Secondary bile acid metabolite; Endogenous Metabolite

Through FXR-mediated ACE2 modulation, Ursodeoxycholic acid (10 μM; 24 h) lowers SARS-CoV-2 infection in different cell types and reduces ACE2 and SHP levels in primary airways and damaged organoids [4].

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FXR regulates viral infection in vitro [4]
Our results show that suppressing FXR signalling with the clinically approved drug Ursodeoxycholic acid/UDCA—which is used as a first-line treatment in primary biliary cholangitis (PBC)—or with the over-the-counter drug ZGG reduces the expression of ACE2 in multiple cell types. To consider the relevance of this finding for COVID-19, we investigated whether the FXR-mediated downregulation of ACE2 could reduce susceptibility to SARS-CoV-2 infection in vitro. For this, we exposed gall bladder cholangiocyte, airway and intestinal organoids to physiological levels of CDCA, to simulate the baseline level of FXR activation that is present in vivo, and infected them with SARS-CoV-2 isolated from a patient’s nasopharyngeal swab in the absence or presence of UDCA or ZGG (Fig. 1e,f). Suppressing FXR signalling with UDCA or ZGG reduced viral infection in all three types of organoid (Fig. 1e,f and Extended Data Fig. 5a). We then investigated whether the observed reduction in viral infection was a direct result of the FXR-mediated downregulation of ACE2. First, we showed that knockdown of FXR using shRNAs decreases the expression of ACE2 and inhibits viral infection in cholangiocyte organoids independently of the presence of CDCA or that of UDCA or ZGG (Extended Data Fig. 4d). Accordingly, after knockdown, treatment with UDCA or ZGG had no effect on viral infection (Extended Data Fig. 4d). Next, to determine whether the modulation of ACE2 is the only mechanism by which UDCA and ZGG reduce SARS-CoV-2 infection, we treated HEK293T cells that had been genetically engineered to overexpress ACE2 independent of FXR (Extended Data Fig. 6a,b) with UDCA or ZGG, and then infected them with SARS-CoV-2. As expected, in the absence of ACE2 modulation, UDCA and ZGG did not affect viral replication (Extended Data Fig. 6c). Together, these results confirm that UDCA and ZGG reduce susceptibility to SARS-CoV-2 infection in multiple cell types in vitro through the FXR-mediated regulation of ACE2.

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To further explore the physiological and pharmacological implications of hepatic FATP inhibition by secondary bile acids we tested the effects of Ursodeoxycholic acid/UDCA on LCFA uptake by primary hepatocytes. Using a FACS-based LCFA uptake assay that allows for the gating of viable cells, we found that UDCA but not TUDCA inhibited LCFA uptake by primary human hepatocytes (Sup. Fig. 5). UDCA also inhibited LCFA uptake by primary mouse hepatocytes from C57Bl/6 animals without any detectable cytotoxic effects (Fig. 5A right). Importantly, this effect was entirely FATP5 dependent, as UDCA failed to inhibited LCFA uptake by primary hepatocytes from FATP5-null animals (Fig. 5A). As predicted form our stable cell line results, the secondary bile acid DCA inhibited hepatocyte LCFA uptake significantly (Fig. 5B) while LCA showed no inhibition of LCFA uptake by primary mouse hepatocytes (Fig. 5D). Further, DCA mediated inhibition was not associated with toxicity (Fig. 5B right) and, importantly, was primarily dependent on FATP5 as the effect was abolished in FATP5-null hepatocytes (Fig. 5B). We confirmed DCA inhibition of fatty acid uptake by primary hepatocytes using 14C-labeled oleate (Sup. Fig. 6). Subsequent assays focused on the uptake of radiolabeled metabolites by primary hepatocytes and demonstrated that DCA can inhibit the uptake of a wide range of fatty acids without affecting uptake of a 2-deoxy-D-[3H]glucose/glucose mix (Fig. 5C) [5].

In C57BL/6J wild-type mice, ursodeoxycholic acid (50, 150, and 450 mg/kg; orally; once daily for 21 days) salt induces weight loss [1]. In mice and hamsters, ursodeoxycholic acid (1% w/w or 416 mg/kg; port; 7 days) decreases ACE2 expression [4]. In hamsters, ursodeoxycholic acid (416 mg/kg; side wall; 7 days) is effective in reducing SARS-CoV-2 infection [4].

