Changes in Bile Acid Composition and Effect on Cytolytic Activity of Fecal Water by Ursodeoxycholic Acid Administration: a Placebo-Controlled Cross-over Intervention Trial in Healthy Volunteers

Gorkom, B A P van; Meer, Roelof van der; Ek, Wytske Boersma-van; Termont, D. S. M. L.; Vries, Elisabeth G.E. de; Kleibeuker, Jan H.

doi:10.1080/003655202760230955

Cited by 18 publications

(15 citation statements)

References 35 publications

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“…This is in agreement with previous studies on epimerizing bacteria [19]. 1), as inferred from bile acid profiles in feces, blood and bile [1,2,40] and in vitro incubation of total human fecal flora with CDCA [22]. However, in the human gut, 7a-dehydroxylation is usually the major bacterial transformation of CDCA, generating LCA (Fig.…”

Section: Discussionsupporting

confidence: 92%

Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces

Lepercq

2004

FEMS Microbiology Letters

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Ursodeoxycholic acid-producing bacteria are of clinical and industrial interest due to the multiple beneficial effects of this bile acid on human health. This work reports the first isolation of 7-epimerizing bacteria from feces of a healthy volunteer, on the basis of their capacity to epimerize the primary bile acid, chenodeoxycholic acid, to ursodeoxycholic acid. Five isolates were found to be active starting from unconjugated chenodeoxycholic acid and its tauro-conjugated homologue, but none of these strains could epimerize the glyco-conjugated form. Biochemical testing and 16S ribosomal DNA sequencing converged to show that all five isolates were closely related to Clostridium baratii (99% sequence similarity), suggesting that this bacterial species could be responsible at least partially, for this bioconversion in the human gut.

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Section: Discussionsupporting

confidence: 92%

Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces

Lepercq

2004

FEMS Microbiology Letters

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“…Since serum levels of deoxycholic acid correlate with deoxycholic acid concentrations in stool [37], we conclude that in man UDCA does not decrease fecal deoxycholic acid concentrations. This conclusion is supported by the recent finding of van Gorkom et al [38]who found that in healthy volunteers, orally given UDCA does not decrease fecal deoxycholic acid concentrations.…”

Section: Discussionsupporting

confidence: 81%

“…The lithocholate/deoxycholate ratio in feces has been found increased in patients at high risk for colorectal cancer and has been proposed to be of diagnostic value [44]. The increase of fecal lithocholic acid concentrations under UDCA therapy was also observed in an animal model [14]and recently confirmed in man in the paper of Van Gorkom et al [38]. …”

Section: Discussionsupporting

confidence: 54%

Does Ursodeoxycholic Acid Change the Proliferation of the Colorectal Mucosa?

et al. 2003

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Background: In animal models ursodeoxycholic acid (UDCA) showed a chemoprotective effect against colon cancer. To explain this, a reduced proliferation of the colorectal mucosal proliferation was suggested. We, therefore, examined the influence of UDCA on the proliferation of normal colorectal mucosa in humans. Methods: Following endoscopic polypectomy, 20 patients with colorectal adenomas were randomized to receive either UDCA (750 mg/day, n = 10, group A) or placebo (n = 10, group B) for 6 months in a double-blinded way. Colorectal biopsies were sampled before and at the end of the medication by total colonoscopy. Colorectal mucosal proliferation was measured by FACScan analysis of propidium iodine labeling. Serum was sampled, and serum bile acids were analyzed by gas chromatography. Results: The proliferation rates at the end of the study were similar in both groups (median 15.4%; range 12.0–20.9 in group A; median 16.0%, 14.0–20.2 in group B, p = 0.41). Serum lithocholic acid levels at the end of the study were significantly higher in group A (1.3 µmol/l, 0.9–1.8) than in group B (0.7 µmol/l, 0–1.7, p < 0.02), whereas serum deoxycholic acid levels were similar in both groups. Conclusions: In this study, UDCA treatment for 6 months does not seem to induce changes in the proliferative behavior of the colorectal mucosa in patients with adenomas. It seems likely that a putative chemopreventive effect of UDCA in humans is not exerted by a reduction of the colorectal proliferation.

