Discovery of tauroursodeoxycholic acid biotransformation enzymes from the gut microbiome of black bears using metagenomics

Song, Can; Wang, Bochu; Tan, Jun; Zhu, Lingyu; Lou, Deshuai

doi:10.1038/srep45495

Cited by 31 publications

(28 citation statements)

References 27 publications

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“…Conjugated or unconjugated primary BAs enter the gallbladder and are released in the small intestine, where BA are structurally modified into various secondary BAs that are less toxic to the host and can exert multiple hormonal regulatory roles (44). 7a-HSDH and 7b-HSDH are two key enzymes that drive the efficient biosynthesis of secondary BAs such as TUDCA from TCDCA (28). Thus, the change in microbiome composition affects the enzymatic activity of these pathways and alters the BA pool.…”

Section: Discussionmentioning

confidence: 99%

“…Bear bile is highly enriched in TUDCA (45). Recently, the bear gut microbiome was used to isolate new, undiscovered 7b-HSDH enzymes for more efficient production of TUDCA (28). Little is known regarding the protective effects of TUDCA in the diabetic retina (46-52).…”

Section: Discussionmentioning

confidence: 99%

“…6C). TCDCA is converted to TUDCA by the actions of both 7a-and 7b-HSDH (28), and TUDCA was significantly increased in the plasma of db/db-IF mice (Fig. 6D).…”

Section: If Altered Ba Metabolismmentioning

confidence: 97%

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Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice

et al. 2018

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Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with mice on ad libitum feeding, changes in the microbiome of the mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in on IF but not in on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice

et al. 2018

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“…Genes encoding 7α‐HSDH have been identified in a relatively wide range of bacteria, including Clostridium and Bacteroides species, whereas genes encoding 7β‐HSDH have only been demonstrated in Clostridium absonum , Collinsella aerofaciens , Ruminococcus gnavus, and Ruminococcus torques . ( 49,50 ) This suggests that the Prevotellaceae, Ruminococcaceae and Lachnospiraceae families may either prevent the production of UDCA from CDCA, or increase conversion of UDCA to LCA. Conversely, Bacteroides species may directly contribute to the transformation of CDCA to UDCA.…”

Section: Discussionmentioning

confidence: 99%

Bile Acid Changes Associated With Liver Fibrosis and Steatosis in the Mexican‐American Population of South Texas

Kwan

Jiao

et al. 2020

Hepatol Commun

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Biomarkers to predict risk of liver fibrosis in subjects with nonalcoholic fatty liver disease, a common risk factor for hepatocellular carcinoma, would allow for early preventive interventions. We sought to characterize bile acid profiles associated with liver fibrosis in subjects from the community‐based Cameron County Hispanic Cohort, a population in South Texas with high rates of nonalcoholic fatty liver disease, liver fibrosis and hepatocellular carcinoma. Plasma bile acid levels were measured in 390 subjects. These subjects were screened with liver elastography, detecting significant liver fibrosis in 58 subjects and steatosis in 186 subjects. Unsupervised clustering of the bile acid profiles revealed five clusters that differed by liver fibrosis, liver steatosis, liver injury, age and gender, identifying these parameters as major determinants of circulating bile acid changes. Total bile acid levels were significantly higher in subjects with fibrosis, with chenodeoxycholic acid displaying the greatest increase among individual bile acids. The primary conjugated bile acids, glycocholic and glycochenodeoxycholic acids, displayed the strongest association with fibrosis by logistic regression. High lithocholic acid levels were strongly associated with advanced fibrosis. In contrast, deoxycholic acid and total unconjugated secondary bile acids were positively associated with steatosis, whereas relative glycoursodeoxycholic acid abundance was negatively associated. Milk and yogurt intake notably contributed to fibrosis‐associated bile acid changes. In addition, multiple families within the Firmicutes phylum, Prevotellaceae, and Bacteroides species in stool significantly correlated with fibrosis‐associated and steatosis‐associated bile acid parameters, suggesting that the gut microbiome contributes to bile acid changes in the context of liver disease. Conclusion: Circulating bile acid levels were markedly but differently changed in liver fibrosis and steatosis in a high‐risk Mexican‐American population.

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“…P0AET8) . Previously, we cloned five 7α‐HSDHs (S1‐a‐1, S1‐a‐2, H1‐a‐1, H1‐a‐2, and Y1‐a‐1) and one 7β‐HSDH from the genomes of gut microbiota via a metagenomic approach . According to the literature, 7α‐HSDHs have been reported to have their optimal enzyme activity in the pH range of 7.5–11 .…”

Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of a novel acidophilic 7α‐hydroxysteroid dehydrogenase

et al. 2019

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7α-Hydroxysteroid dehydrogenase (7α-HSDH) is an NAD(P)H-dependent oxidoreductase belonging to the short-chain dehydrogenases/reductases. In vitro, 7α-HSDH is involved in the efficient biotransformation of taurochenodeoxycholic acid (TCDCA) to tauroursodeoxycholic acid (TUDCA). In this study, a gene encoding novel 7α-HSDH (named as St-2-1) from fecal samples of black bear was cloned and heterologously expressed in Escherichia coli. The protein has subunits of 28.3 kDa and a native size of 56.6 kDa, which suggested a homodimer. We studied the relevant properties of the enzyme, including the optimum pH, optimum temperature, thermal stability, activators, and inhibitors. Interestingly, the data showed that St-2-1 differs from the 7α-HSDHs reported in the literature, as it functions under acidic conditions. The enzyme displayed its optimal activity at pH 5.5 (TCDCA). The acidophilic nature of 7α-HSDH expands its application environment and the natural enzyme bank of HSDHs, providing a promising candidate enzyme for the biosynthesis of TUDCA or other related chemical entities.

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Discovery of tauroursodeoxycholic acid biotransformation enzymes from the gut microbiome of black bears using metagenomics

Cited by 31 publications

References 27 publications

Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice

Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice

Bile Acid Changes Associated With Liver Fibrosis and Steatosis in the Mexican‐American Population of South Texas

Structural and functional characterization of a novel acidophilic 7α‐hydroxysteroid dehydrogenase

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