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Ursodeoxycholic 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 in conventional mice. 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 healthy gastrointestinal ecosystem in conventional mice. Further studies to investigate how these changes in turn modify the host physiologic response are important.[1]

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There is debate over the mortality and malignancy risk in people with primary biliary cirrhosis (PBC) and whether this risk is reduced by use of Ursodeoxycholic acid. To investigate this issue, we identified 930 people with PBC and 9,202 control subjects from the General Practice Research Database in the United Kingdom. We categorized regular ursodeoxycholic acid as treatment with 6 or more prescriptions and nonregular treatment as less than 6. We found a 2.7-fold increase in mortality for the PBC cohort compared with the general population [adjusted hazard ratio (HR), 2.69; 95% CI, 2.35-3.09]. In those having regular ursodeoxycholic acid (43%), the mortality increase was 2.2-fold (HR, 2.19; 95% CI, 1.66-2.87) and in those not treated 2.7-fold (HR, 2.69; 95% CI, 2.18-3.33). This apparent reduction in mortality was not explained by less severe disease in the ursodeoxycholic acid-treated group. The increased risk of primary liver cancer in ursodeoxycholic acid-treated patients was 3-fold (HR, 3.17; 95% CI, 0.64-15.62), in contrast to an 8-fold increase in those not treated (HR, 7.77; 95% CI, 1.30-46.65). Conclusion: We found that people with PBC had a 3-fold mortality increase when compared with the general population, which was somewhat reduced by regular treatment with Ursodeoxycholic acid. However, the observed effect of ursodeoxycholic acid was not statistically significant.[2]

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Bile acids are known to play important roles as detergents in the absorption of hydrophobic nutrients and as signaling molecules in the regulation of metabolism. We tested the novel hypothesis that naturally occurring bile acids interfere with protein-mediated hepatic long chain free fatty acid (LCFA) uptake. To this end, stable cell lines expressing fatty acid transporters as well as primary hepatocytes from mouse and human livers were incubated with primary and secondary bile acids to determine their effects on LCFA uptake rates. We identified Ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) as the two most potent inhibitors of the liver-specific fatty acid transport protein 5 (FATP5). Both UDCA and DCA were able to inhibit LCFA uptake by primary hepatocytes in a FATP5-dependent manner. Subsequently, mice were treated with these secondary bile acids in vivo to assess their ability to inhibit diet-induced hepatic triglyceride accumulation. Administration of DCA in vivo via injection or as part of a high-fat diet significantly inhibited hepatic fatty acid uptake and reduced liver triglycerides by more than 50%. Conclusion: The data demonstrate a novel role for specific bile acids, and the secondary bile acid DCA in particular, in the regulation of hepatic LCFA uptake. The results illuminate a previously unappreciated means by which specific bile acids, such as UDCA and DCA, can impact hepatic triglyceride metabolism and may lead to novel approaches to combat obesity-associated fatty liver disease [5].

Modulation of FXR activity [4]
CDCA, ZGG and UDCA/Ursodeoxycholic acid were purchased from xxx and reconstituted following the manufacturer’s instructions. To modulate FXR activity, organoids were incubated with a final concentration of 10 μM CDCA, or 10 μM CDCA in combination with 10 μM of UDCA or ZGG.

ChIP [4]
Approximately 6 × 106 cells were used for each ChIP, and cells were incubated with fresh medium with 100 μM of CDCA, UDCA/Ursodeoxycholic acid or ZGG 2 h before collection. ChIP was performed using the True Micro ChiP kit according to the manufacturer’s instructions. In brief, following pre-clearing, the lysate was incubated overnight with the FXR antibody (Supplementary Table 1) or non-immune IgG. ChIP was completed and immunoprecipitated DNA was purified using MicroChip DiaPure columns. Samples were analysed by qPCR using the ΔΔCt approach as previously described51 (see Supplementary Table 3 for primer sequences). Primers flanking the FXRE on the well-known FXR target gene OSTα (also known as SLC51A; ref. 54) were used as a positive control, whereas primers flanking a site distant from the FXRE on the ACE2 promoter were used as a negative control. The results were normalized to the enrichment observed with non-immune IgG ChIP controls.

