The Gut–Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious condition that affects around one-third of the UK population ¹. What some people may not know is that the gut-liver axis can play an important role in the development and progression of MASLD. Read on to explore the relationship between fatty liver and gut health, how changes in the gut microbiome may contribute to liver inflammation and metabolic dysfunction, and the emerging evidence for dietary strategies and probiotics for fatty liver.

What Is MASLD?

MASLD, previously known as non-alcoholic fatty liver disease (NAFLD), affects 30% of the global population ¹. MASLD is defined as hepatic fat buildup in the context of at least one cardiometabolic risk factor, such as diabetes, high blood pressure, abnormal cholesterol, or increased waist size. This diagnosis is made when other causes of liver disease are excluded, and alcoholic intake is not high ².

MASLD is closely linked to obesity, insulin resistance, and metabolic syndrome. Excess body fat, especially around the abdomen, can make the body less responsive to insulin. This leads to higher blood sugar and increased release of fatty acids into the blood, ultimately promoting fat build-up in the liver.

Disease progression of MASLD can look like ³:

• Simple steatosis: Fat buildup in the liver, but there is little or no inflammation or scarring.
• Metabolic dysfunction-associated steatohepatitis (MASH): Liver fat plus inflammation and liver cell injury.
• Fibrosis: Repeated liver injury leading to scar tissue forming in the liver.
• Advanced fibrosis or cirrhosis: Severe scarring that can affect normal liver function.
• Liver-related complications: Cirrhosis that can lead to liver failure, portal hypertension, and an increased risk of hepatocellular carcinoma.
• Extra-hepatic complications: MASLD has also been linked to increased risk of cardiovascular disease, type 2 diabetes, and chronic kidney disease.

Understanding the Gut–Liver Axis

The pathogenesis of MASLD is complex and involves many overlapping processes. These include changes in fat tissue function, altered lipid metabolism, inflammation, genetic factors, and communication between the gut and the liver (i.e., the gut-liver axis) ².

To focus on the gut-liver axis, the liver receives a lot of its blood supply from the gut through the portal vein. Meaning nutrients, gut-derived metabolites, bacterial products, and immune signalling from the gut can travel directly to the liver ².

Normally, the gut barrier helps to control what passes from the intestine into the bloodstream. A balanced gut microbiome also supports digestion, immune regulation, and metabolism. But when the gut microbiome is disrupted or when the gut barrier becomes more permeable, more bacterial products may reach the liver, which may trigger inflammation and contribute to liver injury ².

MASLD and Gut Microbiome

Recent research has highlighted that many people with MASLD also show signs of imbalance in the gut microbiome community, known as gut dysbiosis ^2,4. In one meta-analysis of 54 studies, they found that in the majority of the studies, patients with MASLD had reductions in potentially beneficial anti-inflammatory microbes such as Ruminococcaceae and Coprococcus and an increase in pro-inflammatory microbes such as Fusobacterium and Escherichia ⁴.

Dysbiosis can also increase the production of bacterial products such as endotoxins, like lipopolysaccharide (LPS). These can pass from the gut into the bloodstream and reach the liver through the portal circulation ². In addition, dysbiosis may reduce the synthesis of short-chain fatty acids such as butyrate, alter bile acid profiles, and increase endogenous ethanol production ². These changes ultimately influence inflammation, gut barrier integrity, insulin resistance, and liver fat metabolism, all of which may contribute to MASLD progression.

Intestinal Permeability and Liver Inflammation

Another important aspect of the gut-liver axis and MASLD is intestinal permeability, also known as leaky gut. This happens when the gut barrier is weakened, and it allows bacterial products and metabolites such as LPS to move more easily from the intestine into the bloodstream ².

A meta-analysis of 14 studies found that markers of intestinal permeability were raised in patients with steatotic liver disease compared with healthy controls ^2,5, suggesting that impaired gut barrier function may be involved in the development and progression of MASLD. Over time, this may drive the progression from simple steatosis to steatohepatitis, and ongoing inflammation and injury, leading to fibrosis ⁶.

