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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.
The Role of Fecal Microflora in Colon Carcinogenesis
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
Cholesterol may be metabolized to coprostanol and coprostanone (Figure 2) by a range of fecal bacteria including bacteroides, bifidobacteria, and Clostridia, although the reproducibility of this process clearly depends upon the incubation conditions.35,36 In a separate study, incubation of cholesterol with E. coli in the presence of DNA led to the formation of DNA-bound products.37 This observation is particularly important as the somatic theory of chemical carcinogenesis correlates the induction of cancer with the modification of cellular DNA as the initial lesion. The major breakdown products from cholesterol are not in themselves carcinogens, but may be further degraded to active species via side chain loss. In model systems, such as incubation of sitosterol with mycobacterium fortuitum strains38 or Cortisol with human fecal suspensions,39 there was a loss of side-chain substituents leading to the formation of unsaturated androstane derivatives. Identification of the DNA-bound products isolated from the E. coli incubations would yield valuable information on the possible role of choiesterol metabolites in carcinogenesis. Reddy et al.40 have demonstrated the presence of 3β, 5α, 6β,trihydroxy cholestane, presumably derived from cholesterol-5α, 6α-epoxide in the feces of cancer patients, although there is no direct evidence that this substrate is microbially derived.
The Role of Gut Microbiota in the Pathogenesis and Treatment of Obesity
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Stephen J. Walker, Puja B. Patel
In the 1930s, researchers discovered the transformation of cholesterol to saturated product coprostanol via microorganisms in the intestine. Coprostanol is not easily absorbed by the human intestine; a converse association has been seen between serum cholesterol levels and the coprostanol-to-cholesterol ratio in human feces [2]. The transformation of cholesterol to coprostanol by the gut microbiota may cause a decline in cholesterol uptake, which causes cholesterolemia. In addition to cholesterol, when conventional and germ-free mice were compared, it was shown that the gut microbiota altered many lipid species in the liver, adipose tissue, and serum, with the highest impact on the phosphatidylcholine and triglyceride species. Phosphatidylcholine is significant when considering the function of gut microbiota in cardiovascular diseases; gut microbiota are responsible for the conversion of phosphatidylcholine and dietary choline to trimethylamine (TMA); then the absorbed TMA is metabolized to TMAO, a proatherosclerotic metabolite, by hepatic flavin monooxygenases [2]. Gut microbiota may also participate in bile acid metabolism that may help control serum lipids. Bile acids are considered exceptionally efficient detergents that stimulate solubilization and uptake of dietary lipids in the intestine [2]. Bile acids are able to forego enterohepatic circulation and instead go through bacterial metabolism in the large intestine, a process that accounts for the presence of more than 20 varying secondary bile acids in human feces [2]. When the enzyme bile salt hydrolase (BSH) decouples bile acids, it causes a modification to cholesterol levels in the blood. The deconjugation of bile acids allows glycine and taurine to separate from the steroid moiety of the molecule, which is responsible for the creation of free bile acids that are not readily absorbed like conjugated bile acids [2]. This leads to the excretion of these deconjugated acids in the feces. Cholesterol is then fragmented to compensate for processed bile acids, which leads to diminishing levels of serum cholesterol [2].
Gut associated metabolites and their roles in Clostridioides difficile pathogenesis
Published in Gut Microbes, 2022
Andrea Martinez Aguirre, Joseph A. Sorg
The gut microbiome is complex, with interactions occurring between resident and invading bacteria that result in the generation of secondary metabolites. One such metabolite is coprostanol. Coprostanol is generated through the reduction of the double bond between C5 and C6 of cholesterol.80 In the metabolome of healthy controls vs. CDI patients, 63 bacterial OTUs were identified that positively correlated with the presence of coprostanol, which in turn negatively correlated with CDI patients.81 The majority of phylotypes that correlated with coprostanol presence were members of the Lachnospiraceae and Ruminococcaceae families. Coprostanol may enhance resistance to CDI by decreasing the availability of cholesterol which could reduce the abundance of metabolites (i.e., primary bile acids) that are necessary for germination by C. difficile spores (Figure 3(a,b).81
From taxonomy to metabolic output: what factors define gut microbiome health?
Published in Gut Microbes, 2021
Tomasz Wilmanski, Noa Rappaport, Christian Diener, Sean M. Gibbons, Nathan D. Price
Fecal metabolites may provide additional insight into gut microbiome health, with recent evidence indicating a high level of correspondence between gut microbiome function and fecal metabolite profiles.86,139 Some studies have also shown diagnostic value in measuring fecal metabolites for several diseases including IBD89 and early colorectal cancer detection,140 which correlated with changes in gut microbial composition across the same disease states. While there is considerable overlap between blood and fecal metabolites,139 many of the compounds measured in feces are not absorbed by the host and do not enter circulation. For example, the poorly absorbed fecal microbial metabolite coprostanol was recently shown to reflect the gut microbiota’s capacity for cholesterol metabolism. Higher fecal coprostanol concentrations reflected greater microbial metabolism of cholesterol by microbial cholesterol dehydrogenases, thereby lowering cholesterol availability to the host and improving blood lipid profiles.96 Hence, combined metabolomics approaches analyzing both feces and blood may yield more specific and detailed insight into exactly how the gut microbiome contributes to modulating host phenotypes.
Gut microbes from the phylogenetically diverse genus Eubacterium and their various contributions to gut health
Published in Gut Microbes, 2020
Arghya Mukherjee, Cathy Lordan, R. Paul Ross, Paul D. Cotter
Nearly one gram of cholesterol from dietary and extra-dietary sources reach the human colon daily, where it is metabolized by commensal gut bacteria to coprostanol. Unlike cholesterol, coprostanol is poorly absorbed in the intestine, and is suggested to have an impact on modulation of cholesterol metabolism and serum cholesterol levels.162 This notion has been reinforced by findings that an inverse relationship exists between plasma cholesterol levels and the ratio of cholesterol to coprostanol in the feces.163 Cholesterol conversion to coprostanol has been therefore considered as a new strategy for management of cholesterol homeostasis in humans. As an extension, Eubacterium spp., which are highly involved in coprostanol metabolism in the gut have been investigated for their hypocholesterolemic effects. Li et al. reported a reduction in the plasma cholesterol levels and an increase in the coprostanol/cholesterol ratios in the digestive contents of hypercholesterolemic rabbits that were fed E. coprostanoligenes.164 The effects observed in these rabbits were further ascribed to cholesterol reduction by E. coprostanoligenes due to its preferential colonization in the jejunum and ileum, both of which are sites for cholesterol absorption. Similar observations have also been reported in germ-free mice.165 Additional results from a combined metabolomic and metagenomic study have identified multiple bacterial phylotypes including Eubacterium eligens ATCC 27750 (p = 1.477e-02) to be significantly correlated to high fecal coprostanol.166