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Luciferase reporter [4]
Two different fragments containing the FXRE IR-1 in the ACE2 gene and in the SHP gene (also known as NR0B2) were amplified using human genomic DNA as a template and inserted onto a pGL3-promoter luciferase vector. The ACE2 and SHP IR-1 mutants were generated using a site-directed mutagenesis approach. Sequences of primers used are reported in Supplementary Table 4. These gene reporter constructs were co-transfected with a commercially available FXR expression plasmid into HEK293 cells using TransIT-293 Transfection Reagent. Twenty-four hours after transfection, cells were treated with 50 μM of CDCA, UDCA/Ursodeoxycholic acid and ZGG in fresh medium for 8 h. Luciferase activity was determined with the GLO-Luciferase Reporter Assay System and values were normalized to the empty pGL3 vector.

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Cytotoxicity and viability [4]
Primary organoids were treated with 0.1 μM–100 μM of CDCA, UDCA/Ursodeoxycholic acid or ZGG and the percentage of viable cells was counted using trypan blue and a Countess II cell counter. Cellular viability in primary organoids treated with 10 μM of CDCA, UDCA or ZGG was measured using the resazurin-based assay PrestoBlue using SoftMax Pro 5.4.4 on a SpectraMax M2.

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Luciferase reporter for SARS-CoV-2 replication [4]
A luciferase reporter for SARS-CoV-2 protease activity during viral replication was generated as previously described28 In brief, HEK293T reporter cells stably expressing ACE2, renilla luciferase (Rluc) and SARS-CoV-2 papain-like protease-activatable circularly permuted firefly luciferase (FFluc) were seeded in flat-bottomed 96-well plates. The following morning, cells were treated with the indicated doses of CDCA, UDCA/Ursodeoxycholic acid and ZGG, and infected with SARS-CoV-2 at a MOI of 0.01. The SARS-CoV-2 RdRp inhibitor remdesivir and a neutralizing antibody cocktail blocking the interaction between SARS-CoV-2 spike and ACE2 (REGN-COV2) were included as positive controls. After 24 h, cells were lysed in Dual-Glo Luciferase Buffer diluted 1:1 with PBS and 1% NP-40. Lysates were then transferred to opaque 96-well plates, and viral replication quantified as the ratio of FFluc/Rluc activity measured using the Dual-Glo kit according to the manufacturer’s instructions. FFluc/Rluc ratios were expressed as a fraction of the maximum, then analysed using the Sigmoidal, 4PL, X is log(concentration) function in GraphPad Prism.

Animal/Disease Models: 5weeks old C57BL/6J WT mice (male and female) [1]
Doses: 50, 150 and 450 mg/kg dissolved in corn oil
Route of Administration: po (oral gavage); one time/day for 21 days
Experimental Results: Mice in the 50 mg/kg and 450 mg/kg groups continued to lose significant weight over a week. At the 50 mg/kg dose, this weight loss persisted throughout the experiment. At the 450 mg/kg dose, weight loss was initially noted during the first and third weeks of ursodiol administration. At the 150 mg/kg dose, there was no significant difference in body weight compared to untreated mice.

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Animal/Disease Models: FVB/N mice and Syrian golden hamsters [4]
Doses: 1% w/w for mice, 416 mg/kg for hamsters.
Route of Administration: feed or po (oral gavage), 7 days.
Experimental Results: ACE2 expression diminished.

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Animal/Disease Models: Syrian golden hamster, SARS-CoV-2 infection model [4]
Doses: 416 mg/kg
Route of Administration: po (oral gavage), 7 days
Experimental Results: n = 6 of 9 sentinel animals prevented SARS -Transmission of CoV-2 (33% infected vs. 67% uninfected).

