Tauroursodeoxycholic Acid
Description:
Tauroursodeoxycholic acid, more commonly referred to as TUDCA, is a bile salt that is found naturally occurring in the body. When regular bile salts reach the intestines, they can be metabolized by bacteria into UDCA and then later bound to a taurine molecule to become TUDCA.
TUDCA is a water-soluble bile salt, which is in contrast to regular bile salts possessing both water soluble and fat-soluble ends and conferring a detergent effect. This is good for the bile salt’s biological purpose (emulsifying fats in the intestines to help with absorption) but when bile acids back up in the liver, a clinical state called cholestasis which occurs when the liver is unhealthy, these bile salts can be damaging to cells by destroying the membranes and signaling for cell death. TUDCA and other water-soluble bile salts like UDCA compete with this toxicity and thus indirectly protect cells from death.
Additionally, it seems that TUDCA is able to reduce stress to any cell’s Endoplasmic Reticulum; an organelle in cells that serves as a highway from the nucleus out into the cytoplasm, and aids in folding proteins. Through reducing ER stress, TUDCA has been implicated in a wide range of beneficial metabolic effects such as reducing insulin resistance and diabetes, and being a neurological protection agent. However, usages of TUDCA beyond the liver are preliminary whereas usage of TUDCA for helping an already harmed liver is quite reliable as TUDCA is used in clinical settings (hospitals) for treating cholestasis.
History:
Bear bile, which contains large amounts of TUDCA, has been used in traditional Chinese medicine for more than 3,000 years. However, TUDCA obtained from bears is extremely controversial due to animal welfare concerns.
Bile is either extracted from live bears on “farms,” where bears are kept in small cages and are subjected to either perpetually open wounds or to constant invasive surgery or wild bears are hunted for their gallbladders. These practices persist even though TUDCA can be chemically synthesized.
However, TUDCA and UDCA are nowadays mostly synthetically produced. Scientists are continuously developing new methods for environmentally- and animal-friendly large-scale TUDCA and UDCA production, such as through the fermentation of certain bacterial strains.
Mechanism of Action:
Scientists propose TUDCA may act by:
1- Increasing glucose-induced insulin release via the cAMP/PKA pathway, increasing insulin sensitivity.
2- Relieving endoplasmic reticulum (ER) stress. The ER makes sure proteins are folded properly. Reducing programmed cell death (apoptosis) in healthy cells.
3- TUDCA prevents the molecule BAX from reaching the mitochondria. BAX causes mitochondria to release cytochrome C, which causes enzymes (caspases) to initiate apoptosis.
4- Inactivating Bcl-2-associated death promoter (BAD), a molecule involved in apoptosis.
5- Removing toxic bile acids from the liver and preventing them from damaging liver cells
Effect of Fat Mass and Obesity:
Thyroid and Metabolic Rate
Circulating Bile Acids (those not found in the liver, but the blood) have been found to be correlated with energy expenditure in humans. With correlation coefficients of 0.648 in healthy persons and 0.833 in those with cirrhosis, although other smaller studies (n=24) find no such correlations.
TUDCA has been shown in vitro to increase protein content and mRNA levels for the deiodinase enzyme D2 in cells expressing this protein normally; this protein converts relatively low-activity thyroid hormone T4 to T3, and incubation with TUDCA was able to double protein content of the enzyme and increase T3 levels at concentrations between 100-800uM, reaching three-fold increases at the highest level. Although the delayed response to max potency and prior evidence that deiodinases are regulated post-transcriptionally, the authors noted that the increase in deiodinase mRNA (Dio2) makes it unlikely that the effects seen are secondary to protein stabilization.
When fed to mice at 0.5mg/kg bodyweight, TUDAC was unable to induce fat loss over 7 days but induced a change in respiratory quotient by 5% towards using fatty acids as substrate. Serum levels of T3 and T4 were unchanged in these animals, suggesting localized usage of T3 or a mechanism independent of thyroid hormones. Another report noted small but statistically significant decreases in body weight in mice over 15-30 days, but did not specify dose of TUDCA used. It is possible that these effects are through increasing activity of the D2 receptor, which has been demonstrated in animals with 0.5% cholic acid in the diet that induced similar effects such as an increase in metabolic rate alongside a decrease in respiratory quotient (indicative of a greater % of energy from fatty acids).
These mechanisms may be relevant to humans due to muscle cells expressing the same D2 receptor, and at least cholic acid has been found to increase human myocyte mRNA of this receptor (TGR5) and similar trends were found with all tested bile acids.
Adipokines
It has been noted that the obesity-related suppression of adiponectin content may be related to ER stress, and one rat study has shown TUDCA in diet-induced obesity was able to increase circulating adiponectin levels via the protein DsbA-L.
