scholarly journals A metabolic pathway for bile acid dehydroxylation by the gut microbiome

2019 ◽  
Author(s):  
Masanori Funabashi ◽  
Tyler L. Grove ◽  
Victoria Pascal ◽  
Yug Varma ◽  
Molly E. McFadden ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Lithocholic Acid ◽  
Primary Biliary Cholangitis ◽  
Bile Acid Pool ◽  
Secondary Bile Acid ◽  
Acid Pool ◽  
Road Map ◽  
Host Physiology

ABSTRACTThe gut microbiota synthesize hundreds of molecules, many of which are known to impact host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at ~500 μM and are known to block C. difficile growth1, promote hepatocellular carcinoma2, and modulate host metabolism via the GPCR TGR53. More broadly, DCA, LCA and their derivatives are a major component of the recirculating bile acid pool4; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Despite the clear impact of DCA and LCA on host physiology, incomplete knowledge of their biosynthetic genes and a lack of genetic tools in their native producer limit our ability to modulate secondary bile acid levels in the host. Here, we complete the pathway to DCA/LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the 8-step conversion of cholic acid to DCA. We then engineer the pathway into Clostridium sporogenes, conferring production of DCA and LCA on a non-producing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool, and provide a road map for deorphaning and engineering pathways from the microbiome as a critical step toward controlling the metabolic output of the gut microbiota.

scholarly journals Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon

2017 ◽  
Vol 312 (6) ◽  
pp. G550-G558 ◽  
Author(s):  
Joseph B. J. Ward ◽  
Natalia K. Lajczak ◽  
Orlaith B. Kelly ◽  
Aoife M. O’Dwyer ◽  
Ashwini K. Giddam ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Inflammatory Responses ◽  
Lithocholic Acid ◽  
Primary Metabolite ◽  
Secondary Bile Acid ◽  
Colonic Inflammation ◽  
Anti Inflammatory

Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions. NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.

Bacterial deconjugation and enterohepatic circulation of norursocholic acid conjugates in rats

1991 ◽  
Vol 261 (6) ◽  
pp. G1065-G1071
Author(s):  
J. Lillienau ◽  
B. Borgstrom
Keyword(s):  
Bile Acid ◽  
Enterohepatic Circulation ◽  
Cecal Content ◽  
Acid Biosynthesis ◽  
Bile Acid Pool ◽  
Distal Small Intestine ◽  
Acid Pool ◽  
System 2 ◽  
Small Intestinal

Experiments were performed to define the metabolism of norusocholic acid (nUC) conjugates and to quantify to what extent the bile acid pool can be enriched in these bile acids. In vitro incubations of norusocholylglycine (nUCG) and -taurine (nUCT) with small intestinal or cecal content showed deconjugation with only cecal content. Cholylglycine (CG) was deconjugated by small intestinal and cecal content. Infusion of nUCG and CG showed that only a small proportion of nUCG was deconjugated after 24 h of enterohepatic circulation, whereas all CG was deconjugated. When nUCT was administered orally, deconjugation was shown to take place mainly in the cecum. Chronic feeding of nUCT enriched the bile acid pool with only 20% nUCT. We conclude that nUC conjugates are deconjugated primarily by bacteria in the cecum and colon, in contrast to CG, which, in addition to cecum and colon, is deconjugated in the distal small intestine. nUCT and its metabolites do not enrich in the circulating bile acid pool mainly for the following reasons: 1) nUC conjugates have a low affinity for the ileal transport system; 2) nUC, even if formed by deconjugation, is not passively absorbed at a sufficient rate; 3) the small amount of norursodeoxycholic acid formed from nUC is glucuronidated in the liver and glucuronide conjugates do not undergo enterohepatic circulation; and 4) nUC conjugates do not suppress bile acid biosynthesis.

scholarly journals Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine

mSphere ◽  
2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Casey M. Theriot ◽  
Alison A. Bowman ◽  
Vincent B. Young
Keyword(s):  
Bile Acid ◽  
Clostridium Difficile ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Large Intestine ◽  
Spore Germination ◽  
Secondary Bile Acid ◽  
Content Type ◽  
Secondary Bile Acids