Dietary Strategies to Support the Gut–Liver Axis

Research is ongoing into dietary strategies to improve gut microbiome and liver health for MASLD. Here is a breakdown of some of the key studies:

• Fibre intake and microbiome: In a study involving MASLD patients, they consumed fibre-enriched rolls for 2 months. This led to favourable changes in gut microbiota composition, including abundance of Firmicutes and Bacteroidetes, and increased diversity ⁷.
• Mediterranean diet: In a study involving MASLD patients, two years of adherence to a Mediterranean diet-based lifestyle intervention improved body measurements, cholesterol levels, liver enzyme levels, and lowered inflammation scores and liver fat ⁸.
• Reducing ultra-processed food intake: In a clinical study of adults with MASLD, reductions in ultra-processed food intake were associated with greater reductions in liver fat. Those who reduced ultra-processed foods the most also had better Mediterranean diet adherence, lower calorie intake, and reduced meat and sweets consumption ⁹.

Probiotics and the Gut–Liver Axis: What Does the Evidence Show?

Emerging evidence is also being produced for probiotics for fatty liver. Here is a breakdown of some of the key research:

• In a study carried out with MASLD patients, supplementation with the probiotic strains Lactobacillus rhamnosus GG and Bifidobacterium longum, alongside the prebiotics inulin and fructooligosaccharides, improved liver enzyme levels, including alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyl transferase (GGT) ¹⁰.
• In a clinical trial in MASLD patients, they investigated probiotic strains Lactobacillus delbrueckii subsp. lactis LL001, Lactobacillus helveticus LH001, and Pediococcus pentosaceus KID7 alongside silymarin. Lactobacillus delbrueckii subsp. lactis LL001 improved ALT and AST levels, Lactobacillus helveticus LH001 was linked with weight reduction, and Pediococcus pentosaceus KID7 reduced cholesterol levels. Probiotic use also altered the stool microbiome, including reduced Proteobacteria and increased Ruminococcaceae and Lachnospiraceae ¹¹.
• In a clinical study involving patients with MASLD, a multi-strain synbiotic containing Bifidobacteria, Lacticaseibacillus, Lactobacillus, Streptococcus, and the prebiotic fructooligosaccharides was combined with lifestyle changes. Compared with placebo, the synbiotic group showed improvements in total cholesterol, LDL cholesterol, fasting blood sugar, liver enzymes, and inflammatory markers ¹².
• In a clinical trial involving obese patients with MASLD, a multispecies probiotic mixture containing six bacterial species reduced body weight, total body fat, intrahepatic fat, and triglyceride levels compared with baseline. However, after adjusting for changes in body weight, the improvements in liver fat and triglycerides were no longer significantly different between the probiotic and placebo groups ¹³.
• However, not all studies have shown clear liver-related benefits. In another clinical study involving MASLD patients, a synbiotic combination of fructooligosaccharides plus Bifidobacterium animalis subsp. lactis BB-12 changed the faecal microbiome but did not reduce liver fat content or markers of liver fibrosis ¹⁴.

So it’s important to keep in mind that evidence is promising but is still emerging. Probiotics and synbiotics may help improve liver enzymes, inflammation, glucose metabolism, or lipid markers in some studies, but the effects on liver fat and fibrosis appear less consistent.

Clinical Takeaways

The gut-liver axis plays an important role in MASLD by linking gut microbiome changes, intestinal permeability, inflammation, and metabolic dysfunction. Diet and lifestyle changes are key to MASLD management. Potential strategies include a Mediterranean-style diet, increasing fibre intake, and reducing ultra-processed foods.

Evidence for probiotics for MASLD is still emerging, but promising. Some studies show improvements in liver enzymes, inflammation, glucose metabolism, and lipid markers, but effects on liver fat and fibrosis are less consistent.

References

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