Bile acids dehydroxylation

A portion of the primary bile acids in the intestine is subjected to further changes by the activity of the intestinal bacteria. These include deconjugation and 7a-dehydroxylation, which produce the secondary bile acids, deoxycholic acid and hthocholic acid. 

Wells JE, PB Hylemon (2000) Identification and characterization of a bile acid 7a-dehydroxylation operon in Clostridium sp. strain TO-931, a highly active 7a-dehydroxylating strain isolated from human feces. Appl Environ Microbiol 66 1107-1113. 

Masuda N, H Oda, S Hirano, M Masuda, H Tanaka (1984) 7a-dehydroxylation of bile acids by resting cells of a Eubacterium lentum-like intestinal anaerobe, strain c-25. Appl Environ Microbiol AT. 735-739. 

Dehydroxylase Dehydroxylation of C- and N-hydroxy Bile acids, N-hydroxyfluorenyl-... 

The 7a-dehydroxylation is the most important bacterial transformation of bile acids, rapidly forming secondary from primary bile acids and is seemingly... 

Alternative potential strategies for reduction of mucosal secondary bile acid exposure are to target deconjugation of glycine/taurine bile salts by bacterial bile salt hydrolases and/or bacterial 7-dehydroxylation of primary bile acids to secondary bile acids. Sequestration of bile acids in the intestinal lumen using probiotic bacteria has also been proposed as an area for future research. ... 

A and B are in cis position relative to each other (see p. 54). One to three hydroxyl groups (in a position) are found in the steroid core at positions 3, 7, and 12. Bile acids keep bile cholesterol in a soluble state as micelles and promote the digestion of lipids in the intestine (see p.270). Cholic add and cheno-deoxychoMc acid are primary bile acids that are formed by the liver. Their dehydroxylation at C-7 by microorganisms from the intestinal flora gives rise to the secondary bile acids lithocholic acid and deoxycholic acid. 

Intestinal bacteria produce enzymes that can chemically alter the bile salts (4). The acid amide bond in the bile salts is cleaved, and dehydroxylation at C-7 yields the corresponding secondary bile acids from the primary bile acids (5). Most of the intestinal bile acids are resorbed again in the ileum (6) and returned to the liver via the portal vein (en-terohepatic circulation). In the liver, the secondary bile acids give rise to primary bile acids again, from which bile salts are again produced. Of the 15-30g bile salts that are released with the bile per day, only around 0.5g therefore appears in the feces. This approximately corresponds to the amount of daily de novo synthesis of cholesterol. 

The secondary bile acids result from the activity of anaerobic intestinal microorganisms in the ileum, caecum and colon, (s. fig. 3.3) Deconjugation, with the subsequent release of free bile acids, is a prerequisite for these reactions. This is followed by 7a-dehydroxylation of cholic acid and chenodeoxycholic acid to yield deoxy-cholic acid and lithocholic acid, respectively. 7a-de-hydrogenation and oxidation of chenodeoxycholic acid also yield ketolithocholic acid ... 

The gut microflora metabolize the bile acids produced by the human host. Their enzymes catalyze the deconjugation of the bile acids, that is, removal of the taurine and glycine groups. These enzymes also catalyze dehydroxylation, converting cholic acid to deoxycholic acid. Gut bacteria convert bile acids to compounds that appear to be carcinogenic and possibly contribxite to cancer of the colon. 

The two bile acids, cholic acid and chenodeoxycholic acid, which are synthesized from cholesterol in the liver, are termed primary bile acids. Each day, around one-third to one-quarter of the primary bile acid pool is lost or converted to secondary bile acids by anaerobic bacteria in the intestine. This is achieved by 7a-dehydroxylation, a process which converts cholic acid to deoxycholic acid (3a,12a-dihydroxy-5p-cholan-24-oic acid) and chenodeoxycholic acid into lithocholic acid (3a-hydroxy-5 -cholan-24-oic acid). 

As a consequence of the 7a-dehydroxylation process, the bile acid composition of bile in healthy subjects usually comprises around 30 to 40% conjugated cholic acid, 30 to 40% conjugated chenodeoxycholic acid, 10 to 30% conjugated deoxycholic acid, and less than 5% conjugated lithocholic acid, of which the majority is sulfated (H18). 

The transformation of sterols and bile acids has been examined quite thoroughly in the context of their intestinal metabolism, and a number of reactions that are otherwise quite unusual have been observed, most frequently in organisms belonging to the genus Eubacterium. These reactions may be very briefly summarized (1) reduction of the A4 5 bond with production of 5(3-reduced compounds (Mott et al. 1980) and (2) reductive dehydroxylation of 7a -hydroxy bile acids (Masuda et al. 1984) and 16a-hydroxy and 21-hydroxy corticosterols (Bokkenheuser et al. 1980). 

