Diving into how the gut and the liver talk to each other

What is the origin of the crosstalk between our gut microbiota, gut, and liver?

At birth, the shift from umbilical to gut-based nutrition fosters a bidirectional communication between gut microbiota, immune system, and metabolism, initiating the microbiota-gut-liver axis. This axis is essential for maintaining overall health, as it helps regulate immune responses, metabolic processes, and detoxification, relying on several barriers to protect and filter substances from the gut before they reach the blood circulation.

Over time, lifestyle factors such as diet, exercise, and antibiotics use can alter the gut microbiota, affecting gut-liver communication. Disruptions in this communication are linked to diverse liver diseases. Depending on the cause—metabolic dysfunction or alcohol abuse—the disease is termed metabolic dysfunction-associated steatotic liver disease (MASLD) or alcohol-associated liver disease (ALD). Both conditions begin with abnormal fat accumulation in the liver, progressing to steatosis, hepatitis, cirrhosis, and potentially hepatocellular carcinoma. In advanced stages, these diseases can also lead to hepatic encephalopathy, a serious brain disorder resulting from the liver’s reduced ability to filter toxins.

How does gut microbiota influence gut-liver communication?

The interactions between the gut and other organs, including the liver, are tightly regulated by three barriers of defense¹:

• Gut barrier: microbial byproducts (e.g., short-chain fatty acids, indole) and liver-derived bile acids help maintain epithelial homeostasis and barrier integrity.

• Immune barrier: gut-resident immune cells patrol and digest pathogens and harmful substances, preventing them from entering the bloodstream. Additionally, these interactions shape anti/pro-inflammatory responses in the gut-liver axis.

• Gut-vascular barrier: is analogous to that in the brain and prevents the translocation of large molecules from the gut lumen. However, bacterial infections can disrupt it, allowing the passage of larger molecules and facilitating bacterium spread.

In a healthy state, these barriers control the flow of microbes and compounds from the gut to the liver². Once in the liver, these materials are detoxified before reaching systemic circulation. The liver, in turn, produces bile, which is secreted into the intestines. While most bile acids are reabsorbed, a small portion reaches the terminal gut, where gut microbes convert them into secondary bile acids. This interaction modulates gut immunity and prevents bile acid overload, supporting intestinal health.

What is the role of gut microbiota in liver diseases?

Gut microbiota imbalances, or dysbiosis, are implicated in liver conditions such as viral hepatitis, colorectal cancer metastasis to the liver, and drug-induced liver injury. Dysregulation of the gut-liver axis contributes to the development and progression of various liver diseases. Chronic hepatic inflammation, fibrosis, and portal hypertension disrupt the intestinal barrier, leading to systemic inflammation and complications including multi-organ failure or death in the worst scenarios.

While much of the research comes from animal studies, human clinical trials are emerging. For example, increased intestinal permeability is closely linked to liver disease. High-fat diets and alcohol intake can weaken the intestinal barrier, allowing bacterial toxins to reach the liver and trigger inflammation. Over time, this persistent inflammation contributes to conditions like fatty liver disease, which now affects approximately 1 in 5 Americans³. Additionally, specific gut microbiota patterns are being linked to improved responses to hepatic cancer immunotherapies in humans⁴.

Evidence-backed gut microbiota interventions for liver diseases

Several therapies targeting the gut-liver axis are under investigation, including those targeting gut microbiota:

• Antibiotics^1,5: Rifaximin has been shown to improve gut barrier function and reduce systemic inflammation in liver disease in placebo-controlled randomized controlled trials.

• Prebiotics^1,2,5: prebiotics such as lactulose are frequently used for the prevention and treatment of severe liver diseases such as hepatic encephalopathy, reducing toxins, and supporting gut barrier integrity^6,7.

•Probiotics²: although some clinical trials involving interventions with Lactobacillus and Bifidobacterium genera have shown moderate success, the wide variability in formulations and the unclear therapeutic targets have made consistent replication challenging.

• Symbiotics²: a year-long treatment with a probiotic-prebiotic combination demonstrated the ability to modify the fecal microbiome but failed to reduce liver fat content or relevant biomarkers in patients with MASLD.

• Postbiotics²: supplementation with pasteurized Akkermansia muciniphila in a small clinical trial, and with components from Lactobacillus paracasei in a preclinical study, both demonstrated enhanced insulin sensitivity. Additionally, a recent Spanish randomized controlled trial demonstrated that a multifactorial intervention—including home exercise, branched-chain amino acid supplements, and a multi-strain probiotic—positively impacted frailty in patients with cirrhosis⁸.

• Fecal microbiota transfers (FMT)^1,2,5: transferring stool from healthy donors has shown promise in treating hepatic encephalopathy. It was linked to improved cognitive function, reduced inflammation, and corrected dysbiosis while also leading to fewer hospitalizations due to liver-related complications ^9,10.

• Engineered microorganisms^1,2,5: emerging therapies include bacteriophages, viruses targeting harmful bacteria, and engineered bacteria that break down toxic metabolites. For example, SYNB1020, an engineered probiotic strain of Escherichia coli Nissle 1917, was well tolerated in a Phase I clinical study for hyperammonemia disorders caused by impaired ammonia processing in the liver¹¹.

While these therapies hold promise, more research is needed to tailor interventions to specific liver diseases, considering their heterogeneous nature12. Exploring combinations of probiotics, prebiotics, and other gut-targeted treatments could enhance therapeutic outcomes.

Take home messages

The gut-liver axis is regulated by three biological firewalls and acts as a key communication network for maintaining health, with gut microbiota playing an essential role.
A diet low in ultra-processed and high-fat foods, avoiding alcohol, and with regular exercise significantly impact both gut and liver health.
Microbiota-based therapies, such as the prebiotic lactulose and some probiotic blends, are emerging as potential treatments for some liver diseases.