The Little-Known Connection between Leaky Gut, Gluten Intolerance, and Gallbladder Problems

Do you have patients who have trouble digesting fatty foods? Back pain or nausea? A sluggish gallbladder may be to blame. Recent evidence suggests that inflammation in the gut is closely related to gallbladder function. Read on to learn about the gut–biliary connection, how gluten might be involved, and how to get things flowing again.

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As Hippocrates once said: “All disease begins in the gut.” Researchers have indeed found that many diseases are linked to changes in gut microbes or gut function. I’ve written many articles on connections between the gut and other organs on my blog:

• Gut-brain
• Gut-bone health
• Gut-thyroid
• Gut-skin

While I have helped many patients resolve gallbladder and other biliary conditions in my clinic, I haven’t covered gallbladder issues on the blog before. In this article, I’ll discuss what the biliary system does, how it relates to the gut and inflammation, and the functional medicine approach to treatment.

The Function of the Biliary Tract

The biliary tract, or biliary system, refers to the liver, gallbladder, and bile ducts, which work together to make, store, and secrete bile. After production in the liver, bile travels via the common bile duct to the gallbladder for storage. When dietary fats enter the small intestine, they are sensed by enteroendocrine cells, which release the hormone cholecystokinin. Cholecystokinin, in turn, stimulates contraction of the gallbladder and the release of bile into the small intestine (“chole” = gall, “cyst” = bladder, “kinin” = relating to contraction).

Try placing a single drop of oil in the center of a glass of water. The oil remains in one spot and doesn’t reach the edge of the glass, right? Add some dish soap, however, and the detergent encapsulates the oil, forming an emulsion and making the oil drop soluble in water. This is exactly how bile works in the small intestine. Bile is made up of 97 percent water, with the remaining 3 percent consisting of a mixture of bile acids, cholesterol, phospholipids, bilirubin, inorganic salts, and trace minerals (1). Bile acids act like a detergent, helping to emulsify lipids in food. A lipid droplet from food does not mix well with the rest of the contents of the intestinal lumen. For the droplet (oil) to be absorbed, it must first be encapsulated by bile acids (detergent) to form a micelle. This micelle is then soluble in the luminal contents (water) and is able to diffuse from the center of the lumen to the intestinal epithelium (edge of the glass) for absorption. Without bile, these lipids go undigested, resulting in fatty stools, a condition called steatorrhea. Bile is also crucial for proper absorption of the fat-soluble vitamins A, D, E, and K and cholesterol, all of which are transported to the epithelium in micelles (2).

Are gluten intolerance and gall bladder issues related?

(All Too) Common Gallbladder Diseases

Gallbladder disease symptoms can be steady or occur in acute episodes. Though symptoms will vary slightly depending on the exact disease, pain is usually located in the upper abdomen and may be accompanied by features such as jaundice (a yellowing of the skin), nocturnal onset, nausea, vomiting, and radiation of pain through to the back (3). The most common gallbladder diseases are:

Cholestasis: The backup of bile flow in the liver or in the biliary ducts.

Gallstones: Stones formed in the gallbladder from the components of bile. About 20 to 25 million Americans (10 to 15 percent of the adult population) are affected by gallstones (4). Gallstone disease is the leading cause for hospital admissions related to GI problems, yet over 80 percent of individuals with gallstones never experience biliary pain or more serious complications (5).

Cholecystitis: A complication of prolonged cholestasis and gallstone disease characterized by inflammation of the gallbladder tissue due to cholestasis and lack of blood flow. About 6 to 11 percent of patients with gallstones develop cholecystitis (6).

Cholangitis: A serious infection of the bile ducts that sometimes occurs as a complication of cholestasis or gallstones when the flow of bile is blocked. The infection can also spread to the liver, so quick diagnosis and treatment is very important (7).

Gallstone pancreatitis: In rare cases, a blockage of the pancreatic bile duct by a gallstone can cause inflammation of the pancreas. This occurs at the sphincter of Oddi, a small round muscle located where the bile duct opens into the small intestine (8). Like cholangitis, this is a dangerous condition and prompt treatment is crucial.

Risk Factors for Gallbladder Disease

Those who are overweight, female, and over the age of 40 have an increased risk of gallbladder disease. In fact, females are almost twice as likely to develop gallstones (9), and 25 percent of those who are morbidly obese have gallstones (10). Underlying diseases such as inflammatory bowel disease, liver disease, and cystic fibrosis can contribute to gallbladder disease, as well as a number of prescription medications (11, 12, 13). Pregnancy, oral contraceptives, and antibiotic use have all been associated with the onset of cholestasis (14, 15, 16, 17).

Lifestyle factors also play a role. Reduced physical activity is associated with a higher risk for gallbladder surgery (18, 19). Gallstones have also been associated with a Western-type diet high in processed foods and sugar (20, 21). In a later section, we’ll also look at the role that gluten might play in gallbladder disease.

Leaky Gut Affects the Biliary System

When intestinal barrier function is compromised (“leaky gut”), gut bacteria that are normally confined to the intestinal lumen can cross the gut barrier and enter the bloodstream. The immune system sees these microbes and their microbial products as foreign invaders and quickly launches an immune response. This can affect the biliary system, as the resulting inflammatory signaling from such a microbial invasion has been shown to alter the gene expression and function of key transport systems involved in bile uptake and secretion in the liver (22).

The connection between microbes and biliary function has been known since as early as 1901. In his classic textbook, The Principles and Practice of Medicine, Sir William Osler reports that pneumonia can lead to jaundice:

“In this form there is no obstruction in the bile-passages, but the jaundice is associated with toxic states of the blood, dependent upon various poisons which either act directly on the blood itself, or in some cases on the liver-cells as well” (23).