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Ursodiol/Ursodeoxycholic acid dosing experiment and sample collection [1]
Groups of 5 week old C57BL/6J WT mice (male and female) were treated with ursodiol/Ursodeoxycholic acid at three distinct doses (50, 150, and 450 mg/kg dissolved in corn oil) given daily via oral gavage for 21 day. These distinct doses were selected for a proof of concept experiment in order to achieve sufficient intestinal concentrations of ursodiol to alter the life cycle of Clostridioides difficile in vivo. The total volume gavaged was consistent between the three distinct doses in order to control for the volume of corn oil administered. Ursodiol dosing was adjusted once weekly, based on current weight. Two independent experiments were performed, with a total of n = 8 mice (female/male) per treatment group. Mice were weighed daily over the course of the experiment. Fecal pellets were collected twice daily, flash-frozen and stored at -80°C until further analysis. A control group of mice were necropsied prior to initiating any treatments (pretreatment group). This pretreatment group serves as a microbiome and bile acid metabolome baseline prior to mice receiving ursodiol treatment. An additional control group of mice underwent daily handling similar to the treatment groups, but were not administered ursodiol (no treatment control). Necropsy was performed at day 21 in all ursodiol treated mice and the no treatment control mice. Gastrointestinal contents and tissue from the ileum and cecum were collected, flash frozen in liquid nitrogen, and stored at -80°C until further analysis. Serum and bile aspirated from the gallbladder was obtained flash frozen in liquid nitrogen, and stored at -80°C until further analysis.

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Mice [4]
Mice were housed in a 12 h–12 h dark–light cycle, with a humidity of 45–65% and temperature of 20–24 °C. Age-matched female mice were used. Mice were assigned randomly to treatment and control groups. Mice in the treatment group received chow supplemented with 1% w/w UDCA/Ursodeoxycholic acid and 1% w/w cholic acid, whereas mice in the control group received chow supplemented with 1% w/w cholic acid58. Cholic acid was used to activate FXR and study the effects of UDCA on FXR activation19. The mice were fed ad libitum for seven days. Data were analysed blinded to the identity of the experimental groups.

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Hamsters [4]
Golden Syrian hamsters were purchased from Janvier Labs. Hamsters were housed in a 12 h–12 h dark–light cycle, with a humidity of 45–65% and temperature of 20–24 °C. Age-matched male hamsters were used, weighing between 80 g and 100 g. Hamsters were assigned randomly to treatment and control groups. Hamsters in the treatment groups received a daily oral regimen of UDCAUrsodeoxycholic acid (416 mg per kg) by oral gavage, whereas those in the control group received vehicle only. The hamsters were fed ad libitum and treatment continued for seven days to achieve a similar blood concentration of UDCA to that observed in patients taking UDCA29 (Extended Data Fig. 9a). [4]
For testing the effects of Ursodeoxycholic acid/UDCA against SARS-CoV-2 infection, one hamster was directly inoculated by the intranasal route with 1 × 102 plaque-forming units (PFU) in 100 µl PBS. Each infected hamster was placed on one side of a transmission cage. The cage was divided with an aerated barrier that allowed the infected hamster to be co-housed with previously treated uninfected hamsters housed on the other side, permitting us to study viral infection by aerosol transmission. Daily swabs were collected from all hamsters to monitor the infection by qPCR for the viral N gene. On day 4 after infection, the hamsters were euthanized and lungs and nasal turbinates were collected for quantification of viral infection. The experiment was repeated n = 3 times for a total of n = 9 UDCA and n = 6 vehicle hamsters. Data were analysed blinded to the identity of the experimental groups.

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Animal Experiments [5]
The generation of FATP5 null mice has been described previously Mice were fed standard chow prior to the high-fat diet experiments (60% calories from fat). All experiments were performed with individually housed animals. For the bile acid injection experiments mice were injected subcutaneously with 3.2mg/kg DCA or LCA in 20 μl DMSO on the back above the right hip once a day for 7 weeks while consuming a high-fat diet. For bile acid feeding experiments 5mg/g Ursodeoxycholic acid/UDCA, 0.5mg/g DCA or 0.5mg/g LCA in high fat food were mixed. The mice were fed the supplemented high fat diet for 7 weeks. Their food intake and body weight were recorded once a week. During this time, the mice had ad libitum access to water and high fat food. For tissue and plasma collection, mice were fasted 4 hours prior to euthanization. After euthansia by CO2 asphyxiation, subcutaneous injection sites were examined to verify that no bile acid precipitates had accumulated. Liver and other organs were removed, lysed and the protein and TAG concentrations of organ lysates were assayed using the BCA protein assay kit and infinity TAG kit respectively. All procedures were approved by the UC Berkeley ACUC.