ABSTRACT Antibiotics alter the gastrointestinal microbiota, allowing for Clostridium difficile infection, which is a significant public health problem. Changes in the structure of the gut microbiota alter the metabolome, specifically the production of secondary bile acids. Specific bile acids are able to initiate C. difficile spore germination and also inhibit C. difficile growth in vitro, although no study to date has defined physiologically relevant bile acids in the gastrointestinal tract. In this study, we define the bile acids C. difficile spores encounter in the small and large intestines before and after various antibiotic treatments. Antibiotics that alter the gut microbiota and deplete secondary bile acid production allow C. difficile colonization, representing a mechanism of colonization resistance. Multiple secondary bile acids in the large intestine were able to inhibit C. difficile spore germination and growth at physiological concentrations and represent new targets to combat C. difficile in the large intestine. It is hypothesized that the depletion of microbial members responsible for converting primary bile acids into secondary bile acids reduces resistance to Clostridium difficile colonization. To date, inhibition of C. difficile growth by secondary bile acids has only been shown in vitro. Using targeted bile acid metabolomics, we sought to define the physiologically relevant concentrations of primary and secondary bile acids present in the murine small and large intestinal tracts and how these impact C. difficile dynamics. We treated mice with a variety of antibiotics to create distinct microbial and metabolic (bile acid) environments and directly tested their ability to support or inhibit C. difficile spore germination and outgrowth ex vivo. Susceptibility to C. difficile in the large intestine was observed only after specific broad-spectrum antibiotic treatment (cefoperazone, clindamycin, and vancomycin) and was accompanied by a significant loss of secondary bile acids (deoxycholate, lithocholate, ursodeoxycholate, hyodeoxycholate, and ω-muricholate). These changes were correlated to the loss of specific microbiota community members, the Lachnospiraceae and Ruminococcaceae families. Additionally, physiological concentrations of secondary bile acids present during C. difficile resistance were able to inhibit spore germination and outgrowth in vitro. Interestingly, we observed that C. difficile spore germination and outgrowth were supported constantly in murine small intestinal content regardless of antibiotic perturbation, suggesting that targeting growth of C. difficile will prove most important for future therapeutics and that antibiotic-related changes are organ specific. Understanding how the gut microbiota regulates bile acids throughout the intestine will aid the development of future therapies for C. difficile infection and other metabolically relevant disorders such as obesity and diabetes. IMPORTANCE Antibiotics alter the gastrointestinal microbiota, allowing for Clostridium difficile infection, which is a significant public health problem. Changes in the structure of the gut microbiota alter the metabolome, specifically the production of secondary bile acids. Specific bile acids are able to initiate C. difficile spore germination and also inhibit C. difficile growth in vitro, although no study to date has defined physiologically relevant bile acids in the gastrointestinal tract. In this study, we define the bile acids C. difficile spores encounter in the small and large intestines before and after various antibiotic treatments. Antibiotics that alter the gut microbiota and deplete secondary bile acid production allow C. difficile colonization, representing a mechanism of colonization resistance. Multiple secondary bile acids in the large intestine were able to inhibit C. difficile spore germination and growth at physiological concentrations and represent new targets to combat C. difficile in the large intestine.

scholarly journals Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson’s Disease

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 29
Author(s):  
Peipei Li ◽  
Bryan A. Killinger ◽  
Elizabeth Ensink ◽  
Ian Beddows ◽  
Ali Yilmaz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lipid Metabolism ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Secondary Bile Acid

The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD). The vermiform appendix is a lymphoid tissue in the cecum implicated in the storage and regulation of the gut microbiota. We sought to determine whether the appendix microbiome is altered in PD and to analyze the biological consequences of the microbial alterations. We investigated the changes in the functional microbiota in the appendix of PD patients relative to controls (n = 12 PD, 16 C) by metatranscriptomic analysis. We found microbial dysbiosis affecting lipid metabolism, including an upregulation of bacteria responsible for secondary bile acid synthesis. We then quantitatively measure changes in bile acid abundance in PD relative to the controls in the appendix (n = 15 PD, 12 C) and ileum (n = 20 PD, 20 C). Bile acid analysis in the PD appendix reveals an increase in hydrophobic and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). Further proteomic and transcriptomic analysis in the appendix and ileum corroborated these findings, highlighting changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism. Microbially derived toxic bile acids are heightened in PD, which suggests biliary abnormalities may play a role in PD pathogenesis.

scholarly journals Metagenomic analysis of bile salt biotransformation in the human gut microbiome

2019 ◽  
Author(s):  
Promi Das ◽  
Simonas Marcišauskas ◽  
Boyang Ji ◽  
Jens Nielsen
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Salt ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Healthy Controls ◽  
Bile Acid Pool ◽  
Metabolomics Data ◽  
Acid Pool ◽  
Secondary Bile Acids

