Introduction

Liver cirrhosis (LC) represents the terminal stage of chronic liver diseases, including viral hepatitis, alcoholic liver disease, autoimmune hepatitis, and metabolic dysfunction-associated fatty liver disease (MASLD or MAFLD). Globally, it affects an estimated 200–300 individuals per 100,000 population and is associated with high morbidity and mortality. Cirrhosis is characterised by progressive fibrosis and architectural distortion of hepatic parenchyma, culminating in portal hypertension and hepatic insufficiency. Although compensated cirrhosis may remain clinically silent for years, the development of decompensating events such as ascites, hepatic encephalopathy (HE), or variceal bleeding significantly shortens survival, with 1-year mortality exceeding 20% [1, 2].

In recent years, research has highlighted the central role of the gut-liver axis in the pathogenesis and progression of cirrhosis. Disruptions in intestinal permeability, microbial composition, and mucosal immunity all contribute to bacterial translocation, systemic inflammation, and organ dysfunction. Understanding these mechanisms is essential to developing novel diagnostic and therapeutic strategies.

Bacterial translocation and the gut-liver axis

The gut-liver axis refers to the bidirectional communication between the gastrointestinal tract and the liver, primarily through the portal vein. Under normal conditions, the liver acts as a gatekeeper, clearing bacteria and their products from the portal circulation. In cirrhosis, this immunological surveillance is impaired.

Bacterial translocation (BT) is defined as the migration of viable bacteria, bacterial fragments (e.g. lipopolysaccharide [LPS]), or microbial DNA from the intestinal lumen into mesenteric lymph nodes and eventually into systemic circulation. BT is facilitated in cirrhotic patients by several mechanisms: compromised intestinal barrier integrity, small intestinal bacterial overgrowth (SIBO), delayed intestinal transit, and reduced mucosal immune responses [3, 4].

Liver-resident macrophages known as Kupffer cells (KCs) recognise bacterial products via pattern recognition receptors, including Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors. This leads to the secretion of proinflammatory mediators such as tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and reactive oxygen species (ROS), which promote hepatic inflammation, fibrosis, and systemic complications [5, 6].

Gut dysbiosis and microbial metabolites in cirrhosis

Patients with liver cirrhosis exhibit profound alterations in gut microbiota composition, a condition referred to as gut dysbiosis. In healthy individuals, the microbiota is predominantly composed of Firmicutes and Bacteroidetes. In cirrhosis, there is a notable shift toward an increased abundance of Proteobacteria and Actinobacteria, particularly the families Enterobacteriaceae and Streptococcaceae [7]. This state is characterised by reduced microbial diversity, depletion of beneficial commensals, and overgrowth of potentially pathogenic bacteria.

To quantify this imbalance, the cirrhosis dysbiosis ratio (CDR) has been proposed. This ratio compares beneficial autochthonous taxa (e.g. Lachnospiraceae, Ruminococcaceae) to potentially harmful ones (e.g. Enterobacteriaceae). A low CDR correlates with increased Model for End-Stage Liver Disease (MELD) scores, higher levels of endotoxaemia, more frequent hospitalisations, and reduced survival [8].

Culture-independent sequencing methods have revealed microbial signatures associated with specific clinical presentations. For instance, patients with viral cirrhosis and minimal HE show enrichment of Staphylococcus spp. and Escherichia coli, whereas those with overt HE demonstrate increased Alcaligenaceae [9, 10].

In metabolic dysfunction-associated fatty liver disease (MAFLD)-related cirrhosis, dysbiosis is characterised by a higher abundance of ethanol-producing bacteria such as Klebsiella pneumoniae and a significant reduction in short-chain fatty acid (SCFA)-producing bacteria. These microbial shifts exacerbate gut permeability, trigger systemic inflammation, and promote hepatic steatosis and fibrogenesis, accelerating progression to cirrhosis [11].

SCFA-producing bacteria, including Faecalibacterium prausnitzii, Eubacterium, Roseburia, and members of the Lachnospiraceae and Ruminococcaceae families, are crucial for intestinal health. They ferment dietary fibres into SCFAs – butyrate, propionate, and acetate – which help maintain epithelial integrity, modulate mucosal immunity, and serve as energy substrates for colonocytes.

Among these, butyrate is especially important for its anti-inflammatory properties and its role in reinforcing tight junctions in the gut epithelium. In cirrhosis, reduced abundance of SCFA producers contributes to “leaky gut”, systemic endotoxaemia, and increased bacterial translocation.

Moreover, SCFA deficiency has extraintestinal consequences. Butyrate and propionate influence hepatic lipid and glucose metabolism and regulate muscle protein synthesis via AMP-activated protein kinase (AMPK) and mTOR pathways. Their depletion may exacerbate metabolic dysfunction and contribute to sarcopenia, a common complication in advanced liver disease.

Restoring SCFA-producing bacteria through dietary intervention, prebiotics, and microbial-based therapies represents a promising strategy for reducing inflammation and improving clinical outcomes in cirrhotic patients [12].

