Targeting gut microbiota in liver disease: A pharmacological approach for hepatic encephalopathy and beyond

Abstract

The gut microbiota plays a pivotal role in the pathogenesis of liver diseases, particularly hepatic encephalopathy (HE), in which dysbiosis contributes to ammonia production, systemic inflammation, and neurocognitive dysfunction. Emerging evidence suggests that targeting the gut-liver axis through pharmacological and microbiota-based interventions can mitigate liver disease progression and HE severity. This review explored the latest therapeutic strategies aimed at modulating gut microbiota in liver disease, focusing on traditional approaches such as non-absorbable disaccharides (lactulose, lactitol), antibiotics (rifaximin), and probiotics as well as novel interventions, including postbiotics, synbiotics, and fecal microbiota transplantation. Additionally, bile acid modulators, short-chain fatty acid derivatives, and microbiome-targeted small molecules are being investigated for their potential to restore gut-liver homeostasis. We also discussed the implications of gut microbiota modulation in conditions beyond HE, such as metabolic dysfunction-associated steatotic liver disease and cirrhosis. By integrating gut microbiota-targeted therapies into liver disease management, we may develop more effective, personalized approaches to improve patient outcomes and reduce complications.

Key Words: Gut microbiota; Hepatic encephalopathy; Gut-liver axis; Probiotics; Fecal microbiota transplantation; Cirrhosis; Fatty liver

Core Tip: The gut microbiota is a key player in the progression of liver diseases, especially hepatic encephalopathy, by influencing ammonia levels, inflammation, and neurocognitive function. This review discussed current and emerging therapies that target the gut-liver axis, including non-absorbable disaccharides, antibiotics, probiotics, synbiotics, postbiotics, and fecal microbiota transplantation. Novel agents such as bile acid modulators and microbiome-targeted molecules were also explored. Modulating gut microbiota may not only alleviate hepatic encephalopathy but also benefit conditions like metabolic dysfunction-associated steatotic liver disease and cirrhosis, facilitating the way for more personalized and effective liver disease management strategies.

INTRODUCTION

Gut-liver axis: A key player in liver disease

The gastrointestinal tract harbors a dense and diverse community of commensal microbes that play a vital role in maintaining physiological balance and are increasingly recognized as key contributors to disease development[1,2]. Among the organs most affected by microbial activity is the liver, which is closely connected to the gut through the portal circulation. This gut-liver axis involves bidirectional communication driven mainly by the gut microbiota and its metabolites, which can influence liver health or contribute to hepatic injury. The gastrointestinal barrier, composed of epithelial and endothelial cells along with innate and adaptive immune components, helps regulate this interaction. Blood from the intestines drains into the liver via the portal vein, making it a central conduit for microbial signals and metabolites and a crucial component in the pathogenesis of many liver diseases[3,4].

Dysbiosis and its role in hepatic encephalopathy

Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder primarily associated with advanced liver disease, especially cirrhosis, and is closely linked to alterations within the gut-liver axis. A central contributor to its pathogenesis is gut dysbiosis, an imbalance characterized by the overgrowth of pathogenic bacteria and a reduction in beneficial microbial populations. This shift disrupts the production of microbial metabolites and compromises intestinal barrier integrity, promoting bacterial translocation, systemic inflammation, and endotoxemia. One of the hallmark features of HE is the accumulation of neurotoxic substances, including ammonia, phenylethylamine, indoles, and oxindoles. In healthy individuals these compounds are detoxified by the liver; however, in cirrhosis impaired hepatic clearance allows them to accumulate, leading to neuroinflammation and cognitive dysfunction (Figure 1)[5,6].

