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 7alpha/beta-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.
Highlights
Secondary bile acids (DCA and lithocholic acid (LCA)) predominate in human feces (Fig. 3)
Even though 3sulfo-LCA glycine and taurine conjugates are deconjugated and to some extent desulfated by intestinal bacteria, 3-sulfo-LCA/LCA is lost in feces and does not normally accumulate in the enterohepatic circulation [8]
bile salt hydrolase (BSH) differ in subunit size and composition, pH optimum, Bile salt biotransformations by human intestinal bacteria 243 of a lack of conservation observed in residues making up the substrate binding pocket of the conjugated bile acid hydrolase gene product of C. perfringens (CBAH-1) and the corresponding residues predicted in amino acid multiple sequence alignment with other BSHs (Fig. 4)
Summary
Bile acids are saturated, hydroxylated C-24 cyclopentanephenanthrene sterols synthesized from cholesterol in hepatocytes. They are cleared efficiently from the circulation by active transporters on the sinusoidal membrane of hepatocytes and rapidly secreted into bile. This process is known as the enterohepatic circulation. Bile salts encounter populations of facultative and anaerobic bacteria of relatively low numbers and diversity in the small bowel. The secondary bile acids deoxycholic acid (DCA; 3a,12adihydroxy-5b-cholan-24-oic acid) and lithocholic acid (LCA; 3a-hydroxy-5b-cholan-24-oic acid) are produced solely by microbial biotransforming reactions in the human large intestine. Even though 3sulfo-LCA glycine and taurine conjugates are deconjugated and to some extent desulfated by intestinal bacteria, 3-sulfo-LCA/LCA is lost in feces and does not normally accumulate in the enterohepatic circulation [8]
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