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Bile Acids: Beyond Gut Health

The role bile acids play in metabolic and liver health

The use of bile therapeutically dates to ancient times. Bile from many different animals, and even humans in the time of battle, have record in traditional Chinese medicine (TCM) beginning in the Zhou dynasty from 1046-256 BCE.[1] In TCM, bile acids are used for the treatment of gallstones, infectious skin diseases or burns, vision and eye conditions, respiratory infections, and even coma and epilepsy.[1] Ox bile was one of the first forms of bile to be used in TCM and contains many of the same bile acids found in human bile.

Our discovery of the distinct constituents of bile goes back to the mid-19th century.[2] With the continuing advancement of scientific techniques, we now know not only the typical composition of the bile acid pool, we also know how altered bile acid metabolism and levels may contribute to different disease states,[3],[4],[5] and much more about the receptors they activate.[6] In addition to the role they play in gastrointestinal conditions, bile acids have a significant impact on metabolic function and liver/gallbladder health,[7],[8] and even may impact the health of the skin, improving psoriasis.[9] Herein, we take a closer look at the impact bile acids have on metabolic and liver disease, and how they may be of use therapeutically.

Bile acid metabolism and receptor interactions

The human bile salt pool is primarily comprised of cholic acid (CA), chenodeoxycholic acid (CDCA), and deoxycholic acids (DCA), with smaller amounts of lithocholic acid (LCA) and ursodeoxycholic acid (UDCA).[10],[11] The primary bile acids CA and CDCA are produced in the cells of the liver (hepatocytes) from cholesterol.[12] They are then conjugated with glycine or taurine (increasing their water solubility) prior to being excreted from liver across via transporters also associated with Phase III detoxification.[13] In the digestive tract, enzymes produced by certain microbes in the gut deconjugate and dehydroxylate these bile acids, forming the secondary bile acids DCA (from CA) and LCA (from CDCA).[14]

In addition to the role they play in gastrointestinal conditions, bile acids have a significant impact on metabolic function and liver/gallbladder health, and even may impact the health of the skin, improving psoriasis.

Bile acids have a multitude of effects throughout the body due to their interactions with the nuclear receptors farnesoid X receptor (FXR),[15] pregnane X receptor,[16] and the vitamin D receptor, as well as multiple G-protein coupled receptors (GPCRs), which are found in the cell membrane.[7] In the liver, the majority of these functions are mediated by FXR, which also plays a role in the synthesis, transport, and enterohepatic circulation of the bile acids themselves. Interactions of bile acids with FXR in the hepatocyte serves a self-regulatory role, protecting them from damage due to excessive amounts of bile by increasing transcription of bile salt export pumps[17] and reducing bile acid synthesis,[18] which both help lower the intracellular bile acid concentration when necessary – such as biliary duct blockage due to gallstones or other forms of cholestasis.

In addition to protecting hepatocytes,[19] activation of FXR by bile acids induces genes involved in the different phases of detoxification,[20] protecting the cells of the liver from drug and xenobiotic toxicity.[21],[22] This is one reason why supplemental bile acids are a life-saving intervention for individuals with bile acid synthesis disorders,[23] as they help protect the liver by increasing bile acid-dependent bile flow and toxin transport out of the hepatocyte. For individuals with bile acid synthesis disorders, CA, the main bile acid found in ox bile, is the primary bile acid used as a therapy.[24]

In addition to protecting hepatocytes, activation of FXR by bile acids induces genes involved in the different phases of detoxification.

FXR is known to be expressed in the liver, pancreas, ileum, kidney, and adrenal glands, and at lower levels in the heart, central nervous system, adipose tissue, and arterial walls.[11] The ability of the different bile acids to activate FXR varies, with CDCA (also found in ox bile[25]) being the strongest activator and CA the weakest. Animal and in vitro studies suggest that activation of FXR by bile acids decreases plasma triglycerides, cholesterol, and hepatic steatosis; reduces gluconeogenesis; and increases insulin sensitivity, cellular glucose uptake, and glycogen synthesis.[26],[27],[28],[29],[30] Stimulation of the enterocytes of the digestive tract with bile acids also activates FXR and increases secretion of fibroblast growth factor 19 (FGF19), which has insulin-sensitizing and cholesterol-reducing effects.[31]

Interactions of bile acids with G-protein-coupled bile acid receptor, Gpbar1 (TGR5), a cellular membrane receptor, is another major route via which their metabolic actions are exerted. TGR5 is not expressed in the hepatocyte but is expressed in brown adipose tissue (BAT), pancreatic beta cells, and the biliary tract, which collectively impact metabolic and liver disease.[32] Interactions of bile acids with TGR5 increases cyclic-AMP synthesis, which impacts energy production and increases insulin secretion by pancreatic beta cells;[33] and increases production of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY),[34] which play important roles in appetite and blood sugar regulation.