Figure 1 Dysbiosis and its role in hepatic encephalopathy. During chronic liver disease gut dysbiosis and disruption of the intestinal barrier lead to bacterial overgrowth and a reduction in beneficial commensal organisms. This imbalance results in the release of pathogen-associated molecular patterns such as lipopolysaccharide, flagellin, and peptidoglycan. These molecules along with bacteria translocate across the compromised intestinal barrier, triggering immune cell activation and the production of proinflammatory cytokines. These cytokines travel through the portal vein to the liver. In the context of liver dysfunction, toxins like ammonia are not properly metabolized and can reach the brain, contributing to blood-brain barrier disruption. The combination of systemic inflammation and elevated ammonia levels leads to astrocyte swelling, a hallmark of hepatic encephalopathy. Astrocyte swelling results from ammonia-induced glutamine accumulation within these brain cells, leading to osmotic imbalance and cerebral edema, which contribute to neuroinflammation and the cognitive impairments characteristic of hepatic encephalopathy. PAMPs: Pathogen-associated molecular patterns; sBA: Secondary bile acids; SCFA: Short-chain fatty acids; LPS: Lipopolysaccharide; IL: Interleukin; TNF-α: Tumor necrosis factor-alpha; TLR-4: Toll-like receptor 4.

The gut-liver-brain axis further highlights the role of microbiota in HE. Dysbiosis not only increases neurotoxin production but also modulates immune pathways that affect brain function. For example, in patients with cirrhosis elevated levels of phenylalanine decarboxylase genes correlate with increased phenylethylamine levels and are linked to the neurological manifestations of HE. Additionally, hyperammonemia remains a defining feature of the condition with both its generation and absorption heavily influenced by the gut microbial composition[7,8].

Therapies aimed at correcting dysbiosis, including probiotics, antibiotics like rifaximin, and fecal microbiota transplantation (FMT), seek to restore microbial balance and reduce neurotoxin levels. These strategies have shown encouraging results in mitigating cognitive decline and improving overall outcomes in patients with HE[9].

TRADITIONAL APPROACHES TO MODULATE GUT MICROBIOTA IN LIVER DISEASE

Non-absorbable disaccharides: Lactulose and lactitol

Non-absorbable disaccharides, such as lactulose and lactitol, are well-established therapies for managing HE, mainly in patients with cirrhosis. Their therapeutic effect is primarily achieved through modulation of the gut microbiota and reduction of ammonia production and absorption, a key neurotoxin implicated in HE pathogenesis. These compounds bypass absorption in the small intestine and are fermented by colonic bacteria into short-chain fatty acids (SCFAs), such as acetate, in the colon. This fermentation process lowers colonic pH, creating an acidic environment that suppresses urease-producing, ammonia-generating bacteria. Additionally, their osmotic action draws water into the bowel lumen, increasing stool volume and promoting intestinal transit, which facilitates the excretion of ammonia[10].

A Cochrane review by Gluud et al[11] demonstrated that non-absorbable disaccharides are associated with significant improvements in both mortality and HE severity compared with placebo or no treatment although the quality of evidence varies. The review found no significant difference in efficacy between lactulose and lactitol, supporting the use of either agent based on availability and patient tolerance.

Beyond ammonia-lowering effects emerging evidence suggests these agents may also positively shape the gut microbial landscape. For example, a study by Odenwald et al[12] showed that lactulose therapy in patients with cirrhosis increased the abundance of Bifidobacteria, which ferment lactulose into beneficial SCFAs like acetate. This synbiotic-like interaction may enhance mucosal health, reduce bacterial translocation, and potentially lower the risk of systemic infections.

Rifaximin and other antibiotics: Mechanisms and efficacy

Rifaximin, a non-absorbable, broad-spectrum antibiotic, is a cornerstone therapy for the prevention of recurrent HE in patients with liver cirrhosis. Its effectiveness has been consistently demonstrated in multiple clinical trials, and it is widely recommended in clinical practice for this indication. While its antimicrobial activity contributes to its therapeutic effect, rifaximin also exerts significant benefits through microbiota modulation[13,14].

Rather than causing widespread microbial eradication, rifaximin selectively targets pathogenic bacteria associated with HE while fostering a more favorable gut microbial profile. This contributes to a reduction in gut-derived endotoxins and systemic inflammation, two key drivers of HE. Mechanistically, rifaximin downregulates toll-like receptor expression on immune cells such as neutrophils and suppresses proinflammatory cytokines like tumor necrosis factor alpha, thereby dampening inflammatory signaling. Another critical aspect of the action of rifaximin is its role in preserving intestinal barrier integrity. By enhancing gut barrier function, it limits bacterial translocation and lowers systemic endotoxemia, both of which are implicated in the progression of HE (Figure 2)[15,16].