Abstract Background: In the biochemical milieu of human colon, bile acids act as signaling mediators between the host and its gut microbiota. Biotransformation of primary to secondary bile acids have been known to be involved in the immune regulation of human physiology. Several 16S amplicon-based studies with inflammatory bowel disease (IBD) subjects were found to have an association with the level of fecal bile acids. However, a detailed investigation of all the bile salt biotransformation genes in the gut microbiome of healthy and IBD subjects has not been performed. Results: Here, we report a comprehensive analysis of the bile salt biotransformation genes and their distribution at the phyla level. Based on the analysis of shotgun metagenomes, we found that the IBD subjects harbored a significantly lower abundance of these genes compared to the healthy controls. Majority of these genes originated from Firmicutes in comparison to other phyla. From metabolomics data, we found that the IBD subjects were measured with a significantly low level of secondary bile acids and high levels of primary bile acids compared to that of the healthy controls. Conclusions: Our bioinformatics-driven approach of identifying bile salt biotransformation genes predicts the bile salt biotransformation potential in the gut microbiota of IBD subjects. The functional level of dysbiosis likely contributes to the variation in the bile acid pool. This study sets the stage to envisage potential solutions to modulate the gut microbiome with the objective to restore the bile acid pool in the gut.

scholarly journals Secondary bile acid ursodeoxycholic acid (UDCA) alters weight, the gut microbiota, and the bile acid pool in conventional mice

2019 ◽  
Author(s):  
Jenessa A. Winston ◽  
Alissa Rivera ◽  
Jingwei Cai ◽  
Andrew D. Patterson ◽  
Casey M. Theriot
Keyword(s):  
Community Structure ◽  
Bile Acid ◽  
Microbial Community ◽  
Gut Microbiota ◽  
Ursodeoxycholic Acid ◽  
Microbial Community Structure ◽  
Cecal Content ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Gut Microbial Community

AbstractUrsodeoxycholic acid (commercially available as Ursodiol) is a naturally occurring bile acid that is used to treat a variety of hepatic and gastrointestinal diseases. Ursodiol can modulate bile acid pools, which have the potential to alter the gut microbiota community structure. In turn, the gut microbial community can modulate bile acid pools, thus highlighting the interconnectedness of the gut microbiota-bile acid-host axis. Despite these interactions, it remains unclear if and how exogenously administered ursodiol shapes the gut microbial community structure and bile acid pool. This study aims to characterize how ursodiol alters the gastrointestinal ecosystem in conventional mice. C57BL/6J wildtype mice were given one of three doses of ursodiol (50, 150, or 450 mg/kg/day) by oral gavage for 21 days. Alterations in the gut microbiota and bile acids were examined including stool, ileal, and cecal content. Bile acids were also measured in serum. Significant weight loss was seen in mice treated with the low and high dose of ursodiol. Alterations in the microbial community structure and bile acid pool were seen in ileal and cecal content compared to pretreatment, and longitudinally in feces following the 21-day ursodiol treatment. In both ileal and cecal content, members of the Lachnospiraceae family significantly contributed to the changes observed. This study is the first to provide a comprehensive view of how exogenously administered ursodiol shapes the gastrointestinal ecosystem. Further studies to investigate how these changes in turn modify the host physiologic response are important.ImportanceUrsodeoxycholic acid (commercially available as ursodiol) is used to treat a variety of hepatic and gastrointestinal diseases. Despite its widespread use, how ursodiol impacts the gut microbial community structure and bile acid pool remains unknown. This study is the first to provide a comprehensive view of how exogenously administered ursodiol shapes the gastrointestinal ecosystem. Ursodiol administration in conventional mice resulted in significant alterations in the gut microbial community structure and bile acid pool, indicating that ursodiol has direct impacts on the gut microbiota-bile acid-host axis which should be considered when this medication is administered.Bile Acid AbbreviationsαMCA – α–Muricholic acid; βMCA –β–Muricholic acid; ωMCA –ω–Muricholic acid; CA – Cholic acid; CDCA – Chenodeoxycholic acid; DCA – Deoxycholic acid; GCDCA – Glycochenodeoxycholic acid; GDCA – Glycodeoxycholic acid; GLCA – Glycolithocholic acid; GUDCA – Glycoursodeoxycholic acid; HCA – Hyodeoxycholic acid; iDCA – Isodeoxycholic acid; iLCA – Isolithocholic acid; LCA – Lithocholic acid; TCA – Taurocholic acid; TCDCA – Taurochenodeoxycholic acid; TDCA – Taurodeoxycholic acid; THCA – Taurohyodeoxycholic acid; TUDCA – Tauroursodeoxycholic acid; TβMCA – Tauro-β-muricholic acid; TωMCA –Tauro ω-muricholic acid; UDCA – Ursodeoxycholic acid.

