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Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Bile acids are the main end-products of cholesterol metabolism (Figure 12); significant amounts are converted to coprosterol in the stool, and smaller amounts are used to the production of steroid hormones (Figure 13). The majority of bile acids is eliminated in the feces and small amounts, about 5%, are excreted in the urine. The fecal bile acid fraction represents a complex mixture of bile acids derived from the liver and of metabolites produced by the gut flora. The bile acid composition depends upon the intestinal flora and is influenced by changes brought about by diet, antibiotics, or other drugs. Some of these bile acids are reabsorbed from the distal portion of the small intestines and processed again in the liver. During enterohepatic circulation of the bile, primary metabolites are modified by intestinal microorganisms in the cecum and colon (Figure 14). Starting with the removal of the 7α-hydroxyl group, hydrolysis yields free bile acids, mainly deoxycholic and lithocholic acids. These components are then reabsorbed from the gut in various amounts. Deoxycholic acid constitutes about 20% of bile acids in human bile, while lithocholic acid is poorly reabsorbed under normal circumstances, because it is trapped intracellularly in bacteria or firmly bound to water-insoluble structures.
Mechanisms of Cholestasis
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Toxicity associated with bile has been of interest since the days of Hippocrates and Galen and the idea that yellow bile or black bile was the cause of human diseases (Palmer, 1972). More modern studies demonstrated that the bile salts are primarily responsible for the toxicity of bile. Holsti (1956) first showed that feeding of desiccated hog bile to rabbits induced hepatic cirrhosis and subsequently demonstrated that this effect could also be produced by lithocholate and glycolithocholate (Holsti, 1960). Lithocholic acid (Figure 8) is a naturally occurring bile acid, present in trace amounts in the bile of humans and other species, including the rat (Kakis and Yousef, 1978). It is a secondary, 3α-monohydroxy bile acid which is formed primarily in the colon by the bacterial 7α-dehydroxylation of the primary bile acid chenodeoxycholate. Recent studies of lithocholate-induced cholestasis have been stimulated by the use of chenodeoxycholate for the solubilization of cholesterol gallstones (Danziger et al., 1973).
In Vitro Effect of Bile Acids
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
Nair et al.48 reported on the presence of tissue-bound lithocholic acid that was isolated from human liver. Analysis of the tissue-bound bile acid indicated a covalent link of the bile acid to the ε-amino group of lysine. In studies of carcinogen (methylazoxymethanol)-treated rats, tissue-bound lithocholic acid was found in the livers of these animals. Patnaik49 described the binding of lithocholic acid to a lysine-rich histone derived from calf thymus. Zachariah et al.50 also found that certain enteric bacteria catalyzed the binding of cholic and deoxycholic acid to calf thymus DNA. These results suggest that bile acids may be involved in mutagenesis or transcriptional events.
Parabacteroides distasonis: intriguing aerotolerant gut anaerobe with emerging antimicrobial resistance and pathogenic and probiotic roles in human health
Published in Gut Microbes, 2021
Jessica C. Ezeji, Daven K. Sarikonda, Austin Hopperton, Hailey L. Erkkila, Daniel E. Cohen, Sandra P. Martinez, Fabio Cominelli, Tomomi Kuwahara, Armand E. K. Dichosa, Caryn E. Good, Michael R. Jacobs, Mikhail Khoretonenko, Alida Veloo, Alexander Rodriguez-Palacios
Recently, Wang et al.106 demonstrated that P. distasonis alleviated obesity, hyperglycemia, and hepatic steatosis in ob/ob and high-fat diet mice via the production of secondary bile acids and a previously mentioned byproduct of fermentation: succinate. Here, succinate was found to bind to fructose-1,6-bisphosphatase, a rate-limiting enzyme involved in intestinal gluconeogenesis (IGN), decreasing hyperglycemia in ob/ob mice. Furthermore, treatment with live P. distasonis dramatically altered the bile acid profiles of the mice, increasing the levels of lithocholic acid (LCA) and ursodeoxycholic acid (UDCA), in turn reducing hyperlipidemia by activating the FXR pathway and, as a result, repairing gut barrier integrity, highlighting additional suspected benefits of P. distasonis in relation to obesity and gut barrier integrity.106 Of interest, the abundance of P. goldsteinii in feces has been reported to also have an inverse (protective) correlation with obesity in rats.107
The ‘in vivo lifestyle’ of bile acid 7α-dehydroxylating bacteria: comparative genomics, metatranscriptomic, and bile acid metabolomics analysis of a defined microbial community in gnotobiotic mice
Published in Gut Microbes, 2020
Jason M. Ridlon, Saravanan Devendran, João Mp Alves, Heidi Doden, Patricia G. Wolf, Gabriel V. Pereira, Lindsey Ly, Alyssa Volland, Hajime Takei, Hiroshi Nittono, Tsuyoshi Murai, Takao Kurosawa, George E. Chlipala, Stefan J. Green, Alvaro G. Hernandez, Christopher J. Fields, Christy L. Wright, Genta Kakiyama, Isaac Cann, Purna Kashyap, Vance McCracken, H. Rex Gaskins
Serum total bile acids were detected at a concentration of 7.38 ± 3.33 μmol/L. There was near equal concentration of serum conjugated bile acids (51.0 ± 25.3%) and serum unconjugated bile acids (49.9 ± 30.9%) reflecting absorption of host conjugated and microbial bile acid metabolites. Of total unconjugated bile acids (3.93 μmol/L), 30.9% are products of bile acid 7α-dehydroxylation (2.30 μmol/L), showing that in this model, microbial bile acid products are being absorbed from the gut, and returned to the liver. Of the bile acid 7α-dehydroxylation products in serum, LCA and its derivatives predominate, comprising 79.9% of secondary bile acids and 23% of total serum bile acids (Figure 7(b)). Lithocholic acid derivatives included isolithocholic acid (3β-monohydroxy-5β-cholan-24-oic acid) and allo-isolithocholic acid (3β-monohydroxy-5α-cholan-24-oic acid). The formation of 3β-isomers of LCA can be explained by expression of 3α-HSDH and 3β-HSDH by B. producta.29 Bile acid 7α-dehydroxylating bacteria are capable of forming allo-secondary bile acids from host primary bile acids.41,50 Deoxycholic acid (0.52 ± 0.51 μmol/L) and taurodeoxycholic acid (0.38 ± 0.27 μmol/L) were also detected in serum.
Pharmacological effects of nanoencapsulation of human-based dosing of probucol on ratio of secondary to primary bile acids in gut, during induction and progression of type 1 diabetes
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Armin Mooranian, Nassim Zamani, Ryu Takechi, Hesham Al-Sallami, Momir Mikov, Svetlana Goločorbin-Kon, Bozica Kovacevic, Frank Arfuso, Hani Al-Salami
The secondary bile acid, lithocholic acid has shown significant cytotoxicity and proinflammatory effects. Woolbright et al. have shown that chronic administration of lithocholic acid in diet caused significant intrahepatic cholestasis, hepatotoxicity and bile infarcts [12]. Other studies have suggested that improving lipid profile via cholesterol-lowering agents, and improving inflammatory profile via anti-inflammatory agents can exert glucose regulatory effects and improve functions of pancreatic β-cells, thus, improving T1D therapy [13–15]. Accordingly, one potential way to optimise T1D therapy or delay its onset is by administering cholesterol-lower drug with β-cell protective effects, encapsulated with an anti-inflammatory agent. Various encapsulation techniques such as the use of polymeric systems can be deployed to deliver bioactive molecules such as proteins [16]. Another approach is to deploy artificial cell encapsulation using the vibrational nozzle technology [17].