Testing The Liver-Gut Axis For the Integrative Treatment of Liver Disease

Many have heard of the gut-brain axis, and some have heard of the thyroid-gut axis. But very few are aware of the liver-gut axis.

Scientists are continuing to validate that the health of our gut likely impacts all other body systems. For example, 70% of immune cells are present in the digestive tract, and our gut microbiota, the trillions of tiny microbes inhabiting our body, communicate with our brain bidirectionally. The gut also communicates with and impacts the liver.

The imbalance of our gut microbes leads to a breakdown in the liver-gut axis, which results in inflammation and liver disease. The healthy interplay between the liver and the gut is vital to optimal wellness. Functional medicine can help to optimize digestive and liver functioning and enhance liver-gut communication.

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What is the Liver Gut Axis?

Similar to the two-way communication between the gut-brain and the gut-thyroid, there is a bidirectional crosstalk between the gut-liver. This communication influences gastrointestinal and liver health and impacts overall health due to the vital roles these two organs have in the body. (2-9)

The gut-liver axis is influenced by genetic, environmental, and lifestyle factors. Diet, microbe population, microbial metabolites, and bile acids all regulate metabolism and immunity in the gut and liver. This, in turn, shapes microbiome health which modulates liver function. (2-9)

The portal vein (a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas, and spleen to the liver) is the reciprocal link between the gut microbiota and the liver. This vein carries gut-derived products to the liver. The liver responds with the production of bile and antibodies, which it then secretes into the intestine.

Beyond the interaction between the liver and gut via circulation, their metabolites also impact each other. Bile acids, which are synthesized in the liver from cholesterol, impact metabolic function systemically and are also critical in influencing the gut microbiota. These molecules are released from the liver into the gut, where the microbiota can further metabolize them. (2-9)

The feedback loop between the gut and liver, called the enterohepatic circulation, determines the amount of bile acids produced. In the liver, primary bile acids are first conjugated to amino acids (glycine or taurine), then released into the bile. In the small intestine, primary bile acids are reabsorbed and recycled back into the liver through the portal circulation. Within the intestinal epithelium, bile acids are transformed into secondary bile acids. This process can impact epithelial barrier properties in the intestine and the gut vascular barrier (GVB). (2-4, 8-9)

The Importance of Intestinal Barrier Integrity: What is Leaky Gut?

Typically, the inner lining of the intestinal wall is a closed barrier that selectively allows water and nutrients to cross into the bloodstream and prevents unwanted particles, such as undigested food, toxins, bacteria, and viruses, from entering circulation. This gut mucosal barrier, comprised of intestinal cells, acts as the interface between the liver and the microbiome. It maintains gut homeostasis by separating gut microbiota and human immune cells.

Under healthy conditions, there are multiple layers of defense. The mucus serves as the external layer. It is composed of microbiota on the outside and a sterile inner layer. Tight junctions (formed by one layer of intestinal cells) underneath seal the layer below. The gut vascular barrier (GVB) is the final layer of protection. It controls the systemic release of microbial metabolites into the portal circulation. This segregation between microbes and host immune cells prevents exaggerated inflammatory responses.

Medications, stress, lifestyle, toxic exposures, inflammatory diets, alcohol, food sensitivities, and low stomach acid can inflame and damage the inner lining of the intestinal wall. Intestinal barrier disruption can occur in several places within the liver-gut axis (the mucus layer, tight junctions, or the GVB).

A breakdown in the gut barrier can no longer prevent larger, unfiltered particles from crossing into the bloodstream, allowing damaging substances to travel in the systemic circulation. When the GVB is affected, inflammatory metabolites or microbes can spread throughout the body and liver, inducing liver inflammation, liver disease, and numerous other health conditions. These changes in intestinal permeability are sometimes called "leaky gut."

