Higher Fecal Bile Acid Hydrophobicity Is Associated with Exacerbation of Dextran Sodium Sulfate Colitis in Mice

Stenman, Lotto. K.; Holma, Reetta; Forsgård, Richard A.; Gylling, Helena; Korpela, Riitta

doi:10.3945/jn.113.180810

Cited by 32 publications

(32 citation statements)

References 33 publications

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“…125 Higher levels of fecal secondary bile acids have been shown to worsen the severity of colitis in DSS-treated mice. 126 These data suggest stimulation of secondary bile acid formation by sulfide, and exacerbation of inflammation by the combination of DCA and H 2 S.…”

Section: ¡mentioning

confidence: 85%

Taurocholic acid metabolism by gut microbes and colon cancer

Ridlon¹,

Wolf²,

Gaskins³

2016

Gut Microbes

250

229

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Colorectal cancer (CRC) is one of the most frequent causes of cancer death worldwide and is associated with adoption of a diet high in animal protein and saturated fat. Saturated fat induces increased bile secretion into the intestine. Increased bile secretion selects for populations of gut microbes capable of altering the bile acid pool, generating tumor-promoting secondary bile acids such as deoxycholic acid and lithocholic acid. Epidemiological evidence suggests CRC is associated with increased levels of DCA in serum, bile, and stool. Mechanisms by which secondary bile acids promote CRC are explored. Furthermore, in humans bile acid conjugation can vary by diet. Vegetarian diets favor glycine conjugation while diets high in animal protein favor taurine conjugation. Metabolism of taurine conjugated bile acids by gut microbes generates hydrogen sulfide, a genotoxic compound. Thus, taurocholic acid has the potential to stimulate intestinal bacteria capable of converting taurine and cholic acid to hydrogen sulfide and deoxycholic acid, a genotoxin and tumor-promoter, respectively.

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Section: ¡mentioning

confidence: 85%

Taurocholic acid metabolism by gut microbes and colon cancer

Ridlon¹,

Wolf²,

Gaskins³

2016

Gut Microbes

250

229

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“…Although hydrophobic bile acids have the potential to damage cell membranes, hydrophilic bile acids possess cytoprotective properties. 9 A remarkable secondary bile salt that has long been studied for its cytoprotective actions is TUDCA, which is only found in trace amounts in human bile. The use of TUDCA has been proposed as a new therapeutic option for UC because of its ability to inhibit endoplasmic reticulum stress induced by TUDCA prevents intestinal epithelial cell death D Laukens et al inflammatory stimuli.…”

Section: Dss-induced Colitismentioning

confidence: 99%

mentioning

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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“…Based on the observation that fecal bile acid hydrophobicity correlates with the severity of colitis (14), it is reasonable to assume that conjugates of UDCA, which are more hydrophilic than unconjugated UDCA, might be more favorable therapeutic agents for intestinal inflammation. In this regard, we and others have shown that tauroursodeoxycholic acid (TUDCA) alleviates dextran sodium sulfate (DSS)-induced colitis in mice (15,16).…”

mentioning

confidence: 99%

Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice

Bossche

Hindryckx

Devisscher

et al. 2017

Appl Environ Microbiol

106

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The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes. Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila, bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD.IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered. Here, we studied the alterations in the fecal microbial abundance in colitic mice following the administration of secondary bile acids. Our results show that secondary bile acids reduce the severity of colitis and ameliorate colitis-associated fecal dysbiosis at the phylum level. This study indicates that secondary bile acids might act as a safe and effective drug for inflammatory bowel disease.

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Higher Fecal Bile Acid Hydrophobicity Is Associated with Exacerbation of Dextran Sodium Sulfate Colitis in Mice

Cited by 32 publications

References 33 publications

Taurocholic acid metabolism by gut microbes and colon cancer

Taurocholic acid metabolism by gut microbes and colon cancer

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

Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice

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