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“…This suggests that different mechanisms might underlie the anti‐secretory effects of UDCA on Ca 2+ ‐ and cAMP‐dependent agonists. Although the concentrations at which UDCA has its anti‐secretory actions (50 μ m –1 m m ) might not normally occur in vivo (De Kok et al 1999), during conditions of bile acid malabsorption or when it is used therapeutically, levels of the bile acid increase significantly in the colonic lumen and serum (van Gorkom et al 2002; Hess et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…While the underlying cause of this diarrhoeal effect is not known, it has been hypothesised to be due to bacterially mediated re‐epimerisation of the 7 β‐OH group of UDCA to give CDCA, which is prosecretory (Hempfling et al 2003). However, UDCA is preferentially metabolised in vivo to the monohydroxy bile acid LCA, which has been shown to be the predominant colonic bile acid in humans treated with UDCA (van Gorkom et al 2002). We also found caecal LCA levels to increase dramatically upon administration of UDCA to mice.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic acid attenuates colonic epithelial secretory function

Kelly

Mroz

Ward

et al. 2013

The Journal of Physiology

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Key points• Although diarrhoeal diseases represent a significant health and economic burden to society, therapeutic options remain limited.• While several bile acids are known to stimulate epithelial Cl − secretion, the major driving force for fluid secretion in the intestine, the effects of ursodeoxycholic acid (UDCA) on epithelial transport function are not well described.• We report that in contrast to other bile acids, UDCA exerts anti-secretory actions on colonic epithelial cells in vitro.• In contrast, in vivo administration of UDCA enhances epithelial secretory function, an affect we ascribe to being due to its bacterial metabolism to lithocholic acid. In keeping with this hypothesis, in vivo administration of a metabolically stable analogue of UDCA, 6α-methyl-UDCA, was anti-secretory.• Our findings reveal novel anti-secretory actions of UDCA and suggest that metabolically stable analogues of bile acid may be useful for development as a new class of anti-diarrhoeal drug.Abstract Dihydroxy bile acids, such as chenodeoxycholic acid (CDCA), are well known to promote colonic fluid and electrolyte secretion, thereby causing diarrhoea associated with bile acid malabsorption. However, CDCA is rapidly metabolised by colonic bacteria to ursodeoxycholic acid (UDCA), the effects of which on epithelial transport are poorly characterised. Here, we investigated the role of UDCA in the regulation of colonic epithelial secretion. Cl − secretion was measured across voltage-clamped monolayers of T 84 cells and muscle-stripped sections of mouse or human colon. Cell surface biotinylation was used to assess abundance/surface expression of transport proteins. Acute (15 min) treatment of T 84 cells with bilateral UDCA attenuated Cl − secretory responses to the Ca 2+ and cAMP-dependent secretagogues carbachol (CCh) and forskolin (FSK) to 14.0 ± 3.8 and 40.2 ± 7.4% of controls, respectively (n = 18, P < 0.001). Investigation of the molecular targets involved revealed that UDCA acts by inhibiting Na + /K + -ATPase activity and basolateral K + channel currents, without altering their cell surface expression. In contrast, intraperitoneal administration of UDCA (25 mg kg −1 ) to mice enhanced agonist-induced colonic secretory responses, an effect we hypothesised to be due to bacterial metabolism of UDCA to lithocholic acid (LCA). Accordingly, LCA ( agonist-induced secretory responses in vitro and a metabolically stable UDCA analogue, 6α-methyl-UDCA, exerted anti-secretory actions in vitro and in vivo. In conclusion, UDCA exerts direct anti-secretory actions on colonic epithelial cells and metabolically stable derivatives of the bile acid may offer a new approach for treating intestinal diseases associated with diarrhoea.

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Changes in Bile Acid Composition and Effect on Cytolytic Activity of Fecal Water by Ursodeoxycholic Acid Administration: a Placebo-Controlled Cross-over Intervention Trial in Healthy Volunteers

Abstract: These results do not support a protective effect of UDCA supplementation against colorectal cancer in man.

Cited by 18 publications

References 35 publications

Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces

Epimerization of chenodeoxycholic acid to ursodeoxycholic acid by Clostridium baratii isolated from human feces

Does Ursodeoxycholic Acid Change the Proliferation of the Colorectal Mucosa?

Ursodeoxycholic acid attenuates colonic epithelial secretory function

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