Effect of Fasting and lleal Resection on the Concentration of Deoxycholic Acid in Rat Portal Blood
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Bile acids in the serum of rat portal blood have been examined. Fasting (20 hr) caused a marked increase in the deoxycholic acid concentration, mainly of deoxycholyltaurine. Studies with [24-14C]deoxycholic acid failed to show that this was due to decreased rehydroxylation by the liver. Resection of the terminal ileum caused a three- to fourfold reduction in the total bile acid concentration in male animals, cholyltaurine being most affected although it remained the predominant bile acid. In contrast the concentration of deoxycholic acid increased in half the animals. In female animals the concentrations of chenic acid and lithocholic acid also increased so that the total bile acid concentration only decreased slightly. Ileal resection combined with a right hemicolectomy caused the disappearance of deoxycholic acid.Keywords:
Deoxycholic acid
Lithocholic acid
The population levels of intestinal microflora and bile acid composition in the digestive tract were examined in rats fed bile acids to determine the relationships between gastrointestinal microflora and the host. The population level of Bacteroides was increased in the ceca of rats fed cholic acid or deoxycholic acid. In the ileum, the concentration of conjugated bile acid in rats fed cholesterol, cholic acid, hyodeoxycholic acid or lithocholic acid was higher than that in control rats, and was very low in ceca and feces of all the rats. The concentration of total free bile acid was much higher in the ceca than in the ilea of rats fed hyodeoxycholic acid or lithocholic acid. Cholic acid and deoxycholic acid were found in the ilea, ceca and feces of the cholic acid-fed rats. In the deoxycholic acid-fed rats, cholic acid was localized in the ileum. 7-Ketodeoxycholic acid was also found in the ceca of the cholic acid-fed rats. 12-Ketolithocholic acid was found in the feces of rats fed cholic acid or deoxycholic acid. 3-Ketocholanic acid was found in some samples from the lithocholic acid-fed rats. Therefore, some kinds of bile acids influence the population levels of gastrointestinal microflora and bile acid composition in the intestine.
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Deoxycholic acid
Chenodeoxycholic acid
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The gut microbiota synthesize hundreds of molecules, many of which influence host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at concentrations of around 500 μM and are known to block the growth of Clostridium difficile1, promote hepatocellular carcinoma2 and modulate host metabolism via the G-protein-coupled receptor TGR5 (ref. 3). More broadly, DCA, LCA and their derivatives are major components of the recirculating pool of bile acids4; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Nonetheless, despite the clear impact of DCA and LCA on host physiology, an incomplete knowledge of their biosynthetic genes and a lack of genetic tools to enable modification of their native microbial producers limit our ability to modulate secondary bile acid levels in the host. Here we complete the pathway to DCA and LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the eight-step conversion of cholic acid to DCA. We then engineer the pathway into Clostridium sporogenes, conferring production of DCA and LCA on a nonproducing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool. PMID: 32555455 Funding information This work was supported by: Howard Hughes Medical Institute, United States NIDDK NIH HHS, United States Grant ID: R01 DK110174 NIGMS NIH HHS, United States Grant ID: U54 GM093342 NIGMS NIH HHS, United States Grant ID: U54 GM094662 NIDDK NIH HHS, United States Grant ID: DP1 DK113598 NICHD NIH HHS, United States Grant ID: DP2 HD101401 NHLBI NIH HHS, United States Grant ID: P01 HL147823 NIGMS NIH HHS, United States Grant ID: P01 GM118303 More Less keyboard_arrow_down
Deoxycholic acid
Lithocholic acid
Metabolic pathway
Chenodeoxycholic acid
Gut microbiome
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Individual bile acids were determined in twenty-nine amniotic fluid specimens obtained from twenty-six women between the 32nd and 41st week of gestation. Total bile acid concentration ranged from 0.4 to 4.8 mumol/l with a mean of 1.57 mumol/l. Besides the two major bile acids of man, cholic acid and chenodeoxycholic acid, 3beta-hydroxy-5-cholenoic acid was found in all, lithocholic acid in ten and deoxycholic acid in nine of the twenty-nine amniotic fluid samples. 3beta-Hydroxy-5-cholenoic acid averaged 39.8% of total bile acids during 32-37 weeks of gestation and 20.2% at term (P less than 0.01). These findings point towards important differences between fetal and adult bile metabolism and may reflect maturation of hepatic bile acid biosynthesis near term.