Figure 2 Rifaximin in hepatic encephalopathy. Rifaximin is a non-absorbable antibiotic that acts locally in the gut to modulate the intestinal microbiota. In patients with hepatic encephalopathy, this antibiotic reduces the abundance of ammonia-producing bacteria, leading to decreased production of ammonia and other gut-derived toxins. This reduction helps limit bacterial translocation and the associated release of proinflammatory cytokines. As a result fewer microbial products enter the portal circulation, contributing to decreased hepatic inflammation and potentially slowing the progression of liver fibrosis. Additionally, by lowering systemic levels of neurotoxic substances, rifaximin helps reduce neuroinflammation and improves cognitive function in patients with hepatic encephalopathy.

Importantly, the therapeutic benefits of rifaximin are achieved without significantly disturbing the overall diversity of the gut microbiome. Its minimal systemic absorption and action at subinhibitory concentrations reduce the selective pressure that typically drives antibiotic resistance, making it a relatively safe long-term option in HE management[17].

Probiotics: Restoring microbial balance

Probiotics have emerged as a promising adjunctive therapy for HE, particularly in restoring gut microbial balance. Some meta-analyses have highlighted their ability to lower systemic ammonia levels, improving cognitive performance and reducing the incidence of minimal HE (MHE)[18,19], which represents the earliest and mildest form of HE and is characterized by subtle cognitive and psychomotor impairments that are not clinically obvious but can be detected through specialized neuropsychological testing. Although less severe than overt HE, MHE significantly affects patient quality of life and functional abilities, such as driving and work performance, and may progress to overt HE if left untreated[18,19].

Comparative trials have assessed probiotics against established therapies such as lactulose and rifaximin. While probiotics may not consistently outperform this standard treatment, their efficacy in reversing MHE and delaying progression to overt HE has been shown to be comparable. Moreover, probiotics are generally well-tolerated with fewer adverse effects, making them an attractive option in long-term management[20,21].

The therapeutic effect of probiotics is primarily attributed to their ability to reshape gut microbiota. They promote the growth of beneficial bacteria like Lactobacillus and Bifidobacterium while suppressing harmful species such as Enterobacter and Enterococcus. This shift reduces gut-derived endotoxins and systemic inflammation, contributing to symptomatic relief and neurocognitive improvement in patients with HE[21].

EMERGING THERAPIES TARGETING GUT MICROBIOTA

Synbiotics and postbiotics: A new frontier

Synbiotics, which combine both probiotics and prebiotics in a single formulation, aim to optimize the therapeutic potential of each component by promoting the growth and activity of beneficial gut microbes. Although the theoretical advantage lies in their synergistic effects, clinical evidence supporting this synergy remains limited[21].

First, synbiotics restore microbial diversity and increase the abundance of beneficial commensals, such as Lactobacillus. This rebalancing of the microbiota helps suppress the overgrowth of pathogenic bacteria and reduces the production of harmful microbial metabolites. Second, synbiotics enhance intestinal barrier integrity by regulating tight junction proteins and mucins, thereby reducing gut permeability. This limits the translocation of endotoxins and other microbial products into the portal circulation.

Third, synbiotics modulate the metabolic activity of the gut microbiome, notably by increasing the production of SCFAs such as butyrate and acetate[22,23]. In a small single-center study, a synbiotic containing Bifidobacterium longum and fructo-oligosaccharides showed cognitive improvements and reduced serum ammonia levels. Similarly, in patients with MHE, both synbiotics and prebiotics alone were effective in reversing MHE in approximately half of the participants. Interestingly, the synbiotic did not show marked superiority over prebiotics alone. Nonetheless, both groups exhibited favorable changes such as fecal acidification, decreased levels of venous ammonia and serum lipopolysaccharide (LPS) levels as well as a reduction in E. coli concentration in stool samples (Figure 3)[24].