Intestinal permeability (leaky gut) is currently gaining more attention in research and the media because of the links to concerning chronic inflammatory health conditions such as Celiac disease, Crohn's disease, autoimmune disorders, neurological disorders, and mood disorders. (10-11)

"Leaky gut" is not a diagnosis or disease but rather a symptom. Functional medicine can assess and address the underlying triggers and mediators that lead to intestinal wall damage.

The Role of the Gut-Liver Axis in Liver Disease

Studies have found that disturbances in host-microbe interactions can lead to an impaired intestinal barrier, fueling liver inflammation and disease. The gut microbiota is involved in metabolic and regulatory functions that directly affect the liver, such as bile acids metabolism.

Various microbial products and bacteria enter the portal circulation to the liver via the epithelial and vascular barriers. When these products are harmless or mutually beneficial (commensal), the immune system cells remain tolerant in their surveillance. However, an immune response does get activated if gut-derived bacterial pathogens reach the liver. This kind of disruption of the gut-liver axis results in an imbalance in tolerance and immune dysfunction, which can result in various liver diseases.

Clinical studies have indicated that gut-liver dysregulation is associated with various liver pathologies. Metabolic dysfunction-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (a gallbladder disorder), liver cirrhosis (scarring of the liver), metabolic syndrome, weight changes, and autoimmune hepatitis (an autoimmune disease of the liver) all have a root cause of gut-liver dysfunction. (2-9, 12-16)

Dysbiosis and Liver Disease

Genetic and environmental factors, such as diet, alcohol consumption, or certain drugs, influence our microbial composition, which can fuel the fire of a "leaky gut" and impact metabolic microbiome activity. This results in dysbiosis and the alteration of the intestinal barrier, which are associated with inflammation and metabolic disorders.

Dysbiosis has recently been implicated in the pathogenesis of NAFLD/NASH. A dysbiosis microbiota can lead to the overgrowth of pathogens, increased intestinal permeability, inflammation, bacterial distribution throughout the body, and a flow of metabolites to the liver. As a result, this can lead to liver pathologies via the gut-liver axis.

Small Intestinal Bacterial Overgrowth (SIBO) has been shown to be a main cause of intestinal dysbiosis and increased permeability, leading to the progression and development of NAFLD.

With dysbiosis, a series of events are triggered that can add fuel to insulin resistance, more inflammation in the liver, and, eventually, the development of liver fibrosis. The metabolites produced by these various microbes, which reach the liver via the gut-liver axis, have been linked to the manifestation of simple steatosis, NAFLD, and NASH.

There is also evidence emerging that certain microbial profiles and specific bacterial phenotypes are associated with NAFLD. For example, a typical pattern in non-alcoholic fatty liver is an increase in Lactobacillus and Escherichia and a decrease in Coprococcus. The discrepancy in specific findings does exist in other disorders, however.

Conventional Lab Diagnostics for Liver Disease

Labs and imaging can differentiate and diagnose liver diseases and associated symptoms.

Blood Tests

• A Complete Blood Count (CBC) can be ordered to assess white blood (immune) cell ratios, blood chemistry, and inflammation.
• Liver enzymes and function tests can be separately ordered or found in a Comprehensive Metabolic Panel.
• Tests for chronic viral hepatitis (hepatitis A, hepatitis C, and others) are important for ruling out viral causes.
• Celiac disease screening tests detect antibodies to gluten proteins. These antibodies suggest that gluten is triggering the immune system, which can fuel a gut-liver axis dysfunction.
• Tests for metabolic markers include fasting glucose, insulin, and hemoglobin A1c.
• Lipid profile is essential for measuring blood fats, such as cholesterol and triglycerides (17-18)

Imaging Procedures

• Abdominal ultrasound
• Computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the abdomen
• Transient or Magnetic Resonance Elastography, an advanced ultrasound to test for liver stiffness and fibrosis (17-18)

Functional Medicine Labs to Test for Prevention of Disease Associated with Gut-Liver Axis

Functional medicine providers can order the following tests to assess those with gut-liver axis dysfunction.

