European Journal of Cardiovascular Medicine

Alcoholic liver disease (ALD) continues to be a major global health burden, accounting for significant liver-related morbidity and mortality worldwide. The disease encompasses a spectrum of progressive hepatic injury—from simple steatosis to alcoholic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma [1,2]. Despite the high prevalence and clinical severity of ALD, current therapeutic options remain limited, with sustained alcohol abstinence being the only universally accepted intervention [3].

Emerging research highlights the pivotal role of the gut–liver axis in ALD pathogenesis, positioning the gut microbiota as both a contributor to disease progression and a potential therapeutic target [4,5]. The intestinal microbiome, a complex ecosystem of trillions of microorganisms, plays a critical role in regulating metabolism, immunity, and mucosal barrier integrity. Chronic alcohol consumption disrupts this microbial balance, resulting in dysbiosis, intestinal barrier dysfunction, and increased gut permeability [6].

The consequence of this disruption is translocation of microbial products—such as lipopolysaccharides (LPS)—into the portal circulation, activating inflammatory pathways via pattern recognition receptors including Toll-like receptor 4 (TLR4) on Kupffer cells [7]. This cascade amplifies hepatic inflammation and oxidative stress, fuelling the progression from fatty liver to more severe liver injury.

Several studies have demonstrated that the degree of dysbiosis correlates with both clinical outcomes and histopathologic severity of liver damage in ALD, suggesting a mechanistic—not merely associative—role for the gut microbiota in disease progression [8].

This review aims to synthesize current evidence on the gut microbiota as a modifiable therapeutic target in ALD. We explore the mechanisms by which alcohol-induced dysbiosis drives liver injury, assess current and emerging microbiota-targeted therapies, and highlight key research gaps and future directions.

2A. Pathogenesis of Alcoholic Liver Disease

Alcoholic liver disease (ALD) develops through a multifactorial process involving ethanol metabolism, oxidative stress, immune activation, and inflammatory signalling. Chronic and excessive alcohol intake disrupts hepatic lipid metabolism, leading to hepatic steatosis, the earliest and most reversible form of ALD [9]. Ethanol is primarily metabolized in the liver via alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1), both of which generate acetaldehyde and reactive oxygen species (ROS) [10,11]. These metabolites cause mitochondrial dysfunction, lipid peroxidation, and direct hepatocellular injury.

Progression from steatosis to alcoholic hepatitis involves activation of Kupffer cells, the liver’s resident macrophages, which release pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in response to cellular injury and microbial-derived products [12]. This inflammatory cascade triggers neutrophilic infiltration, hepatocyte apoptosis, and impaired liver regeneration.

Chronic injury and inflammation promote stellate cell activation, leading to fibrogenesis and the accumulation of extracellular matrix proteins that result in hepatic fibrosis and, eventually, cirrhosis [13]. The transition from inflammation to fibrosis is mediated by transforming growth factor-beta (TGF-β) and other fibrogenic pathways [14]. Importantly, not all heavy drinkers develop progressive liver disease, indicating that host factors, including genetic susceptibility and gut microbial composition, play a significant role in disease heterogeneity [15].

2B. The Gut–Liver Axis in ALD

The gut–liver axis refers to the bidirectional interaction between the gastrointestinal tract and the liver via the portal circulation, which transports nutrient and microbial signals directly to the liver. In ALD, chronic alcohol consumption disrupts this axis by inducing gut dysbiosis, increasing intestinal permeability, and promoting the translocation of pathogen-associated molecular patterns (PAMPs) such as LPS and peptidoglycans into the liver [16,17].

Alcohol impairs tight junction proteins (e.g., occludin, claudins), which regulate intestinal barrier integrity. As a result, "leaky gut" develops, facilitating the passage of bacterial products into portal blood. These microbial products engage Toll-like receptors (TLRs) on hepatic immune cells, activating NF-κB signaling and promoting hepatic inflammation and injury [18,19].