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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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ABSTRACT The gut microbiota synthesize hundreds of molecules, many of which are known to impact host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at ~500 μM and are known to block C. difficile growth 1 , promote hepatocellular carcinoma 2 , and modulate host metabolism via the GPCR TGR5 3 . More broadly, DCA, LCA and their derivatives are a major component of the recirculating bile acid pool 4 ; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Despite the clear impact of DCA and LCA on host physiology, incomplete knowledge of their biosynthetic genes and a lack of genetic tools in their native producer limit our ability to modulate secondary bile acid levels in the host. Here, we complete the pathway to DCA/LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the 8-step conversion of cholic acid to DCA. We then engineer the pathway into Clostridium sporogenes , conferring production of DCA and LCA on a non-producing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool, and provide a road map for deorphaning and engineering pathways from the microbiome as a critical step toward controlling the metabolic output of the gut microbiota.
Deoxycholic acid
Lithocholic acid
Metabolic pathway
Chenodeoxycholic acid
Ursodeoxycholic acid
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Deoxycholic acid
Lithocholic acid
Metabolic pathway
Chenodeoxycholic acid
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Abstract The effect of chitosan feeding (for 21 days) on intestinal bile acids was studied in male rats. Serum cholesterol levels in rats fed a commercial diet low in cholesterol were decreased by chitosan supplementation. Chitosan inhibited the transformation of cholesterol to coprostanol without causing a qualitative change in fecal excretion of these neutral sterols. Increased fiber consumption did not increase fecal excretion of bile acids, but caused a marked change in fecal bile acid composition. Litcholic acid increased sigificantly, deoxycholic acid increased to a leasser extent, whereas hyodeoxycholic acid and the 6β‐isomer and 5‐epimeric 3α‐hydroxy‐6‐keto‐cholanoic acid(s) decreased. The pH in the cecum and colon became elevated by chitosan feeding which affected the conversion of primary bile acids to secondary bile acids in the large intestine. In the cecum, chitosan feeding increased the concentration of α‐,β‐, and ω‐muricholic acids, and lithocholic acid. However, the levels of hyodeoxycholic acid and its 6β‐isomer, of monohydroxy‐monoketo‐cholanoic acids, and of 3α, 6ξ, 7ξ‐trihydroxy‐cholanoic acid decreased. The data suggest that chitosan feeding affects the metabolism of intestinal bile acids in rats.
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Deoxycholic acid
Cecum
Lipidology
Enterohepatic circulation
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Cerebrotendinous Xanthomatosis
Chenodeoxycholic acid
Ursodeoxycholic acid
Lithocholic acid
Deoxycholic acid
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Bile acid 7alpha-dehydroxylation by intestinal bacteria, which converts cholic acid and chenodeoxycholic acid to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, is an important function in the human intestine. Clostridium scindens is one of the most important bacterial species for bile acid 7alpha-dehydroxylation because C. scindens has high levels of bile acid 7alpha-dehydroxylating activity. We quantified C. scindens and secondary bile acids, DCA and LCA, in fecal samples from 40 healthy Japanese and investigated their correlation. Moreover, we used terminal restriction fragment length polymorphism (T-RFLP) analysis to investigate the effect of fecal microbiota on secondary bile acid levels. There was no correlation between C. scindens and secondary bile acid in fecal samples. On the other hand, T-RFLP analysis demonstrated that fecal microbiota associated with high levels of DCA were different from those associated with low levels of DCA, and furthermore that fecal microbiota in the elderly (over 72 years) were significantly different from those in younger adults (under 55 years). These results suggest that intestinal microbiota have a stronger effect on DCA level than does the number of C. scindens cells.
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Bile acids in the serum of rat portal blood have been examined. Fasting (20 hr) caused a marked increase in the deoxycholic acid concentration, mainly of deoxycholyltaurine. Studies with [24-14C]deoxycholic acid failed to show that this was due to decreased rehydroxylation by the liver. Resection of the terminal ileum caused a three- to fourfold reduction in the total bile acid concentration in male animals, cholyltaurine being most affected although it remained the predominant bile acid. In contrast the concentration of deoxycholic acid increased in half the animals. In female animals the concentrations of chenic acid and lithocholic acid also increased so that the total bile acid concentration only decreased slightly. Ileal resection combined with a right hemicolectomy caused the disappearance of deoxycholic acid.
Deoxycholic acid
Lithocholic acid
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