Chenodeoxycholic acid

Chenodeoxycholic acid, or chenodiol, is a primary bile acid produced by the human liver. The two primary bile acids, chenodeoxycholic acid, and cholic acid, are directly synthesized from cholesterol. They contain four fused rings of 17 carbon atoms with added functional groups or conjugated amino acids. Chenodeoxycholic acid, together with other bile acids, plays essential roles in several physiological processes in the body, such as food absorption and digestion, immune response regulation, and energy metabolism.

Research studies have found several links between chenodeoxycholic acid and the modulation of the gut microbiome, further improving overall health. Chenodeoxycholic acid is also highly effective in dissolving cholesterol gallstones and improving the genetic disorder cerebrotendinous xanthomatosis.

Chenodeoxycholic acid and bile acid metabolism

Chenodiol is the major bile acid synthesized in the liver and is usually of the highest concentration in serum, liver cells, and bile. Chenodeoxycholic acid production increases the bile acid pool size while it reduces cholesterol levels¹.

From the liver, chenodeoxycholic acid is secreted into the bile and transported to the intestine. Here, chenodeoxycholic acid comes in contact with food and is reabsorbed together with dietary fats. However, up to 10% of the primary bile acids are instead metabolized by the gut microbiota.

Intestinal gut bacteria produce the secondary bile acids lithocholic acid, deoxycholic acid, ursodeoxycholic acid, and other bile acid derivatives. These products are reabsorbed and transported back to the liver, where they are recycled as part of the enterohepatic circulation.

Chenodeoxycholic acid and food uptake

Like all bile acids, chenodeoxycholic acid is an amphipathic molecule, able to associate with fat molecules and water at the same time. In the small intestine, chenodeoxycholic acid emulsifies lipids and fats, cholesterol, and fat-soluble vitamins from food. This helps in dissolving these important molecules and transporting them into and throughout the body².

Primary bile acids are essential for absorbing lipids from diet and therefore for extracting energy from lipids. The entire bile acid pool can turn over 3-5 times during a single meal.

Chenodeoxycholic acid and the gut microbiome

In the intestines, the bile acid chenodeoxycholic acid comes in contact with gut bacteria. Chenodeoxycholic acid is a direct antibacterial agent, as it changes or destroys the bacterial cell membrane.

Other resident gut bacteria convert chenodeoxycholic acid into secondary bile acids, short-chain fatty acids (SCFAs), and other metabolites. These products have important functions in the body’s metabolism, as signaling molecules, in the immune response, cardiac function, hormonal status, intestinal barrier function, and gut health.

Hence, bile acids influence the composition of gut microbial communities both directly and indirectly. At the same time, diet and gut bacteria influence the levels and composition of bile acids and bile acid synthesis and support food digestion and energy production³.

Chenodeoxycholic acid in disease and therapy

Due to its tight link to diet and the gut microbiome, defects in bile acid synthesis can impact several metabolic diseases. For example, patients with gut inflammation-associated diseases, such as inflammatory bowel diseases (IBD), celiac disease, and irritable bowel syndrome (IBS), show defects in bile acid synthesis and metabolism and often have high levels of chenodeoxycholic acid and other bile acids⁴.

Bile acid synthesis defects can further impact metabolic, cardiometabolic, and hormonal diseases. As in chenodeoxycholic acid therapy, replacing bile acids was shown to regulate both the microbiome composition and systemic bile acid levels. Together with a healthy diet, various symptoms can be improved, leading to potentially better outcomes of obesity, diabetes, non-alcoholic fatty liver disease (NAFLD), and endometriosis⁵.

On the other hand, unhealthy diet and lifestyle habits can result in cholesterol saturation of bile, which is a major risk factor for developing painful cholesterol gallstones. Yet, this gastrointestinal disorder can be treated with chenodeoxycholic acid as it solubilizes cholesterol, thus reducing its concentration in bile while also dissolving cholesterol gallstones⁶.

Finally, patients with a genetic defect in chenodeoxycholic acid synthesis develop cerebrotendinous xanthomatosis. These patients form depositions containing cholesterol and the side product cholestanol in the joints and in the brain, potentially resulting in neurological impairment. Chenodeoxycholic acid therapy and dietary modifications can improve these depositions⁷.

References

1. Fiorucci S and Distrutti E. Chenodeoxycholic Acid: An Update on Its Therapeutic Applications. Handb Exp Pharmacol 2019;256:265-282.
2. Camilleri M. Bile acid detergency: permeability, inflammation, and effects of sulfation. Am J Physiol Gastrointest Liver Physiol 2022;322(5):G480-G488.
3. Su X, Gao Y, and Yang R. Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity. Front Immunol 2023;14:1127743.
4. Guan B, Tong J, Hao H, et al. Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases. Acta Pharm Sin B 2022;12(5):2129-2149.
5. Podda M, Zuin M, Battezzati PM, et al. Efficacy and safety of a combination of chenodeoxycholic acid and ursodeoxycholic acid for gallstone dissolution: a comparison with ursodeoxycholic acid alone. Gastroenterology. 1989;96(1):222-9.
6. Islam M, Hoggard N, and Hadjivassiliou M. Cerebrotendinous Xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid. Cerebellum Ataxias 2021;8(1):5.