After ingestion of 1,750mg TUDCA for 4 weeks in obese but otherwise healthy persons, no significant effects were observed on body fat or weight. Insulin sensitivity was improved in skeletal muscle and the liver, but not in the adipose (body fat) tissue of these persons. This differs from previous rat studies and may be due to the dose in the rat studies being higher.
Side Effects:
Users very well tolerate TUDCA. However, there still are some side effects worth mentioning. Most important is that you should NOT consume any alcohol when you use TUDCA. Studies showed that this would only increase the damage of your liver instead of protecting it. A study done on the treatment of tauroursodeoxycholic acid for biliary cirrhosis showed that the only side-effect they noticed was diarrhea. Diarrhea was only shown on high dosages of 1000 and 1500mg. Gastrointestinal symptoms are the most known side effects of tauroursodeoxycholic acid. Below you can find a list that users reported as a side-effect: Diarrhea, Constipation, Gas and Bloating, Abdominal Pain, Nausea, Chest pain.
Usage of 500mg TUDCA daily for one year (in persons after liver transplants) was not associated with any adverse effects and in otherwise healthy obese persons doses of 1,750mg have been well tolerated for up to 4 weeks. In persons with primary biliary cirrhosis, 750mg daily for 2 months was not associated with any adverse effects and a similar population was able to tolerate 1,500mg daily for 6 months with no adverse effects. Although TUDCA/UDCA have shown beneficial effects in a number of different experimental and clinical models as noted thus far, a randomized controlled trial evaluating the efficacy of UDCA treatment in patients with primary sclerosing cholangitis (PSC) suggests that high doses for long periods of time may be toxic. PSC is a rare, chronic liver disease characterized by inflammatory fibrosis of the bile ducts and is typically associated with biliary cirrhosis and portal hypertension, which eventually progress to liver failure. In some cases cholangiocarcinoma, (bile duct cancer) can also develop.
Given the poor prognosis of PSC, there have been a number of trials testing the efficacy of UDCA for treating this disease. A few pilot trials testing UDCA in a dose range of 10-15 mg/kg bodyweight/day did show improvements in liver enzymes (an indicator of liver stress), and in certain cases liver histology (i.e. the appearance of liver biopsy sections under a microscope), although patient symptoms were not improved. Given the promising improvements of clinical markers but lack of effect on symptoms in these pilot studies, researchers reasoned that the dose and/or duration of UDCA treatment was insufficient to alleviate symptoms. This was addressed in the Lindor trial, where patients with PSC were administered 28-30 mg/kg bodyweight/day UDCA or a placebo. Treatments were assigned in a randomized, double-blinded fashion and liver biopsies were taken before the trial and after 5 years. The investigators were specifically examining the ability of UDCA to reduce or delay the following primary outcomes: development of cirrhosis, bile duct cancer, liver transplantation, or death. Ultimately the study was terminated after 6 years, because patients receiving the UDCA treatment were substantially worse-off than those who took the placebo. Although liver enzyme levels decreased more in the UDCA group, 39% of these patients reached one of the primary outcomes by the end of the study. In contrast, only 19% of patients that received the placebo reached a primary endpoint. Overall, patients receiving UDCA were 2.3x more likely to reach a primary endpoint and 2.1x more likely to die or require liver transplantation.
Dosage and Administration:
A dose-response study of TUDCA tested doses of 500 mg, 1000 mg, and 1500 mg per day over six months, finding that there was little difference between the doses on liver markers. 1500 mg was the most effective at lowering enzyme levels while 500 mg was the most cost-effective. One study suggested 60 mg/kg/day as a tolerable and administrable dose for humans. TUDCA taken at 10 – 13 mg daily for three months is able to reduce liver enzyme levels. Scientists used 15 – 20 mg/kg body weight of TUDCA for improving bile salt composition. In otherwise healthy obese persons, doses of 1,750 mg daily have been tolerated for up to four weeks. In liver transplant patients, 500 mg of TUDCA taken daily for one year was not associated with any adverse effects. In patients with PBC, 750 mg of TUDCA daily for two months was well-tolerated. Another study in patients with PBC found 1500 mg of TUDCA daily for six months was also well-tolerated.
10-13mg daily has once been shown to improve liver regenesis rates in a clinically ill population, and may be the lowest estimate of an active oral dose. When looking at improving bile salt composition, a dose around 15-20mg/kg bodyweight TUDCA seems best according to one study. Benefits have been seen at 1,750mg daily for muscle and liver insulin sensitivity, which is the highest dose used for treatment of fatty liver disease.