The presence of small amounts of 3a,12 ,22-trihydroxy-5i8-cholestan-26-oic acid as taurine conjugate in Chelonia mydas was reported by Haslewood et al. [52]. This bile acid is the 7-deoxy derivative of 3 ,7a,12a,22-tetrahydroxy-5)8-cholestan-26-oic acid, the major bile acid of this turtle, and is most likely formed by bacterial 7 -dehydroxylation (Chapter 12). 

Although small amounts of the biliary bile acids, 3a,7 ,12a-trihydroxy- and 3a,la-dihydroxy-5)3-cholestan-26-oic acids, were detected, the major fecal bile acids were their 7-deoxy derivatives, 3 ,12 -dihydroxy- and 3a-hydroxy-5 8-cholestan-26-oic acids. Small amounts of 3j8,7a,12a-trihydroxy-5 -cholestan-26-oic acid, 3a,7 -, 3j8,7 -and 3jS,12a-dihydroxy-5)S-cholestan-26-oic acids, and 3 8-hydroxy-5j3-cholestan-26-oic acid were found as well [75]. Since intestinal bacterial in mammals are known to 7a-dehydroxylate C24 bile acids and to interconvert a- and j8-hydroxyl groups (Chapter 12), these C27 bile acids may be products of the intestinal flora in the alligator. 

The intestinal microflora of man and animals can biotransform bile acids into a number of different metabolites. Normal human feces may contain more than 20 different bile acids which have been formed from the primary bile acids, cholic acid and chenodeoxycholic acid [1-5], Known microbial biotransformations of these bile acids include the hydrolysis of bile acid conjugates yielding free bile acids, oxidation of hydroxyl groups at C-3, C-6, C-7 and C-12 and reduction of oxo groups to give epimeric hydroxy bile acids. In addition, certain members of the intestinal microflora la- and 7j8-dehydroxylate primary bile acids yielding deoxycholic acid and lithocholic acid (Fig. 1). Moreover, 3-sulfated bile acids are converted into a variety of different metabolites by the intestinal microflora [6,7]. 

The hydrolysis of bile acid conjugates is probably the initial reaction catalyzed by intestinal bacteria. Therefore, primarily free bile acids are isolated from the feces of man and animals [1-5]. The bulk of the free bile acids in feces of man is deoxycholic acid and lithocholic acid which are generated by the 7 -dehydroxylation of cholic acid and chenodeoxycholic acid, respectively. A portion of fecal acids is absorbed from the intestinal tract, returned to the liver where they are conjugated and again secreted via biliary bile. Therefore, the final composition of biliary bile acids is the result of a complex interaction between liver enzymes and enzymes in intestinal bacteria. 

The epimerizalion of the 7a-hydroxyl group can occur either by intra- or interspecies mechanisms [16]. However, it is difficult to quantitatively assess the degree of 7-hydroxy epimerization in vivo because this transformation competes with the irreversible 7-dehydroxylation of bile acids (Section VI). 7a-HSDH activity has been reported in several genera of intestinal bacteria however, the most complete characterization of this enzyme has been carried out with the enzyme isolated from Escherichia coli [37] and Bacteroides sp. [29,38,39] (Table 2). Both enzymes used both free and conjugated bile acids as substrates, showed alkaline pH optima and lower values for dihydroxy than for trihydroxy bile acids. However, cell extracts prepared from Bacteriodes sp. contained both NAD- and NADP-depen-dent 7 -HSDH activities whereas, extracts from E. coli contained only an NAD-de-pendent enzyme activity. Additional studies showed that the two 7a-HSDH activities detected in Bacteriodes sp. differed in molecular weight, differential heat inactivation and Mn " requirement, suggesting the presence of two distinct enzymes [29]. 

Quantitatively, the most important bile acid microbial transformation of cholic and chenodeoxycholic acid is the 7a-dehydroxylation yielding the secondary bile acids deoxycholic acid and lithocholic acid, respectively. The 7 -dehydroxylation alters markedly the physical properties and physiological effects of the bile acid molecule. There is a decrease in the solubility of secondary bile acids in aqueous solutions and an alteration of the critical micellar concentration (Chapter 13). 

Intestinal bacteria capable of 7a-dehydroxylating bile acids have been isolated by several laboratories [16,50]. Most intestinal bacteria that carry out 7-dehydroxylation have been identified as members of the genera Clostridium [50-52] or Eubacterium [51,53]. Stellwag and Hylemon [52] and Ferrari et al. [54] demonstrated that the fecal population of 7 -dehydroxylating intestinal bacterial in man and rats is in the range of 10 -10 viable organisms/g wet weight feces. 

The reaction mechanism for 7a-dehydroxylation of bile acids was first investigated by Samuelsson [55] using doubly labeled cholic acid fed to conventional rats. The reaction was reported to occur by a diaxial trans elimination of water (6)8-H, 7a-OH) yielding a postulated A -steroid intermediate followed by trans hydrogenation at the 6a and 7 positions generating the secondary bile acids (Fig. 2). Studies... 

Clostridium leptum V.P.I. 10900, C. sordellii, C. bifermentans [62] and several additional clostridial species 7a-dehydroxylate primary bile acids. Whole cells of C. 

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