Assessment of Gall-Bladder Storage Function in Man

1983 ◽  
Vol 65 (2) ◽  
pp. 185-191 ◽  
Author(s):  
R. P. Jazrawi ◽  
R. M. Kupfer ◽  
C. Bridges ◽  
A. Joseph ◽  
T. C. Northfield
Keyword(s):  
Bile Acid ◽  
Gall Bladder ◽  
Bile Acids ◽  
Saturation Index ◽  
Biliary Lipid ◽  
Fasting State ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Lipid Mass

1. We have validated a scintiscanning method for measuring fasting-state gall-bladder (GB) filling in man. 99mTc-labelled diethyl phenylcarbamoylmethyliminodiacetate (Tc-HIDA) was given intravenously, and 90 min later GB and gut activity were measured by using two isosensitive rectilinear scanning heads (anterior and posterior). Studies with a phantom GB in vitro, and studies in man in vivo, showed that the maximum error due to differences in isotope depth was 8%, compared with 300% when only one head was used. 2. By combining this technique with measurement of biliary lipid concentrations of fasting-state GB bile obtained by nasoduodenal intubation and intravenous cholecystokinin infusion, we were able to measure for the first time the total mass of all three biliary lipids in the GB. GB bile samples obtained in this way were divided into three consecutive portions of equal size in order to assess GB mixing. Bile acid pool size was also measured by isotope dilution. 3. We studied 12 healthy non-obese men. Fasting-state GB filling over 90 min (mean ± sem) was 54 ±8%. Biliary lipid mass in GB was 4.9 ±0.5 mmol for bile acids (67 ± 5% of the total bile acid pool), 1.6 ±0.2 mmol for phospholipid and 0.5 ± 0.1 mmol for cholesterol. The three consecutive portions of fasting GB bile gave values of 1.05 ± 0.07, 1.05 ± 0.06 and 1.03 ±0.10 for cholesterol saturation index (SI) and 6.6 ±1.1, 7.4 ± 1.6 and 6.5 ± 1.0 for Tc-HIDA c.p.m. × 1000 per mmol of bile acids. 4. The SI of fasting-state GB bile was significantly correlated with fasting-state GB filling (r = 0.63; P < 0.05). It was also correlated with cholesterol mass in GB (r = 0.64; P < 0.05), but not with bile acid and phospholipid mass. 5. We conclude that: (a) valid measurements of GB filling can be made in man by a simple scintiscanning technique employing 99mTc-HIDA as a biliary marker; (b) biliary lipid mass can also be measured if GB bile is obtained; (c) SI in health is in part determined by the degree of fasting-state GB filling, and in part by cholesterol mass in GB; (d) fasting-state GB content is well mixed in health.

scholarly journals Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction

2021 ◽  
Vol 12 ◽  
Author(s):  
Tilman Sauerbruch ◽  
Martin Hennenberg ◽  
Jonel Trebicka ◽  
Ulrich Beuers
Keyword(s):  
Liver Cirrhosis ◽  
Bile Acid ◽  
Bile Acids ◽  
Enterohepatic Circulation ◽  
Vascular Dysfunction ◽  
Farnesoid X Receptor ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Circulatory Disturbance

The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.

scholarly journals Metagenomic analysis of bile salt biotransformation in the human gut microbiome

2019 ◽  
Author(s):  
Promi Das ◽  
Simonas Marcišauskas ◽  
Boyang Ji ◽  
Jens Nielsen
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Salt ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Healthy Controls ◽  
Bile Acid Pool ◽  
Metabolomics Data ◽  
Acid Pool ◽  
Secondary Bile Acids

Abstract Background: In the biochemical milieu of human colon, bile acids act as signaling mediators between the host and its gut microbiota. Biotransformation of primary to secondary bile acids have been known to be involved in the immune regulation of human physiology. Several 16S amplicon-based studies with inflammatory bowel disease (IBD) subjects were found to have an association with the level of fecal bile acids. However, a detailed investigation of all the bile acid biotransformation genes involved in the secondary bile acid metabolism has not been performed. Results: Here, we report a comprehensive analysis of the bile acid biotransformation genes and their distribution at the phyla level. Based on the analysis of shotgun metagenomes, we found that the IBD subjects harbored a significantly lower abundance of these genes compared to the healthy controls. Majority of these genes originated from Firmicutes in comparison to other phyla. From metabolomics data, we found that the IBD subjects were measured with a significantly low level of secondary bile acids and high levels of primary bile acids compared to that of the healthy controls. Conclusions: Our bioinformatics-driven approach of identifying bile acid biotransformation genes predicts the bile salt biotransformation potential in the gut microbiota of IBD subjects. The functional level of dysbiosis likely contributes to the variation in the bile acid pool. This study sets the stage to envisage potential solutions to modulate the gut microbiome with the objective to restore the bile acid pool in the gut.

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