Figure 3 Synbiotic therapy: Microbial and metabolic benefits. This illustration highlights the key mechanisms through which synbiotic therapy, combining prebiotics and probiotics, exerts beneficial effects on gut microbiota and host metabolism. Synbiotics work synergistically to promote the growth and activity of beneficial bacteria, enhance short-chain fatty acids production through selective fermentation, and lower intestinal pH via organic acid release. These changes suppress pathogenic organisms, reduce systemic endotoxemia, and modulate immune responses. Additionally, synbiotics help decrease intestinal ammonia production and absorption, contributing to improved cognitive outcomes in patients with hepatic encephalopathy. SCFA: Short-chain fatty acids; MHE: Minimal hepatic encephalopathy; E. coli: Escherichia coli.

Moreover, synbiotics have demonstrated potential in improving neurocognitive function as reflected by enhanced performance on tests like the Trail Making Test and Inhibitory Control Test even in the absence of significant changes in ammonia levels. Clinical trials have also associated synbiotics with improved liver function, including reductions in ammonia and better Child-Turcotte-Pugh scores. Overall, synbiotics are well-tolerated and represent a promising, noninvasive alternative for managing MHE[25,26].

The limitations of using synbiotics include heterogeneity in clinical efficacy, lack of standardized formulations, and insufficient long-term safety data. Clinical studies and preclinical models demonstrate that synbiotics can improve gut barrier function and restore beneficial microbial populations, but the magnitude and consistency of these effects vary widely depending on the specific strains and prebiotic components used as well as patient-specific factors such as baseline microbiota composition and severity of liver disease[27].

Postbiotics, bioactive metabolites and structural components derived from probiotics, are emerging as promising microbiome-based therapies. Although their role in HE remains largely underexplored, growing evidence highlights their potential in modulating host physiology. These compounds, which include microbial cell wall components such as peptidoglycans, lipoteichoic acids, and immunomodulatory proteins like p40 and p75, interact with host immune cells to modulate cytokine production, promote anti-inflammatory responses, and regulate both innate and adaptive immune pathways. In addition to their immunoregulatory functions, postbiotics promote intestinal barrier integrity by upregulating tight junction proteins, stimulating mucin secretion, and activating epithelial cell survival pathways.

Furthermore, they can trigger antioxidant defenses through pathways such as Nrf2/ARE signaling, mitigate oxidative stress, and inhibit pro-inflammatory cascades like toll-like receptor 4 (TLR4)/nuclear factor kappa B[28-30]. These compounds, particularly SCFAs, are generated through bacterial fermentation of non-digestible polysaccharides and serve as a vital energy source for colonocytes. Beyond their nutritional value SCFAs play a critical role in maintaining intestinal barrier integrity, modulating immune responses, and promoting tolerance to commensal microbes. While direct clinical evidence in HE is still limited, postbiotics have shown promise in related conditions such as metabolic dysfunction-associated steatotic liver disease (MASLD) in which they enhance barrier function, reduce hepatic inflammation, and support lipid metabolism.

Postbiotics face several limitations in modulating the gut microbiota. As non-viable agents, they cannot colonize or interact dynamically with the host microbiota, resulting in transient effects and minimal long-term impact on microbial composition. Their immunomodulatory and barrier-enhancing actions are often dose-dependent, requiring high or repeated dosing for meaningful outcomes. Moreover, their antimicrobial activity is limited to specific bioactive compounds and lacks adaptability to evolving microbial threats[31,32]. Given the close association of HE with gut dysbiosis and systemic inflammation, these mechanisms suggest that postbiotics could offer therapeutic benefits, positioning them as a promising although still investigational approach in the management of HE[33,34].

FMT: Potential and challenges

In cirrhosis reduced bile acid production disrupts the gut microbiota, leading to a decline in beneficial bacterial groups such as Lachnospiraceae, Ruminococcaceae, and Clostridiales, which are essential for SCFA production and maintenance of gut barrier integrity. Additionally, impaired hepatic detoxification and the presence of portosystemic shunts allow bacterial products, including endotoxins and ammonia, to enter the systemic circulation, contributing to systemic inflammation and cognitive decline[35].

Early-phase clinical trials reported improvements in cognitive performance and gut mucosal microbial diversity following FMT. Specifically, increases in beneficial bacteria such as Lachnospiraceae and Ruminococcaceae along with reductions in harmful groups like Streptococcaceae and Veillonellaceae have been observed. These microbial shifts are associated with enhanced brain function and lower levels of systemic inflammation, including decreased serum LPS-binding protein.