Immune dysregulation in cirrhosis

Cirrhosis is associated with profound immune dysfunction, described as cirrhosis-associated immune dysfunction (CAID). CAID encompasses a paradoxical state of systemic inflammation coexisting with immunodeficiency. This is driven by persistent microbial stimulation via bacterial translocation, coupled with exhaustion of innate and adaptive immune mechanisms.

Key features of CAID include impaired neutrophil chemotaxis and phagocytosis, reduced antigen presentation by monocytes (evidenced by decreased HLA-DR expression), diminished complement production, and increased apoptosis of lymphocytes. These changes increase susceptibility to bacterial and fungal infections, which are leading causes of acute decompensation and acute-on-chronic liver failure (ACLF) [13, 14].

Hepatic encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from liver dysfunction and portosystemic shunting. It affects up to 40% of patients with cirrhosis and manifests as cognitive impairment, asterixis, disorientation, and coma in severe cases.

The pathogenesis of HE is multifactorial. Elevated ammonia levels – produced by urease-expressing gut bacteria – play a central role. Additionally, systemic inflammation and altered blood-brain barrier permeability contribute to astrocyte dysfunction and cerebral oedema.

Patients with HE exhibit a characteristic gut microbiota profile, with increased abundance of Enterobacteriaceae, Alcaligenaceae, and Veillonellaceae. Treatment strategies such as lactulose, rifaximin, and faecal microbiota transplantation (FMT) aim to reduce ammonia-producing bacteria and restore microbial balance. Rifaximin, in particular, has been shown to lower HE recurrence by over 50% [15, 16].

Sarcopenia and the gut-muscle axis

Sarcopenia – the loss of skeletal muscle mass and function – affects 40–70% of patients with cirrhosis and is a strong independent predictor of mortality. It is closely linked to nutritional deficiencies, hyperammonaemia, systemic inflammation, and gut dysbiosis.

The gut-muscle axis is an emerging concept highlighting the role of microbiota-derived metabolites – especially SCFAs – in muscle homeostasis. SCFAs such as butyrate and propionate support mitochondrial function, activate AMPK and mTOR pathways, and suppress muscle proteolysis.

In cirrhosis, the depletion of SCFA-producing bacteria contributes to muscle wasting. Moreover, elevated ammonia levels impair branched-chain amino acid utilisation in muscle tissue, exacerbating catabolism. Therapeutic interventions including nutrition optimisation, exercise, and microbiota modulation may help preserve muscle mass and improve outcomes [17].

Gut microbiota and metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD, is the most common chronic liver disease globally. It involves hepatocellular fat accumulation driven by insulin resistance, chronic inflammation, and gut-liver axis disruption.

In MASLD, gut dysbiosis leads to increased intestinal permeability (“leaky gut”), allowing microbial components like lipopolysaccharide (LPS) to enter the portal circulation. This activates TLR4 signalling in hepatic immune cells, promoting inflammation and fibrogenesis. Dysbiosis also disrupts bile acid metabolism and reduces SCFA production, impairing metabolic and immune regulation.

Specific microbial changes include:

• SCFA-producing bacteria (Faecalibacterium prausnitzii, Roseburia) ® weaker barrier, more inflammation,
• Ethanol-producing bacteria (Klebsiella pneumoniae) ® more steatosis and oxidative stress.

These alterations contribute to MASLD progression and have potential as non-invasive biomarkers [18].

Therapeutic strategies targeting the microbiota are under investigation:

• Probiotics/prebiotics: Improve SCFA levels, reduce LPS load,
• FMT: Modifies microbial composition and reduces systemic inflammation,
• GLP-1 agonists (e.g. semaglutide): Improve liver histology and modulate microbiota [19].

Limitations of current therapies

Despite advances in our understanding of the gut-liver axis, current therapeutic strategies for cirrhosis remain suboptimal and largely symptomatic. Treatments such as lactulose, rifaximin, and nutritional support provide partial benefit but do not address the underlying dysbiosis or metabolic alterations. Microbiota-directed interventions – including faecal microbiota transplantation (FMT), prebiotics, and next-generation probiotics – are promising but require further validation through large-scale, randomised controlled trials. In addition, agents like GLP-1 receptor agonists have shown potential in early studies, but their long-term efficacy and safety in cirrhotic populations have not been fully established. These limitations highlight the urgent need for more personalised, mechanistically informed therapies that target the gut-liver axis at multiple levels.

Conclusions

Liver cirrhosis is a multifaceted systemic disorder in which interactions between the gut microbiota, immune system, and extrahepatic organs play a central role. Key mechanisms include bacterial translocation, which drives systemic inflammation and immune activation; gut dysbiosis, characterised by overgrowth of pathogenic bacteria and depletion of beneficial commensals; and reduced production of SCFAs, which impairs intestinal barrier function and metabolic homeostasis. CAID contributes to heightened infection risk and organ failure, while HE and sarcopenia emerge as downstream complications driven by hyperammonaemia, inflammation, and microbial imbalance.

Understanding the gut-liver axis and its systemic consequences opens promising avenues for the development of targeted diagnostic tools and microbiota-directed therapies. Future strategies that restore microbial equilibrium, enhance SCFA production, and modulate immune responses may significantly improve patient outcomes and quality of life in advanced liver disease.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References