Bile salt biotransformations by human intestinal bacteria

Abstract

Secondary bile acids, produced solely by intestinal bacteria, can accumulate to high levels in the enterohepatic circulation of some individuals and may contribute to the pathogenesis of colon cancer, gallstones, and other gastrointestinal (GI) diseases. Bile salt hydrolysis and hydroxy group dehydrogenation reactions are carried out by a broad spectrum of intestinal anaerobic bacteria, whereas bile acid 7-dehydroxylation appears restricted to a limited number of intestinal anaerobes representing a small fraction of the total colonic flora. Microbial enzymes modifying bile salts differ between species with respect to pH optima, enzyme kinetics, substrate specificity, cellular location, and possibly physiological function. Crystallization, site-directed mutagenesis, and comparisons of protein secondary structure have provided insight into the mechanisms of several bile acid-biotransforming enzymatic reactions. Molecular cloning of genes encoding bile salt-modifying enzymes has facilitated the understanding of the genetic organization of these pathways and is a means of developing probes for the detection of bile salt-modifying bacteria. The potential exists for altering the bile acid pool by targeting key enzymes in the 7a/b-dehydroxylation pathway through the development of pharmaceuticals or sequestering bile acids biologically in probiotic bacteria, which may result in their effective removal from the host after excretion.-Ridlon, J. M., D-J. Kang, and P. B. Hylemon. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 2006. 47: 241-259.

Consequences of bile salt biotransformations by intestinal bacteria

“…1,11 The composition of bile salts in the small intestine more closely resembles the biliary pool; whereas, the fecal bile acid profile is almost entirely unconjugated and secondary bile acids owing to the action of bile salt hydrolases (BSH) and 7a-dehydroxylation. 8 BSH activity is widespread in commensal bacteria inhabiting both the small intestine and large bowel. Grampositive gut bacteria have the most diverse distribution of BSH including; Clostridium, 12,13 Enterococcus, 14 Bifidobacterium, 15,16 and Lactobacillus, 17,18 while the distribution of BSH in Gram-negatives is, so far, detected only in members of the genus Bacteroides.…”

“…Bacterial HSDHs have the ability to epimerize other hydroxyl groups on bile acids in addition to the 7-oxo group, including the 3-and 12-oxo groups. 8 A recent study that elucidated genes responsible for the production of enzymes that epimerize DCA to 3-oxo-DCA and subsequently to 3-iso-DCA in Ruminococcus gnavus reported that these bile acids have reduced toxicity. 92 Given these findings, a reasonable hypothesis is that in response to these membrane-disrupting primary and secondary bile acids, gut microbes utilize HSDHs as a means of detoxifying bile acids.…”

“…Rodent, 61 but not human bile acid 7a-dehydroxylating bacteria are capable of 7a-dehydroxylating muricholic acids (6a, 7b-hydroxy; 6b, 7b-hydroxy). 62 Characterization of the genetics and molecular biology of bile acid 7a/b-dehydroxylation has been performed mainly in strains of Clostridium scindens, 8,63 particularly C. scindens VPI 12708 (formerly Eubacterium sp. strain VPI 12708).…”

Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation

“…Other traits attributed to members of the gut microbiota, however, such as inhibiting the growth (24), attachment (25), or virulence (26) of particular pathogens, helping to regulate host immunity (21)(22)(23) or energy balance (24), or participating with host enzymes in cometabolism of specific substances (27,28), may be restricted to a small subset of the community. Unlike carbon use, these traits are not essential to the microbes; variation in the trait between close relatives is predicted by evolutionary theory (29,30) and observed in practice (24,31,32).…”

Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis: a role for bifidobacteria and lactobacilli?

“…Secondary BAs are produced from primary BAs by the action of the human gut micro biota 7 . For instance, CA is dehydroxylated at the C7 position by the enzymatic action of strains belonging to the genera Clostridium and Eubacterium, resulting in the formation of DCA 8 .…”