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The three lipids in bile, cholesterol, lecithin, and bile salts (about 90 percent of the dry weight of normal gallbladder bile) are amphipathic substances having both hydrophobic and hydrophilic functional groups. Knowledge of the physicochemical factors of gallstone formation (especially cholesterol stones) has increased in the past two decades. The absolute amount of cholesterol supersaturation determines the extent of cholesterol precipitation. The ionic strength of the bile and the types of bile salts present are minor factors, whereas the ratios of bile salts to lecithin at a particular concentration of total lipids are the major factors contributing to gallstone production. Bile acids (salts) form micelles which allow the lecithin and cholesterol to dissolve within the micelles. Thus the administration of bile acids allows for non-invasive dissolution of some cholesterol gallstones. Additional important risk factors are genetic and ethnic, sex (females predominate), obesity, diet (in contrast to animal protein and more refined carbohydrate diets, there is less lithogenicity with diets containing plant protein and unrefined carbohydrates), certain diseases, and drug therapy. Pigment stones make up the majority of radiopaque stones and are predominant in the Orient; they are seen in certain diseases and in infections of the biliary tree.
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Undissociated dihydroxy bile acids, alone or with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), lie with their long axes parallel to aqueous-lipid interfaces [Fahey, D. A., Carey, M. C., and Donovan, J. M. (1995) Biochemistry 34, 10886-10897]. To test the generality of this orientation, we used an automated Langmuir-Pockels surface balance to examine pressure-molecular area isotherms and dipole moments of insoluble monohydroxy bile acids and their salts, which are sparingly soluble because of their presumed high Krafft points. We studied lithocholic acid (LCA) (the natural 3alpha-OH isomer), glycolithocholic acid (GLCA) (its glycine conjugate), and the semisynthetic isomers, 7alpha-OH- and 12alpha-OH-cholanoic acids with and without POPC, at pH values ranging from 2 to 12. Monolayer collapse pressures increased sigmoidally with ionization, giving apparent pK values of 7.0-8.5 and implying a stronger affinity of the bile salt anions for the interface. At monolayer collapse, the molecular area of LCA was approximately 85 A(2) independent of pH, consistent with the steroid nucleus lying flat. In contrast, the interfacial area of 7-OH-cholanoic acid decreased from approximately 80 A(2) at pH 2 to approximately 40 A(2) above pH 9, consistent with a more vertical orientation and approximating 12-OH-cholanoic acid, which exhibited a molecular area of approximately 45 A(2) at all pH values. All monohydroxy bile acids condensed POPC monolayers more effectively at low than at high (ionized) pH. We conclude that the 3-OH group is crucial for anchoring bile acids and their salts to the aqueous interface, with all monohydroxy species condensing phospholipid membranes regardless of ionization state.
Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet-induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at a low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids-including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to reduced hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH.
AcrAB of Escherichia coli, an archetype among bacterial multidrug efflux pumps, exports an extremely wide range of substrates including solvents, dyes, detergents and antimicrobial agents. Its expression is regulated by three XylS/AraC family regulators, MarA, SoxS and Rob. Although MarA and SoxS regulation works by the alteration of their own expression levels, it was not known how Rob, which is constitutively expressed, exerts its regulatory action. We show here that the induction of the AcrAB efflux pump by decanoate and the more lipophilic unconjugated bile salts is mediated by Rob, and that the low-molecular-weight inducers specifically bind to the C-terminal, non-DNA-binding domain of Rob. Induction of Rob is not needed for induction of AcrAB, and we suggest that the inducers act by producing conformational alterations in pre-existing Rob, as was suggested recently (Rosner, Dangi, Gronenborn and Martin, J Bacteriol 184: 1407-1416, 2002). Decanoate and unconjugated bile salts, which are present in the normal habitat of E. coli, were further shown to make the bacteria more resistant to lipophilic antibiotics, at least in part because of the induction of the AcrAB efflux pump. Thus, it is likely that E. coli is protecting itself by the Rob-mediated upregulation of AcrAB against the harmful effects of bile salts and fatty acids in the intestinal tract.
Bile salts and acids have been implicated in the etiology of colon cancer, possibly through their ability to cause DNA damage. Taurine-conjugated and nonconjugated forms of three bile salts and one bile acid were tested for DNA repair-inducing potential and for cellular toxicity in a recently developed Escherichia coli chromotest system. The taurine-conjugated forms of sodium deoxycholate and lithocholic acid had reduced ability to induce DNA repair. Also the taurine-conjugated form of lithocholic acid had a reduced lethal effect. These observations suggest that the biotransformation step, whereby bacteria in the intestine remove the taurine added to bile salts in the liver, may be significant in the etiology of colon cancer.
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