Comprehensive Stool Tests

Assessing for dysbiosis and digestive health is imperative to establish a healthy microbiome that can foster a balanced gut-liver connection.

Comprehensive stool tests offer a complete look at gut health by analyzing digestion, nutrient absorption, inflammation, and immune function, which impact the gut-liver axis.

The GI-MAP can evaluate the stool for pathogens and intestinal permeability, which can fuel dysbiosis and liver disease.

SIBO Test

Testing for small intestinal bowel overgrowth (SIBO) should also be considered because of SIBO's relationship to NAFLD.

Food Sensitivity Testing‍

Food Sensitivities testing can help determine if an individual has an inflammatory reaction to specific foods. If testing reveals an abundance of sensitivities, intestinal permeability (leaky gut) may be the culprit.

Functional Medicine Treatment for Liver-Gut Axis

Nutrition and Lifestyle

The Mediterranean dietary pattern consists of olive oil, vegetables, fruits, nuts, legumes, whole grains, fish, and seafood, low red and processed meat intake, and limiting excess sugars.

Evidence from a meta-analysis found that in comparison to the standard of care and a low-fat diet, the Mediterranean diet (MD) offered improved liver marker parameters, including liver function tests, insulin, blood sugar, lipid parameters, and liver stiffness in those with NAFLD/NASH. A few trials which supplemented the MD with additional "green polyphenols," plant compounds found in green vegetables, further enhanced dietary health markers protective against cellular stress. (19-22)

Caloric restriction, weight reduction (of 5-10%), and exercise have also been shown to improve liver parameters and histologic features in those with NAFLD.

When discussing any dietary elimination or restriction treatments, it is crucial to be mindful of potential eating-disordered behaviors. It's essential to be aware of the negative implications of weight cycling and regaining and the harmful effects of weight stigma on psychological and physical health parameters. Approaching dietary and exercise interventions from a health standpoint, vs. a weight-centric approach, is preferred. (23-24)

Probiotics

The therapeutic application of probiotics can be helpful for NAFLD management due to the influence of the microbiota on intestinal barrier integrity, dysbiosis, inflammation, immune tolerance, and the gut-liver axis. (25-28)

Results from a meta-analysis suggested that probiotics improved liver enzymes, hepatic inflammation, hepatic steatosis, and hepatic fibrosis in those with NAFLD and NASH. Several studies also reported that probiotics, synbiotics (a combination of prebiotics and probiotics), and lifestyle measures demonstrated marked improvements in several liver parameter outcomes.

Probiotic therapy with VSL #3 (a high-potency multi-strain probiotic) was found to decrease triglycerides, inflammatory markers, and liver function tests (ALT, AST, and GGT) and resolve hepatic steatosis (fatty liver) in those with NAFLD. Another study on NAFLD patients found a significant liver improvement after treatment with a multistrain probiotic.

Other Nutraceuticals

Current evidence suggests nutraceuticals such as vitamin D, vitamin E, carnitine, polyunsaturated fatty acids (PUFAs), silymarin, resveratrol, anthocyanins, and betaine may also promote positive effects in patients with NAFLD and NASH. Several studies have demonstrated improvements in liver marker parameters with the use of these agents. Vitamin E has the most robust trials for NASH. Caution should be warranted to avoid excessive dosage for all these interventions to prevent unwanted side effects and nutrient-nutrient interactions.

Summary

The gut and liver are connected via portal circulation and influence each other through the metabolites they produce. Pathological changes in gut flora, dysbiosis, and enhanced intestinal permeability from various lifestyle factors can lead to inflammatory changes in the liver and result in systematic liver disease.

Thankfully, dietary interventions, probiotics, and specific nutraceuticals can be implemented to support the integrity of the gut-liver axis interface and improve liver health. Using functional medicine testing and conventional imaging, clinicians can assess the health of the liver-gut axis and monitor for positive changes to support their patients in healing.