PubMed · 7268751
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J Fernandes. 1981. [Malabsorption].. https://pubmed.ncbi.nlm.nih.gov/7268751/
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Clostridium scindens is a keystone bacterial species in the mammalian gut that, while low in abundance, has a significant impact on bile acid and steroid metabolism. Numerous studies indicate that the two most studied strains of C. scindens (i.e. ATCC 35704 and VPI 12708) are important for a myriad of physiological processes in the host. We focus on both historical and current microbiological and molecular biology work on the Hylemon-Björkhem pathway and the steroid-17,20-desmolase pathway that were first discovered in C. scindens. Our most recent analysis now calls into question whether strains currently defined as C. scindens represent two separate taxonomic groups. Future directions include developing genetic tools to further explore the physiological role of bile acid and steroid metabolism by strains of C. scindens and the causal role of these pathways in host physiology and disease.
The binding of keto- and hydroxy bile salts to human serum albumin, the identity of the bile salts binding sites and the identification of the amino acids present in these sites were studied. The keto bile salts cholanate-3-one (C3), cholanate-3,6-dione (C3-6) and cholanate-3-hydroxy-6-one (KHC) were found to quench the native fluorescence emission of albumin. This suggested that the tryptophan residue of human albumin (residue 214) is accessible to the keto bile salts and not to the hydroxy parent compounds. The binding of the keto bile salts was characterized by a simple population of binding sites with Ka ranging from 22 x 10(4) M-1 for the mono keto bile salt (C3) down to 4 x 10(4) M-1 for the hydroxy-keto bile salt (KHC). The substitution of an oxo group at carbon C3 in C3-6 molecule for a hydroxy group (KHC) produce a significant decreasing of the interaction, suggesting that the hybridization state of the carbon at C3 in the steroid ring of the bile salt molecule is also an essential requirement for bile salts binding. It was found that bile salts are bound to the benzodiazepine binding site on human albumin (site II), producing a perturbation on site I, fatty acids and bilirubin binding site. The presence of only one substituent at C3 (oxo or OH) produce an important perturbation on the fatty acid binding sites, decreasing the polarity of the its microenvironment, while a little effect was observed for the dihydroxy and di-oxo-substituted BS, suggesting that the hydroxy substituents at C6, C7 and C12 do not interact in a significant manner with the fatty acid binding sites on HSA. The participation of specific amino acids in albumin-bile salt binding sites depends on the polar groups on the bile salt molecules as exemplified by the quantitatively different role of lysyl residues like those interacting with KHC, C3 and C3-6, and tyrosyl residue interacting with KHC. The following amino acids in human albumin were found to play a role in the bile salts-albumin interaction: lysyl 195 and 225, several arginyls, histidyl 146 and tyrosyl 411.
Monomolecular layers of undissociated bile acids and membrane lipids at the air/water interface serve as useful models for the interactions between fully ionized bile salts and physiological membranes. Employing an automated Langmuir-Pockels surface balance, surface pressures and dipole moments were measured as functions of molecular area for six dihydroxy bile acids: ursodeoxycholic acid (UDCA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), hyodeoxycholic acid (HDCA), allodeoxycholic acid (alloDCA), and 7 alpha,12 alpha-dihydroxycholanoic acid (7,12-OH-DCA), individually and in mixed mono-molecular layers with 1-palmitoyl-2-oleoyl-sn-3-glycerophosphatidylcholine (POPC) with and without cholesterol on a 5 M NaCl subphase at pH 2. In general, monolayers of hydrophilic bile acids (UDCA, HDCA) had lower collapse pressures and surface dipole moments than hydrophobic bile acids (CDCA approximately DCA approximately alloDCA < 7,12-OH-DCA). In binary mixtures with POPC, all bile acids including the synthetic 7,12-OH-DCA and the uncommon alloDCA condensed mixed monomolecular layers, with the degree of condensation correlating positively with bile acid hydrophobicity. In contrast, none of the bile acids caused further condensation of condensed POPC/cholesterol monomolecular layers. Surface dipole moments of binary bile acid/POPC +/- cholesterol mixtures demonstrated strict additivity, implying that no change in molecular orientation of the interface occurred over film compositions that varied from 0 to 100% bile acid. We conclude that the long axes of the steroid nuclei of dihydroxy bile acids remain parallel to the interface in mixed bile acid/POPC +/- cholesterol monomolecular layers under all conditions. We infer that fully dissociated hydrophobic and, to a lesser extent, hydrophilic bile salts condense phospholipid monomolecular layers and membranes in a similar fashion.