We now know that these “toxic states of the blood” are due to the presence of microbes in the bloodstream (sepsis) and that the “various poisons” Osler describes are inflammatory signaling molecules called cytokines, which affect transporters on liver cells.

The takeaway:

• Healthy gut → microbes remain in the colon → proper gallbladder function
• Leaky gut → microbes leak into the blood → gallbladder dysfunction and disease

Bile Helps Maintain Gut Barrier Function

Like many interorgan networks, the gut–biliary connection is a two-way street. As we covered in the previous section, leaky gut and microbes entering the blood can lead to gallbladder disease and a backup of bile. But a lack of bile entering the intestine can itself cause leaky gut and an alteration in gut bacteria.

How do we know this? Researchers found that when they induced acute liver injury in animals, the animals rapidly showed evidence of increased intestinal permeability. Notably, these changes in the gut barrier preceded any changes in the gut microbiome (24). Another research group using a mouse model of cholestasis found that stimulating certain receptors in the gut with bile acids resulted in less gut inflammation and improved gut barrier function (25). This may occur by stimulating host production of antimicrobial properties at the intestinal barrier (26).

The takeaway:

• Healthy gallbladder → bile acids reduce inflammation → proper gut barrier function
• Gallbladder disease → less bile entering the small intestine → leaky gut and dysbiosis

The Gluten Connection: Leaky Gut, Leaky Bile Duct?

I’ve written before about how gliadin, a protein in gluten, can increase the production of zonulin, a toxin that breaks down the tight junctions between epithelial cells in the gut. This causes gaps between intestinal epithelial cells and allows microbes and dietary proteins from the gut lumen to “leak” into the bloodstream (27). Hepatocytes (liver cells) and cholangiocytes (the cells that line the bile duct) are also connected by tight junctions, forming a selectively permeable barrier between the blood and the biliary system (28). Research has shown that zonulin is associated with the tight junctions in virtually all mammalian epithelia (29). In other words, if gliadin compromises the intestinal barrier and gets into the bloodstream, it can also wreak havoc on other epithelial barriers, including the blood–biliary barrier.

Sure enough, research has linked gluten intolerance and celiac disease to increased prevalence of gallstones and biliary cirrhosis (30, 31). There is also a high prevalence of celiac disease in patients with autoimmune hepatitis (32). One study found that 42 percent of adults with celiac disease had abnormal levels of liver enzymes. Adherence to a gluten-free diet for one to 10 years normalized liver enzyme levels in 95 percent of these patients (33).

Intestinal villi, the fingerlike projections on epithelial cells responsible for nutrient absorption in the small intestine, are typically shortened and damaged in celiac disease. This may impair the sensing of incoming dietary fatty acids by enteroendocrine cells, resulting in reduced release of cholecystokinin and insufficient contraction of the gallbladder (34). Studies have shown that this too can be reversed with a gluten-free diet (35).

Cholecystectomy

Cholecystectomy, the complete removal of the gallbladder, may be unavoidable in some people with late-stage gallbladder disease. In this procedure, the biliary tract is rerouted, such that bile flows directly from the liver to the small intestine via the common bile duct.

Gallbladder removal should be avoided whenever possible, as it has several unintended consequences and significantly alters physiology. Even in the absence of the gallbladder, the liver continues to produce bile. Without a storage organ, intrahepatic cholestasis, the accumulation of bile in the liver, may occur. Altered bile secretion into the small intestine has also been shown to affect gut microbes and gut function (36).

Additionally, even if a patient has undergone cholecystectomy, he or she may still continue to produce gallstones in the liver or bile ducts if the underlying pathophysiology has not been addressed (37). In the final section, we’ll discuss how to treat these conditions and restore gallbladder health.

Treating Gallbladder Disease: The Functional Way

I usually have to convince people that a functional approach is better, but in this case, there really is no conventional treatment available for gallbladder disease other than invasive surgery. Conventional medicine usually just advocates a low-fat diet. While this may alleviate symptoms over the short term, long-term reduction of fat intake only prevents the stimulation of gallbladder contraction by cholecystokinin. This can lead to more sluggishness and an increased risk of gallstones, which is what we are trying to avoid in the first place. In contrast, a high-fat diet may protect against gallstone formation, especially during weight loss.

On the other extreme, many natural health websites are promoting gallbladder flushes. I typically like to look to the scientific evidence to support my treatment recommendations, and as these flushes have yet to be tested in clinical trials, I think it’s better to focus on addressing the underlying causes.

That said, here are my recommendations for approaching a gallstone issue:

Test: Markers of impaired gallbladder function include high ALT, AST, bilirubin, LDH, GGT, ALP, and 5ʹ-nucleotidase. Relative levels of these markers can also help narrow down which gallbladder disease you are dealing with.

Change the diet: I’ve seen many people resolve their gallbladder issues simply by changing their dietary habits. Removing inflammatory foods like gluten, processed foods, and sugar can substantially improve gallbladder health.

Heal the gut: While it’s a bit of a chicken-or-the-egg situation as to which came first, leaky gut and biliary disease certainly go hand in hand. It’s important to address both simultaneously in order to break the cycle of gut inflammation → biliary stasis → lack of bile → more gut inflammation.

Stimulate bile flow: Bitters like curcumin, dandelion, milk thistle, and ginger are well known for their ability to stimulate bile flow (38, 39). These can be taken as supplements, included in meals, or consumed as tea.

Dissolve gallstones: Beet root, taurine, phosphatidylcholine, lemon, peppermint, and vitamin C have all been shown to reduce the impact of or even dissolve gallstones (40, 41, 42).

Consider supplementing with bile: If your patient is having trouble with fat digestion, you can also consider having them supplement with bile itself from a bovine or ox source until his or her bile flow is restored.