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Bile Acids: Their Role in Gut Health Beyond Fat Emulsification

Supplemental bile acids and their potential for dysbiosis, constipation, and inflammatory bowel disease

Generally, when we think of bile, the role it plays in digestion is what we think of first. Produced by the liver and expelled into the digestive tract by the gallbladder (for those of us who have one), bile emulsifies and breaks down dietary fats so they can be absorbed in the small intestine. However, the effects of bile acids in the body go far beyond this.

In the digestive tract, bile acids also affect the balance of flora and gut motility;[1],[2] outside of the gut, they regulate many critical facets of physiology including glucose and cholesterol metabolism,[3] promote intracellular thyroid hormone activation,[4] and serve as signalling molecules, activating farnesoid X receptor (FXR), pregnane X receptor, the vitamin D receptor, and various G-protein coupled receptors.[5] Evidence also suggests that bile acids affect neurological function as well as the response of the hypothalamic–pituitary–adrenal axis.[6] Bile acids have even been suggested to be “novel therapeutic modalities in inflammation, obesity, and diabetes.”[7]

Although collectively referred to in the general practice of medicine as bile or the bile salt pool, the function of bile acids and their metabolites vary considerably. The human bile salt pool is primarily comprised of cholic, chenodeoxycholic, and deoxycholic acids with smaller amounts of lithocholic and ursodeoxycholic acid.[8],[9] The bile acids cholic and chenodeoxycholic acid are conjugated (by the addition of glycine or taurine) which increases their water solubility before they are released from the cells of the liver into the bile canaliculus (which feeds into the larger bile ducts and gallbladder). Certain enzymes produced by microbes in the gut deconjugate and dehydroxylate the bile acids, producing the secondary bile acids deoxycholic acid (from cholic acid) and lithocholic acid (from chenodeoxycholic acid).[10]

Bile acids have even been suggested to be “novel therapeutic modalities in inflammation, obesity, and diabetes.”

Bile salts are amphipathic in nature, having both hydrophobic and hydrophilic qualities in greater or lesser amounts depending on their conjugation and hydroxylation state.[8] Their ability to activate different receptors also varies according to their structure. Deconjugated bile acids are more hydrophobic and have greater detergent action, which increases their ability to facilitate emulsification and absorption of dietary lipids and fat soluble vitamins and to break down bacterial membranes.[11],[12] Deoxycholic acid is a particularly strong antimicrobial agent, having 10 times the antimicrobial activity of cholic acid, its precursor.[13]

Herein, we take a look at the potential of bile acids as a nutritional therapy beyond just supporting fat digestion.

Gastrointestinal impact of bile acids

The relationship between the gut microbiota and bile acids is bi-directional: bile acids affect the composition of the intestinal microbiome, and the bacteria present in the gut affect bile acid metabolism.[14] Lower levels of bile acids in the gut are associated with an overgrowth of bacteria and potential pathogens (examples being Clostridium difficile[15] and Helicobacter pylori[16]), increased inflammation, and increased bacterial translocation.[17] Bile acids have both direct and indirect antimicrobial effects: their detergent action serves to break down bacterial membranes[18] and their binding with FXR induces the secretion of antimicrobial peptides.[19] The binding of bile acids with the nuclear receptor FXR also has been shown to support intestinal barrier integrity and reduce bacterial translocation.

Small intestinal bacterial overgrowth and functional constipation

Small intestinal bacterial overgrowth (SIBO) is a common underlying issue that leads to symptoms of irritable bowel syndrome (IBS), and typically manifests with symptoms of gas, bloating, and altered bowel patterns.[20] Permanent resolution of this condition is often difficult to achieve, as many relapse when they cease following a restrictive diet or using the antimicrobials that help keep it at bay. A tool that may help resolve this condition and prevent its recurrence (particularly when it is constipation driven) that is often neglected is supplemental bile acids.

Lower levels of bile acids in the gut are associated with an overgrowth of bacteria and potential pathogens, increased inflammation, and increased bacterial translocation.

Bile acids have been shown to inhibit the growth of bacteria that produce methane (one of the gases measured in the assessment for SIBO that is associated with constipation) in vitro in a dose-dependent fashion, a finding that was supported by the results of a clinical case study as well.[21] Bile acids have been shown to reduce hydrogen production in vitro as well, likely due to their antimicrobial effects.[22] In rat models of cirrhosis and obstructive jaundice (both being conditions associated with reduced bile secretion),[23] bile acid supplementation reduced bacterial overgrowth, bacterial translocation, and the related endotoxemia,[24],[25] while in the model of cirrhosis, it also led to the normalization of bile secretion.