Clinical studies have shown that FMT is both safe and potentially effective in reducing the recurrence of HE. The THEMATIC trial, a phase II randomized, placebo-controlled study, demonstrated that FMT was well-tolerated with no serious adverse events directly linked to the treatment. Participants who received FMT experienced a notable reduction in HE recurrence compared with the placebo group regardless of the method of delivery, dosage, or donor variation. These findings support the role of FMT as a promising adjunctive strategy in HE management[35-37].

Furthermore, meta-analyses and systematic reviews support the therapeutic potential of FMT in HE[37-39], demonstrating improvements in neurocognitive function, cognitive test scores, reduced hospitalization rates, and fewer serious complications compared with standard therapy alone. FMT offers several advantages over conventional treatments by directly targeting gut dysbiosis. It enhances microbial diversity, decreases the abundance of ammonia-producing bacteria, and leads to better cognitive outcomes. Clinical trials have shown FMT to be safe and potentially effective in reducing hospital admissions and serious adverse events[35,36,38]. However, several limitations remain, including small sample sizes in current studies, lack of standardized donor screening and dosing protocols, potential infection risks in patients who are immunocompromised, and logistical challenges in preparation and administration. Large-scale, well-designed studies are needed to optimize and standardize FMT for routine clinical application[37-40].

Bile acid modulators

Bile acid modulators have gained attention as potential treatments for HE due to their influence on bile acid signaling pathways. Dysregulation of these pathways may contribute to neuroinflammation and increased blood-brain barrier permeability in liver disease. In preclinical models, such as rats with thioacetamide-induced cirrhosis, bile acids have been shown to worsen HE symptoms by activating inflammatory pathways and receptors like TGR5. Certain bile acids can act on the blood-brain barrier and increase permeability themselves. It is believed that these bile acids act on the tight junction protein occludin through Rac1-dependent phosphorylation, and activation of this mechanism was determined to be independent of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Agents that reduce bile acid levels, such as cholestyramine, have helped alleviate HE symptoms in these studies[41-43].

Elevated bile acid levels have also been linked to blood-brain barrier disruption and worsened neurological function in models of acute liver failure. Interventions aimed at lowering serum bile acids, either through diet or pharmacological inhibition of receptors like FXR have delayed cognitive decline in these settings. In murine models of acute liver failure, treatment with bile acid sequestrants such as cholestyramine has been shown to reduce bile acid concentrations in both serum and brain, mitigate cerebral edema, and delay neurological deterioration. Central administration of FXR antagonists attenuated neuroinflammation and prolonged survival while activation of the TGR5 receptor with agonists exerted neuroprotective effects by suppressing microglial activation. A key advantage of bile acid modulators lies in their ability to target non-ammonia-mediated mechanisms of HE, offering a complementary therapeutic approach beyond traditional ammonia-lowering strategies[44]. While these results are encouraging, they stem mostly from animal studies, and further clinical research is needed to determine the therapeutic value of bile acid modulators in HE[42].

EXPANDING THE SCOPE: GUT MICROBIOTA IN LIVER DISEASES

MASLD and gut dysbiosis

MASLD has gained significant attention due to its strong connection with gut dysbiosis, an imbalance in the composition of the intestinal microbiota. The gut-liver axis serves as a critical pathway in the development of MASLD in which disturbances in the microbial community can profoundly impact liver health. Alterations in gut microbiota, particularly reduced microbial diversity, have been consistently observed in patients with MASLD and are closely associated with disease advancement[45].

One of the key mechanisms linking gut dysbiosis to liver pathology is the disruption of intestinal barrier integrity, often resulting in increased permeability or leaky gut. This condition allows microbial components, such as LPS, to translocate into the portal bloodstream, triggering hepatic inflammation and fat accumulation. Endotoxins interact with various receptors, including TLRs and nucleotide-binding oligomerization domain receptors. Specifically, TLR4, which is found on the plasma membranes of hepatocytes and Kupffer cells, plays a key role. Activation of TLR4 triggers downstream signaling pathways involving molecules like nuclear factor kappa B, leading to the production of proinflammatory cytokines such as interleukin 1β and interleukin 18, ultimately contributing to liver injury. Dietary factors, notably high-fat and high-fructose consumption, further compromise the intestinal barrier, intensifying liver exposure to harmful bacterial products and exacerbating inflammation and fibrosis[46,47].