Metabolic disease

Numerous studies have shown altered bile acid homeostasis in individuals with type 2 diabetes (T2D).[35] Several studies suggest that the weight loss and improved glycemic control seen with bariatric surgery, or other weight-loss procedures such as gallbladder bile diversion to the ileum, may be due to altered bile acid availability.[36],[37]

In patients post-gastric bypass, total bile acid levels, as well as the bile acid subfractions, were significantly higher than overweight controls.[38] Total bile acid levels and their subfractions were inversely correlated with 2-hour post-prandial glucose and triglyceride levels as well as thyroid stimulating hormone, and positively correlated with adiponectin and GLP-1 levels. Post-gastric bypass assessment of non-diabetic females also showed an increase in the levels of total bile acids and FGF19 (commonly used to assess FXR activation) and decreased triglyceride levels postprandially as well.[39]

Fasting serum CDCA (the bile acid with the strongest FXR activating ability) and FGF19 levels have been shown to be independently related and significantly lower in individuals with impaired fasting glucose and T2D.[44],[45] Interestingly, serum levels of FGF19 have been observed to be lower in patients with overt and subclinical hypothyroidism,[40] which may contribute to metabolic changes seen in these conditions as well.

Several studies suggest that the weight loss and improved glycemic control seen with bariatric surgery may be due to altered bile acid availability.

Increased expression of the primary cytochrome P450 enzyme that regulates bile acid synthesis was shown in mice to increase the bile acid pool and hepatic cholesterol breakdown and decrease the expression of several genes involved in lipogenesis and glucogenesis.[41] These animals, despite being subject to high-fat diet (HFD) feeding, were resistant to the development of obesity, fatty liver changes, and insulin resistance, and had increased whole body energy expenditure.

Supplementation of CA along with HFD feeding has been shown to prevent weight gain and increased adipose mass in mice, and also reduced the whitening of BAT (which has negative metabolic effects).[42] Additionally, in mice initially fed a HFD for 120 days, the addition of CA to the diet returned their body weight to that of the typical chow-fed mice within 30 days. In a different mouse study of diet-induced obesity, feeding of CDCA in addition to a HFD led to a significant improvements in glucose tolerance and a decrease in weight, restoring the later to that of the mice fed a typical diet.[46]

Both CA and CDCA have been shown to counteract diet-induced obesity in animals by enhancing BAT energy expenditure.[47],[48] In healthy females, short-term oral supplementation with CDCA at a dose of 15 mg/kg/day was shown to significantly increase BAT activity as well as whole body energy expenditure without any deleterious effects such as diarrhea.[49]

In healthy females, short-term oral supplementation with CDCA was shown to significantly increase BAT activity as well as whole body energy expenditure.

One additional item worthy of note in a discussion of bile acids and metabolic disease is the use of probiotic bacteria to modify bile acid metabolism. Known as bile salt hydrolase (BSH)-active bacteria, these bacteria produce the enzyme BSH which deconjugates bile acids, reducing the absorption of cholesterol and increasing FXR activation, as the deconjugated bile acids are strong activators of FXR.[50] Human studies using the BSH-active probiotic strain Lactobacillus reuteri NCIMB 30242 have shown that, indeed, such a probiotic is capable of improving not only the balance and levels of cholesterol,[51],[52] but also improves symptoms of irritable bowel syndrome,[53] which may be somewhat attributable to the antimicrobial effects of the secondary bile acids.

Fatty liver disease

Given that the main uses of bile acids in modern medicine are for the dissolution of cholesterol gallstones and treatment of cholestatic liver diseases,[54],[55],[56],[57] it should not come as a surprise that bile acids have other potential applications in the setting of liver and gallbladder disease. Although UDCA is the primary bile acid indicated for uncomplicated cholelithiasis, at one time, CDCA, found in both human and ox bile, was also a common intervention.[58]

At one time, CDCA, found in both human and ox bile, was also a common intervention for uncomplicated gallstones.

Although the condition of non-alcoholic fatty liver disease (NAFLD), frequently seen in conjunction with obesity and T2D, is primarily attributed to increased triglyceride accumulation in the cells of the liver, it also is associated with dysbiosis, intestinal inflammation, and increased gut permeability.[59],[60] In addition to the antimicrobial, insulin-sensitizing, and triglyceride-reducing effects that bile acids have,[61],[62] activation of FXR by bile acids also supports intestinal barrier integrity and reduces bacterial translocation, positioning bile acids as a very promising agent for the treatment of this condition, which to date has no recommended pharmaceutical intervention. Milk thistle and berberine are FXR agonists that both have clinical evidence for the treatment of NAFLD.[63],[64]

Activation of FXR by bile acids may reduce hepatic inflammation and injury associated with alcoholic liver disease as well,[65],[66] mediated by many of the same mechanisms. Both FXR and TRG5 play a role in protecting the liver from fibrosis,[67] the end stage of both NAFLD and alcoholic liver disease.

 

Clearly, although bile acids have a long history of use medicinally, we are only starting to understand their broad therapeutic application. Unfortunately, we will likely only see such research with regards to their more potent, synthetic, derivatives or isolated fractions – which neglects the importance that a blend of bile acids, similar in composition to what is naturally produced by our body, may offer a natural therapy. Often, lower doses of such substances gently stimulate the body rather than pushing a single pathway very strongly, leading to great potential for their systemic healing action.

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