The overall long-term objective of the current grant proposal is to describe, at the molecular level, intestinal bile salt metabolism and its relevance to important hepatobiliary and intestinal diseases in man. The intestinal bacterial metabolism of bile salts has a number of biomedical implications. The 7alpha-dehydroxylation of cholic acid and chenodeoxycholic acid yield deoxycholic acid and lithocholic acid, respectively. Approximately 20 to 25% of the biliary bile salt pool in man is composed of secondary bile acids, mostly deoxycholic acid. Our laboratories have discovered that in the rat, hydrophobic bile acid i.e.deoxycholic acid are much more powerful regulators of bile acid and cholesterol synthesis in the liver than hydrophilic bile acids. Therefore, secondary bile acid formation may be an important component of the regulation of cholesterol and bile acid metabolism in the liver. The specific objective are as follows: 1) Elucidate the biochemical pathway of 7alpha/7beta-dehydroxylation of chenodeoxycholic acid and ursodeoxycholic acid, respectively, in Eubacterium sp. VIP 12708. Determine if allo-lithocholic acid is formed during 7-dehydroxylation; 2) purify, characterize, clone and sequence 7alpha, 7beta, and 12alpha- hydroxysteroid dehydrogenases from selected gut bacteria; 3) Characterize an ATP-dependent bile acid ligation activity in Eubacterium sp. VIP 12708 and 4) Characterize, clone and sequence bile acid transport proteins from Pseudomonas sp. ATCC 31753 and Eubacterium sp. VIP 12708.
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