Context
The trillions of microorganisms in the human intestine are important regulators of health, and disruptions in the gut microbial communities can cause disease. The gut, liver and immune system have a symbiotic relationship with these microorganisms. Environmental factors, such as high-fat diets and alcohol consumption, can disrupt and alter microbial communities. This dysbiosis can lead to dysfunction of the intestinal barrier, translocation of microbial components to the liver and development or progression of liver disease. Changes in metabolites produced by gut microorganisms can also contribute to liver disease, by fueling hepatic inflammation and disease progression.
Introduction to the Gut-Liver Axis
The Liver and the Gut are closely connected anatomically through the portal vein system and bile duct.
The portal vein
carries nutrient-rich blood from the intestines directly to the liver for processing before it enters the general circulation. This allows the liver to regulate the levels of nutrients, toxins and other substances absorbed from the gut.
Through the portal vein, the liver is also constantly exposed to gut microbial components and metabolites, which have immense effects on the immunity and metabolism of the host.
On the other hand, the bile duct connects the liver and gallbladder to the top of the small intestine (duodenum). Bile is a fluid that is made and released by the liver and stored in the gallbladder. When digestion begins, gallbladder contracts and the bile is released to the duodenum, through these ducts.
Bile helps with digestion, it breaks down fats into fatty acids, improving the absorption thought the gut walls.
The bile also transports all the unnecessary and toxic byproducts and toxins back to the gut where it can be excreted through feces.
How the gut impacts liver function
Gut microbiota dysbiosis (microbiota imbalance) has been found in liver diseases with distinct etiologies. Gut microbiota may have a significant impact on the pathophysiology of liver diseases through inflammatory mechanisms.
Various liver diseases are characterized by an impaired gut barrier and a disturbed gut-liver axis.
When leaky gut occurs, bacteria and other molecules that should not enter the bloodstream can pass through the intestinal barrier. This triggers an immune response that is closely linked to non-alcoholic fatty liver disease (NAFLD). In this situation, the liver becomes overwhelmed by antigens, metabolites, and possibly gut microbes, which can exacerbate existing liver disease through increased inflammation.
A healthy liver harbors mechanisms to counteract and clear endotoxin.
How the liver impacts gut health
The liver detoxifies harmful substances that could negatively affect the gut if allowed to accumulate. It metabolizes drugs, alcohol, and other toxins, converting them into less harmful substances that can be excreted in bile or urine.
The liver produces bile which is then stored in the gallbladder until it is expelled during digestion into the intestine.
Bile is composed of water, bile acids, bilirubin, cholesterol, amino acids, steroids, enzymes, vitamins, and heavy metals, as well as exogenous drugs, xenobiotics and environmental toxins. Bile aids in digestion and acts as antimicrobial, which helps control gut microbial composition and control microbial proliferation. It can inhibit the growth of harmful bacteria while promoting beneficial ones, contributing to a healthy gut environment.
The liver impacts the diversity of the gut microbiome. Bile regulates the growth and activity of gut bacteria. Helping to prevent constipation, microbial overgrowth and leaky gut. Feeding the wrong colony of bacteria can lead to the damage of the gut lining, allowing dangerous pathogens to roam the body.
The liver helps maintain the gut barrier by regulating the production of proteins involved in tight junctions between gut epithelial cells. This barrier prevents harmful substances from leaking into the bloodstream, a condition known as "leaky gut."
Additionally, a dysbiotic intestinal environment can alter the production and transport of important minerals and vitamins to the liver.
An exacerbated immune response by the liver can inflame the gut and vice-versa, creating a negative feedback loop.
Reduced bile secretion due to cholestasis or advanced chronic liver disease results in bacterial overgrowth and bacterial translocation, as bile inhibits bacterial growth and prevents bacterial overgrowth.
Non-Alcoholic Fatty Liver Disease (NAFLD): This condition is closely linked to gut dysbiosis (an imbalance in gut bacteria) and may lead to inflammation that affects both the liver and gut.
Diet to improve gut health to address liver dysfunction?
To best protect the liver and gut health, the food intake is crucial.
The unhealthy foods we eat increase the amount of toxins absorbed and transported to the liver. At certain levels of toxic overload and overconsumption the liver starts to lose its function and toxins start to accumulate in the body, mainly in fatty tissue. Alternatively, healthy eating habits and a diverse diet composition can boost liver function and productivity which in turn aids the gastrointestinal tract to perform its own role.
Dietary protein and carbohydrates are processed in the intestine by the host and its commensals and then enter the liver via the portal vein. Although most of those products/metabolites are essential for life in, e.g., energy metabolism, many have the potential to trigger or deteriorate inflammatory diseases, especially when consumed in excess.
Besides lipids, simple sugars contribute to pathologies along the gut-liver axis. Another important dietary component acting proinflammatory, impairing the intestinal barrier, and affecting the gut microbiome is alcohol. Alcohol consumption has been identified as one of the most critical host variables confounding the gut microbiota and fueling inflammatory responses along the gut-liver axis.
Figure: Tilg H, Adolph TE, Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications. Cell Metab. 2022;34(11):1700-1718. doi:10.1016/j.cmet.2022.09.017
Figure: Tilg H, Adolph TE, Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications. Cell Metab. 2022;34(11):1700-1718. doi:10.1016/j.cmet.2022.09.017
Conclusion
Disruption of the gut barrier, along with dietary components, gut microbes, and their metabolites, underlies the complex host-microbe interactions that either sustain health or contribute to disease.
Recognition of the complex mechanisms that constitute the gut-liver axis holds potential for targeted therapies beyond liver diseases in the future.
References
Tilg H, Adolph TE, Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications. Cell Metab. 2022;34(11):1700-1718. doi:10.1016/j.cmet.2022.09.017
Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol. 2023;21(11):719-733. doi:10.1038/s41579-023-00904-3
Zheng Z, Wang B. The Gut-Liver Axis in Health and Disease: The Role of Gut Microbiota-Derived Signals in Liver Injury and Regeneration. Front Immunol. 2021;12:775526. Published 2021 Dec 10. doi:10.3389/fimmu.2021.775526