Microbiome profiling in both human and animal models has demonstrated that ALD is associated with reduced microbial diversity, overgrowth of Proteobacteria, and depletion of Firmicutes, particularly butyrate-producing species [20]. These changes are closely linked to the severity of liver injury, systemic inflammation, and metabolic dysfunction.

Furthermore, emerging evidence suggests that bile acids, short-chain fatty acids, and other microbial metabolites modulate liver function by acting as signalling molecules through farnesoid X receptor (FXR) and G-protein-coupled receptors (GPRs) [21,22]. These interactions further highlight the gut microbiota's role as a dynamic regulator of host metabolism, immunity, and liver homeostasis.

Taken together, these findings underscore the gut–liver axis as a critical mediator of alcohol-induced liver damage and a potential focal point for therapeutic intervention [23].

3. Microbiota Mechanisms and Dysbiosis in Alcoholic Liver Disease

The gut microbiota exerts a profound influence on liver health, acting through both metabolic signalling and immune modulation. In the context of ALD, chronic alcohol intake leads to a distinct pattern of microbial dysbiosis—characterized by loss of microbial diversity, expansion of pro-inflammatory taxa (e.g., Proteobacteria, Enterobacteriaceae), and depletion of beneficial commensals such as Lactobacillus and Faecalibacterium species [24,25].

This dysbiosis is not merely associative but causally linked to liver injury via several key mechanisms. First, alcohol disrupts the gut epithelial barrier, leading to increased intestinal permeability and allowing translocation of lipopolysaccharide (LPS) and other microbial products into the portal circulation. These products activate Toll-like receptor 4 (TLR4) and NOD-like receptors (NLRs) in the liver, triggering hepatic inflammation [26,27].

Secondly, gut dysbiosis alters the production of short-chain fatty acids (SCFAs)—notably butyrate, acetate, and propionate—which play crucial roles in modulating inflammation, maintaining barrier integrity, and regulating hepatic lipid metabolism. Alcohol-induced suppression of SCFA-producing bacteria exacerbates mucosal inflammation and hepatic steatosis [28,29].

Moreover, alcohol alters microbial bile acid metabolism. Dysbiosis shifts the composition of primary and secondary bile acids, impairing signalling through farnesoid X receptor (FXR) and TGR5, which are critical for lipid and glucose metabolism and anti-inflammatory responses in the liver [30]. This contributes to hepatocellular stress, insulin resistance, and progression to steatohepatitis.

Metabolomic analyses further reveal that alcohol consumption modulates the gut microbial metabolome, increasing levels of ethanol-producing bacteria (e.g., Klebsiella pneumoniae) and toxic microbial metabolites such as acetaldehyde, ammonia, and indoles, all of which can directly damage the liver [31,32].

Notably, fecal microbiota transplantation (FMT) studies in ALD animal models and humans have shown that transferring a healthy microbiota can reduce systemic inflammation and improve hepatic markers—underscoring the functional importance of the microbiota in disease pathogenesis [33–35].

4. Microbiota-Targeted Therapeutic Strategies in Alcoholic Liver Disease

Given the central role of gut microbiota in the pathogenesis of alcoholic liver disease (ALD), numerous therapeutic interventions have emerged aiming to restore microbial balance, strengthen gut barrier function, and mitigate hepatic inflammation. These include probiotics, prebiotics, symbiotics, antibiotics, and fecal microbiota transplantation (FMT)—all designed to manipulate the gut microbiome for therapeutic benefit [36,37].

Probiotics and Symbiotic

Probiotics—live microorganisms with health benefits—have shown promise in ALD by modulating immune responses, reducing endotoxemia, and improving hepatic histology. Studies using Lactobacillus rhamnosus GG, Bifidobacterium, and multi-strain formulations have demonstrated reduced levels of ALT, AST, and TNF-α in animal models and early-phase clinical trials [38,39].

Symbiotic, combining probiotics and prebiotics, further enhance therapeutic potential by stimulating endogenous beneficial bacteria. Clinical trials have reported reductions in oxidative stress and inflammatory cytokines in patients with alcohol-induced steatosis [40].