Absorption, Distribution and Excretion
Normally, endogenous ursodeoxycholic acid constitutes a minor fraction (about 5%) of the total human bile acid pool. Following oral administration, the majority of ursodiol is absorbed by passive diffusion, and its absorption is incomplete. Once absorbed, ursodiol undergoes hepatic extraction to about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. During chronic administration of ursodiol, it becomes a major biliary and plasma bile acid. At a chronic dose of 13 to 15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids.
Ursodeoxycholic acid is excreted primarily in the feces. Renal elimination is a minor elimination pathway. With treatment, urinary excretion increases but remains less than 1% except in severe cholestatic liver disease.
The volume of distribution of ursodeoxycholic acid (UDCA) has not been determined; however, it is expected to be small since UDCA is mostly distributed in the bile in the gallbladder and small intestines.

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Metabolism / Metabolites
Upon administration, ursodeoxycholic acid (UDCA) enters the portal vein and into the liver, where it undergoes conjugation with glycine or taurine. UDCA is also decreased into bile. Glycine or taurine conjugates are absorbed in the small intestine via passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free UDCA that can be reabsorbed and re-conjugated in the liver. Nonabsorbed UDCA passes into the colon, where it undergoes 7-dehydroxylation by intestinal bacteria to lithocholic acid. Some UDCA is epimerized to [chenodeoxycholic acid] via a 7-oxo intermediate. Chenodeoxycholic acid also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine or taurine, and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces.

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Biological Half-Life
The estimated half-life ranges from 3.5 to 5.8 days.

Hepatotoxicity
n multiple clinical trials in a variety of conditions, ursodiol has not been found to cause increases in serum enzyme elevations, worsening of underlying liver disease or clinically apparent liver injury. Nevertheless, there have been rare reports of clinical decompensation in patients with advanced liver disease and cirrhosis started on ursodiol, but the reason for such reactions is not known. In at least one instance, there was recurrence of jaundice on restarting ursodiol. Thus, ursodiol has beneficial effects on several forms of liver disease and has not been convincingly linked to cases of clinically apparent acute liver injury in patients without cirrhosis. There is some concern that ursodiol may be harmful in patients with advanced liver disease (Childs class B and C) and such patients probably should not receive ursodiol.
Likelihood score: D (possible rare cause of acute decompensation of preexisting liver disease).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Ursodiol is naturally present in human milk. Because of the low levels of ursodiol (ursodeoxycholic acid) in breastmilk after exogenous administration, amounts ingested by the infant are small and are not expected to cause any adverse effects in breastfed infants. Ursodiol has been given directly to newborns to safely and successfully treat prolonged neonatal jaundice. No special precautions are required.
◉ Effects in Breastfed Infants
One breastfed (extent not stated) infant developed normally over the first 6 months of life during maternal ursodiol therapy of 750 to 1000 mg daily.
Seven women who were taking ursodiol 14 mg/kg daily near term and postpartum. They reported no adverse reactions in their breastfed infants during the early postpartum period.
A mother receiving oral ursodiol 250 mg 3 times daily for primary biliary cirrhosis reportedly breastfed her infant normally, although the extent and duration of breastfeeding was not stated.
A woman with primary biliary cirrhosis developed severe pruritus and elevated serum bile acids 3 weeks postpartum. Ursodiol was started at a dose of 500 mg (7.5 mg/kg) daily, increasing to 1500 mg (25 mg/kg) daily over the next 8 weeks. Psychomotor development of her breastfed (extent not stated) infant was normal, and no apparent side effects were observed in the infant.
A retrospective review of the medical records of pregnant patients at a hospital in Ankara, Türkiye who had a diagnosis of primary biliary cirrhosis found 8 patients who took ursodiol postpartum in doses of 13–15 mg/kg daily. “Most” of the patients breastfed their infants (extent not stated). No infant side effects were reported.
A woman was breastfeeding her 8-day-old preterm infant 10 times daily for about 15 minutes each time. The infant was born by cesarean section at 34 weeks of gestation with a weight of 3600 grams. She was diagnosed with cholestasis, type 1 diabetes, and hypothyroidism. She was treated with ursodiol 500 mg daily, insulin levemir and aspart, and levothyroxine. She was also taking cefuroxime, flurbiprofen, a combination of acetaminophen, propyphenazone, and caffeine. The mother took the ursodiol for a total of 12 days, cefuroxime and the analgesic combination for 10 days and flurbiprofen for 15 days. No adverse effects were noticed during the period of ursodiol treatment.
Twenty nursing mothers were taking ursodiol for cholestasis in daily dosages of 500 to 1500 mg or 13 to 15 mg/kg, depending on the condition. Ursodiol was discontinued 3 days postpartum. No apparent side effects were observed in any newborn infant based on standard clinical examination during early postnatal period, and no deterioration in postnatal development was observed during routine 1-year follow-up on routine pediatric examinations.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Unconjugated ursodeoxycholic acid is at least 70% bound to plasma proteins in health individuals. There is no information regarding the protein binding of conjugated ursodeoxycholic acid.

