MS targeted method was successfully applied to plasma, serum, and urine samples in order to compare the bile acid pool compositional difference between preprandial and postprandial states, demonstrating the utility of such analysis on human biofluids

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“…Secondary bile acids are particularly damaging to epithelial cells [18]. The conversion of primary bile acids to secondary bile acids is catalyzed by bacterial enzymes [19]. Treatment of rats with PPIs or H 2 receptor antagonists has been shown to markedly increase the cytotoxicity of bile [20].…”

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confidence: 99%

NSAID enteropathy and bacteria: a complicated relationship

et al. 2015

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The clinical significance of small intestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remains under-appreciated. It occurs with greater frequency than the damage caused by these drugs in the upper gastrointestinal tract, but is much more difficult to diagnose and treat. Although the pathogenesis of NSAID enteropathy remains incompletely understood, it is clear that bacteria, bile, and the enterohepatic circulation of NSAIDs are all important factors. However, they are also interrelated with one another. Bacterial enzymes can affect the cytotoxicity of bile and are essential for enterohepatic circulation of NSAIDs. Gram-negative bacteria appear to be particularly important in the pathogenesis of NSAID enteropathy, possibly through release of endotoxin. Inhibitors of gastric acid secretion significantly aggravate NSAID enteropathy, and this effect is due to significant changes in the intestinal microbiome. Treatment with antibiotics can, in some circumstances, reduce the severity of NSAID enteropathy, but published results are inconsistent. Specific antibiotic-induced changes in the microbiota have not been causally linked to prevention of intestinal damage. Treatment with probiotics, particularly Bifidobacterium, Lactobacillus, and Faecalibacteriaum prausnitzii, has shown promising effects in animal models. Our studies suggest that these beneficial effects are due to colonization by the bacteria, rather than to products released by the bacteria.

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Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases

Cited by 672 publications

References 55 publications

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Bile Acid Profiling and Quantification in Biofluids Using Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry

NSAID enteropathy and bacteria: a complicated relationship

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