Moreover, gut microbiota influences liver function through the production of various metabolites, including SCFAs, bile acids, and ethanol. Disruptions in SCFA production and bile acid metabolism have been implicated in MASLD progression and the development of fibrosis. In a dysbiotic state the gut microbiota generates lower levels of protective metabolites, including the SCFA, acetate, and tryptophan derivatives like indole-3-propionic acid and indole-3-acetic acid, which are essential for maintaining gut barrier integrity under healthy conditions. In contrast, microbial and fungal fermentation produces ethanol, leading to inflammation, fibrosis, and cell death. Individuals with MASLD exhibit enhanced microbial conversion of primary bile acids into unconjugated secondary bile acids in the intestine, compounds that are toxic to the liver and lead to disease progression. In addition, this dysregulation may stimulate hepatocytes to increase bile acid synthesis, further exacerbating liver injury[48].

Certain bacterial species, such as Ruminococcus gnavus (R. gnavus), have been linked to liver fat accumulation and inflammatory responses. Nevertheless, the precise mechanisms underlying this relationship and the direction of causality remain uncertain. In experimental studies male mice fed a high-fat diet for 16 weeks or orally colonized with R. gnavus exhibited elevated serum markers associated with fatty liver disease, such as increased levels of low-density lipoprotein, total cholesterol, and liver triglycerides, compared with control mice on a standard diet. Notably, levels of hepatic fibroblast growth factor 21, were significantly reduced in mice subjected to either high-fat feeding or R. gnavus colonization. These findings suggest that R. gnavus can directly disrupt host energy metabolism and cholesterol regulation, mimicking the effects of a high-fat diet in a murine model of steatotic liver disease[49,50].

The immune system also plays a pivotal role in gut-liver interplay. Microbial products are recognized by TLRs on liver cells, initiating immune responses that can lead to chronic hepatic inflammation and progression to steatohepatitis. The widely accepted multiple hit hypothesis suggests that MASLD arises from a combination of factors, including insulin resistance, gut dysbiosis, and genetic predispositions, all converging to disrupt gut-liver homeostasis. Collectively, changes in microbial diversity, metabolite production, and immune system activation create a complex network that drives the onset and progression of MASLD[50].

Gut microbiota in alcoholic liver disease

Alcoholic liver disease (ALD) constitutes a spectrum of liver pathologies resulting from chronic and excessive alcohol consumption. Although its precise pathogenesis remains incompletely understood, emerging evidence highlights intestinal dysbiosis as a key contributor to disease progression[51].

Under physiological conditions enterocytes within the intestinal epithelium form tight junctions that serve as a barrier, limiting the transit of microorganisms and their products from the intestinal lumen to the systemic circulation. In ALD this barrier function is disrupted by the accumulation of ethanol and its metabolite acetaldehyde, which activate TLR4 and protein kinase C in intestinal epithelial cells. This activation leads to the phosphorylation of tight junction proteins, thereby increasing intestinal permeability. Consequently, bacterial translocation into the portal circulation is facilitated, initiating a systemic inflammatory response[52].

TLRs, part of pattern recognition receptors, are expressed in various hepatic and immune cells, including hepatocytes, cholangiocytes, hepatic stellate cells, and systemic immune-competent cells. These receptors recognize conserved microbial structures such as LPS, lipoteichoic acid, lipoarabinomannan, and bacterial DNA. Upon activation TLRs trigger the production of proinflammatory cytokines, contributing to the development of chronic inflammatory microenvironment in the liver[52,53].

The translocation of bacteria and their toxic products through the portal circulation activates hepatic immune cells, particularly Kupffer cells. Once activated these cells secrete proinflammatory cytokines, chemokines, and reactive oxygen species, thereby exacerbating liver injury. Additionally, a significant reduction in the population of natural killer cells has been observed in patients with ALD. The cells exert antifibrotic effects by inducing apoptosis in activated Kupffer cells, and their reduction contributes to the progression of liver fibrosis[53].