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Toxicity Summary
UDCA has been shown to have potentially toxic molecular properties. UDCA breaks down into toxic lithocholic acid. After being absorbed in the small intestine, UDCA undergoes hepatic conjugation. Beyond conjugation, UDCA does not experience further breakdown by the liver or intestinal mucosa. It becomes oxidized or reduced, yielding either 7-keto-lithocholic acid or lithocholic acid. Litcholic acid can be toxic to liver cells and even cause liver failure in those with compromised sulfation. It also leads to segmental bile duct injury, hepatocyte failure, and death.

[1]. Secondary bile acid ursodeoxycholic acid alters weight, the gut microbiota, and the bile acid pool in conventional mice. PLoS One. 2021;16(2):e0246161.

[2]. Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study. Hepatology. 2007 Oct;46(4):1131-7.

[3]. Use of ursodeoxycholic acid in liver diseases. J Gastroenterol Hepatol. 2001 Jan;16(1):3-14.

[4]. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature. 2022 Dec 5.

[5]. Specific Bile Acids Inhibit Hepatic Fatty Acid Uptake in Mice. Hepatology. 2012 Oct;56(4):1300-10.

An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic.

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Pharmacodynamics
Ursodeoxycholic acid (UDCA) is a secondary bile acid with cytoprotectant, immunomodulating, and choleretic effects. It reduces the cholesterol fraction of biliary lipids. UDCA inhibits the absorption of cholesterol in the intestine and the secretion of cholesterol into bile, decreasing biliary cholesterol saturation. UDCA increases bile acid flow and promotes the secretion of bile acids.

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Ursodeoxycholic acid is a bile acid found in the bile of bears (Ursidae) as a conjugate with taurine. Used therapeutically, it prevents the synthesis and absorption of cholesterol and can lead to the dissolution of gallstones. It has a role as a human metabolite and a mouse metabolite. It is a bile acid, a dihydroxy-5beta-cholanic acid and a C24-steroid. It is a conjugate acid of an ursodeoxycholate.
Ursodeoxycholic acid (UDCA), also known as ursodiol, is a naturally-occurring bile acid that constitutes a minor fraction of the human bile acid pool. UDCA has been used to treat liver disease for decades: its first use in traditional medicine dates back more than a hundred years. UDCA was first characterized in the bile of the Chinese black bear and is formed by 7b-epimerization of [chenodeoxycholic acid], which is a primary bile acid. Due to its hydrophilicity, UDCA is less toxic than [cholic acid] or [chenodeoxycholic acid]. UDCA was first approved by the FDA in 1987 for dissolution of gallstones and for primary biliary cirrhosis in 1996. UDCA works by replacing the hydrophobic or more toxic bile acids from the bile acid pool.

Ursodiol is a Bile Acid.
Ursodeoxycholic acid or ursodiol is a naturally occurring bile acid that is used dissolve cholesterol gall stones and to treat cholestatic forms of liver diseases including primary biliary cirrhosis. Ursodiol has been linked to rare instances of transient and mild serum aminotransferase elevations during therapy and to rare instances of jaundice and worsening of liver disease in patients with preexisting cirrhosis.
Ursodeoxycholic acid has been reported in Myocastor coypus with data available. LOTUS - the natural products occurrence database Ursodiol is a synthetically-derived form of ursodiol, a bile acid produced by the liver and secreted and stored in the gallbladder. Also produced by the Chinese black bear liver, ursodiol has been used in the treatment of liver disease for centuries. This agent dissolves or prevents cholesterol gallstones by blocking hepatic cholesterol production and decreasing bile cholesterol. Ursodiol also reduces the absorption of cholesterol from the intestinal tract.