Prebiotics and Diet-Based Modulation

Prebiotics such as inulin, fructooligosaccharides, and polyphenols promote the growth of anti-inflammatory commensals and short-chain fatty acid (SCFA) production. Dietary interventions—including fiber-rich diets, tea polyphenols, and antioxidant compounds like astaxanthin—have been shown to reshape microbial composition and attenuate hepatic injury in alcohol-fed mice [41–43].

Antibiotics

Broad-spectrum antibiotics like rifaximin have been used to reduce gut-derived endotoxemia and inflammation. While effective at reducing LPS levels and hepatic steatosis, antibiotics pose risks of resistance and further dysbiosis, limiting their long-term utility [44].

Fecal Microbiota Transplantation (FMT)

FMT, the transfer of fecal material from healthy donors to restore microbial diversity, has shown encouraging results in small pilot trials in ALD. It improves gut barrier integrity, decreases systemic inflammation, and may reverse early liver damage [45,46]. In murine models, FMT from alcohol-resistant mice to alcohol-sensitive mice conferred hepatoprotection, supporting a causal role of the microbiome in modulating disease severity [47].

Future Therapeutic Directions

Advances in microbial engineering, postbiotic metabolites, and bacteriophage therapies offer next-generation approaches. Personalized microbiome-based interventions—such as tailored probiotics or microbiota-derived bioactives—are being explored for targeted modulation [48,49]. However, long-term data on efficacy, safety, and reproducibility in humans remain limited [50].

5. Limitations and Future Directions

Despite substantial progress in understanding the gut microbiota’s role in alcoholic liver disease (ALD), several limitations continue to hinder translation of this knowledge into effective clinical interventions.

Limitations

First, much of the mechanistic evidence comes from preclinical models. Although animal studies have demonstrated that modulating gut microbiota can attenuate alcohol-induced liver injury, the complexity of the human microbiome and host-microbe interactions makes direct translation challenging [51]. Human studies are limited in size, duration, and often lack standardization in microbiome sequencing, taxonomic classification, and clinical endpoints.

Second, there is inter-individual variability in microbiota composition influenced by genetics, geography, diet, and comorbidities. This makes it difficult to define universal microbiome signatures of ALD or predict individual response to microbiota-targeted therapies.

Additionally, most probiotic or FMT studies are early-phase or uncontrolled, with inconsistent outcomes and lacof long-term safety data. Regulatory challenges and donor selection criteria for FMT further complicate its use in liver disease.

Future Directions

Future research must prioritize large-scale, longitudinal human studies that integrate multi-omics (metagenomics, metabolomics, transcriptomics) with clinical data to establish causal links and therapeutic targets. Personalized microbiome interventions, such as custom probiotics or engineered microbial consortia, represent promising directions .

Emerging tools, including microbiota-derived bioactives (postbiotics) and precision bacteriophage therapy, offer avenues for targeted manipulation of the gut ecosystem. Additionally, incorporating microbiome-based diagnostics into routine clinical practice could help risk-stratify patients, monitor disease progression, and tailor interventions.

Alcoholic liver disease (ALD) is a complex and multifactorial condition in which the gut microbiota plays a pivotal mechanistic and modulatory role. Advances in microbiome research have reshaped our understanding of the gut–liver axis, revealing that alcohol-induced dysbiosis contributes not only to hepatic inflammation and barrier dysfunction but also to disease progression through immune and metabolic pathways.

Therapeutic strategies aimed at restoring microbial balance—ranging from probiotics and prebiotics to fecal microbiota transplantation—have shown promising results in both preclinical and early human studies. However, the field faces key limitations, including individual microbiome variability, inconsistent clinical outcomes, and a lack of long-term efficacy data.

Looking ahead, integration of microbiome profiling into clinical hepatology, combined with personalized microbiota-based therapies, may offer a transformative approach to the prevention and management of ALD. High-quality, large-scale human trials are essential to validate current findings and translate microbial modulation from experimental promise to clinical practice.

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