As a promotility agent, bile acids can help reduce the constipation that is often seen with the overgrowth of methanogenic (methane-producing) bacteria.[2],[26] Bile acids serve to hasten gut transit time by inducing fluid and electrolyte secretion as well as stimulating colonic contractions.[27] Functional constipation in approximately 15% of adults has been shown to be associated with reduced total bile acid and deoxycholic acid levels in the feces,[28] and in a smaller percentage of children also may be due to altered bile acid metabolism.[29]

As a promotility agent, bile acids can help reduce the constipation that is often seen with the overgrowth of methanogenic (methane-producing) bacteria.

Clinically, supplementation with a delayed-release preparation of chenodeoxycholate at 500 or 1000 mg/day for only four days improved bowel function and accelerated colonic transit time in women with constipation-predominate IBS, with the treatment being more effective in individuals with lower bile acid synthesis rates.[30] In healthy volunteers, supplemental chenodeoxycholate also has been shown to accelerate transit time, increasing stool frequency, ease of elimination, and completeness of evacuation.[31] Common adverse effects at both doses were lower abdominal cramping and diarrhea. It stands to reason that side effects such as these may be eliminated at lower doses, however these studies have not yet been done.

Inflammatory bowel disease

The pathogenesis of inflammatory bowel disease (IBD) also may be in part due to altered bile acid metabolism.[32] Often accompanied by dysbiosis, it shouldn’t come as a surprise that the balance of the bile acid pool is also altered in IBD. In addition to their effect on the gut microbial balance, bile acids may impact IBD through interactions with the innate and adaptive immune system, as receptors which bile acids bind (FXR and the G protein-coupled receptor, TGR5) are expressed by cells of the immune system (including macrophages, dendritic cells, and natural killer T cells) and serve to help maintain immune tolerance.[33] Bile acids also stimulate secretion of phosphatidylcholine by the cells of the liver.[34] Phosphatidylcholine is an important component of the protective intestinal mucus barrier,[35] and has been shown to be deficient (and therapeutic when applied as a treatment) in patients with ulcerative colitis.[36],[37]

In patients with IBD, lower levels of the secondary bile acids have been observed (being even lower during a flare), along with a decreased level of the gut bacteria that deconjugate bile acids.

Numerous animal models have shown that the nuclear receptor FXR and the interactions of bile acids with it affect the intestinal barrier integrity.[38] In patients with Crohn’s colitis, reduced activation of FXR in the ileum has been observed,[39] while supplementation of chenodeoxycholic acid to patients with Crohn’s was shown to increase ileal FXR activation as well as gallbladder filling.[40] An animal model of colitis supports further research in this realm, finding that treatment with an FXR-activating agent ameliorated inflammation, protected the intestinal barrier, and improved symptoms.[41]

Interactions of bile acids with TGR5 also may impacts IBD. The elimination of the genetic expression of TGR5 in animals leads to abnormal colonic mucus morphology, increased intestinal permeability, and an increased susceptibility to colitis;[42] treatment with deoxycholic and lithocholic acid or a TGR5 agonist suppresses the release of proinflammatory mediators from immune cells isolated from inflamed tissue of Crohn’s patients;[43] and numerous other animal models show that the absence or lowered expression of TGR5 leads to increased inflammation, or the stimulation of TGR5 with bile acids helps ameliorate it.[44],[45]

In patients with IBD, lower levels of the secondary bile acids (which, as mentioned, are stronger antimicrobials in addition to having a higher affinity for these bile acid receptors) have been observed (being even lower during a flare), along with a decreased level of the gut bacteria that deconjugate bile acids.[32],[46] For this reason, in addition to the potential that supplemental bile acids have for this condition, probiotics that deconjugate bile acids (in particular those that express bile salt hydrolase [BSH], known as BSH-active bacteria) have been suggested as a therapy. Notably, in a study of individuals with elevated cholesterol (a condition that BSH-active probiotics also have been shown to improve), a BSH-active probiotic (Lactobacillus reuteri NCIMB 30242) not only significantly increased levels of deconjugated bile acids in the body but also improved digestive symptoms, particularly that of diarrhea, and reduced inflammation, as assessed by high-sensitivity C-reactive protein.[47],[48]

 

With the broad array of functions the receptors that bile acids interact with have, and the wide distribution of these receptors throughout the body, research regarding their impact on gastrointestinal health is only but a snapshot of the important role bile acids play in maintaining homeostasis and health. Stay tuned future posts where we take a further look at bile acids and the role they play in metabolic and liver disease, as well as a diverse array of research into their application for conditions ranging from neurological disorders to allergies. And, if you can’t wait that long, learn more about the clinical experience of one physician who has found them to be a key tool for improving the condition of psoriasis!

 

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The Clinical Role of Gastrointestinal Binders
You Are What You Eat

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