URSODIOL is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 1987 and is indicated for primary biliary cirrhosis and biliary liver cirrhosis and has 25 investigational indications.
An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic.

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Ursodeoxycholic 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 in conventional mice. 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 healthy gastrointestinal ecosystem in conventional mice. Further studies to investigate how these changes in turn modify the host physiologic response are important.[1]

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Ursodeoxycholic acid is currently the only established drug for the treatment of chronic cholestatic liver diseases. It has cytoprotective, anti-apoptotic, membrane stabilizing, anti-oxidative and immunomodulatory effects. Prolonged administration of ursodeoxycholic acid in patients with primary biliary cirrhosis (PBC) is associated with survival benefit and a delaying of liver transplantation. There is evidence that it might even prevent progression of the histologic stage of PBC. It also has a beneficial effect on primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, liver disease associated with cystic fibrosis, chronic graft versus host disease, total parenteral nutrition associated cholestasis and various pediatric cholestatic liver diseases. In the present review the current knowledge about the mechanisms of the action and role of ursodeoxycholic acid in the treatment of various liver diseases has been discussed. [3]

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Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.[4]

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Bile acids are known to play important roles as detergents in the absorption of hydrophobic nutrients and as signaling molecules in the regulation of metabolism. We tested the novel hypothesis that naturally occurring bile acids interfere with protein-mediated hepatic long chain free fatty acid (LCFA) uptake. To this end, stable cell lines expressing fatty acid transporters as well as primary hepatocytes from mouse and human livers were incubated with primary and secondary bile acids to determine their effects on LCFA uptake rates. We identified ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) as the two most potent inhibitors of the liver-specific fatty acid transport protein 5 (FATP5). Both UDCA and DCA were able to inhibit LCFA uptake by primary hepatocytes in a FATP5-dependent manner. Subsequently, mice were treated with these secondary bile acids in vivo to assess their ability to inhibit diet-induced hepatic triglyceride accumulation. Administration of DCA in vivo via injection or as part of a high-fat diet significantly inhibited hepatic fatty acid uptake and reduced liver triglycerides by more than 50%. Conclusion: The data demonstrate a novel role for specific bile acids, and the secondary bile acid DCA in particular, in the regulation of hepatic LCFA uptake. The results illuminate a previously unappreciated means by which specific bile acids, such as UDCA and DCA, can impact hepatic triglyceride metabolism and may lead to novel approaches to combat obesity-associated fatty liver disease.[5]

C24H39O4-.NA+

414.55386

414.274

C, 69.53; H, 9.48; Na, 5.55; O, 15.44

2898-95-5

Ursodeoxycholic acid;128-13-2

23707110

White to off-white solid powder

2.98E-14mmHg at 25°C

3.143

2

4

4

29

612

10

C[C@H](CCC(=O)[O-])[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@H](C[C@H]4[C@@]3(CC[C@H](C4)O)C)O)C.[Na+]

WDFRNBJHDMUMBL-FUXQPCDDSA-M

InChI=1S/C24H40O4.Na/c1-14(4-7-21(27)28)17-5-6-18-22-19(9-11-24(17,18)3)23(2)10-8-16(25)12-15(23)13-20(22)26;/h14-20,22,25-26H,4-13H2,1-3H3,(H,27,28);/q;+1/p-1/t14-,15+,16-,17-,18+,19+,20+,22+,23+,24-;/m1./s1

sodium;(4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate

2898-95-5; Ursodeoxycholate sodium; Sodium Ursodeoxycholate; Ursodeoxycholic Acid Sodium Salt; YKU915YJNV; Ursodeoxycholic acid (sodium); Cholan-24-oic acid, 3,7-dihydroxy-, sodium salt (1:1), (3alpha,5beta,7beta)-; 2898-95-5 (sodium);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~301.53 mM)
H2O : ≥ 100 mg/mL (~241.23 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.02 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)