Finally, excessive alcohol consumption induces gut dysbiosis, characterized by a reduction in beneficial commensal bacteria, such as certain Firmicutes, Bacteroidetes, and Lactobacillus species and an overgrowth of potentially pathogenic taxa, including Enterobacteriaceae and members of the Proteobacteria phylum. This shift promotes the expansion of both aerobic and anaerobic bacteria while decreasing the production of key microbial metabolites, such as SCFAs and indole derivatives. The loss of these metabolites impairs intestinal barrier function and fosters a chronic systemic inflammatory state, contributing to the progression of ALD[54].

Cirrhosis and microbiota-driven complications

Liver cirrhosis significantly disrupts the intestinal microbiota through multiple mechanisms. First, it reduces the synthesis of bile acids, which plays a crucial role in maintaining microbial balance and gut function. Second, cirrhosis leads to portal hypertension and gastrointestinal blood stasis, impairing the integrity of the intestinal barrier and promoting gut dysbiosis. As the barrier weakens, bacteria and their metabolites can translocate into the portal and systemic circulation, triggering systemic inflammation and endotoxemia. These processes not only accelerate the progression of cirrhosis but also contribute to a range of cirrhosis-related complications (Figure 4)[55,56].

Figure 4 Liver damage progression in gut dysbiosis. This illustration describes the sequence of events linking gut dysbiosis to progressive liver damage. Disruption of the gut microbiota leads to mucus layer depletion and loss of intestinal barrier integrity, resulting in a leaky gut. This facilitates microbial translocation and increases the production of microbial metabolites such as endotoxins. These microbial products enter the portal circulation and reach the liver where they activate Kupffer cells and stimulate the release of proinflammatory cytokines. The resulting chronic inflammation promotes hepatic fat accumulation and initiates fibrotic processes. Over time this inflammatory cascade drives the progression from metabolic dysfunction-associated steatotic liver disease to more severe forms of liver injury, including fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. MASLD: Metabolic dysfunction-associated steatotic liver disease; HCC: Hepatocellular carcinoma.

Evidence of increased systemic endotoxemia in patients with liver cirrhosis has been demonstrated using the Limulus amebocyte lysate test. Subsequent quantitative assays further confirmed that plasma endotoxin levels rise progressively with liver fibrosis and the development of cirrhosis. Studies examining portal blood flow in patients with cirrhosis support the notion that gut barrier dysfunction facilitates the translocation of endotoxins into systemic circulation. Collectively, these findings highlight the close association between endotoxemia due to a leaky gut and the worsening of liver disease, including the development of spontaneous bacterial peritonitis, progression of liver fibrosis, and disturbances in the cardiovascular, renal, pulmonary, and coagulation systems. Moreover, increased intestinal permeability has been correlated with more advanced stages of cirrhosis as reflected in higher Child-Pugh scores[55].

Cirrhosis-associated immune dysfunction further complicates this scenario. Characterized by both systemic inflammation and an impaired immune defense, cirrhosis-associated immune dysfunction is exacerbated by the continuous influx of gut-derived endotoxins and microbial metabolites. This immune dysregulation increases the risk of serious complications such as spontaneous bacterial peritonitis, HE, and acute-on-chronic liver failure, many of which are precipitated by bacterial infections originating from the gut[57].

Given this intricate gut-liver interplay, therapeutic interventions targeting the gut microbiota have gained attention. Strategies such as antibiotics, probiotics, and FMT aim to restore gut eubiosis, a state of balanced and diverse gut microbiota that supports intestinal and systemic health in contrast to dysbiosis, which is characterized by microbial imbalance and associated with disease. Restoring eubiosis helps strengthen the intestinal barrier and reduces bacterial translocation and systemic inflammation, offering a promising approach to mitigate cirrhosis progression and its associated complications[58].

FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS

Precision medicine in microbiota-targeted therapies

Recent advances in microbiome sequencing technologies, such as 16S ribosomal RNA sequencing and metagenomics, have greatly improved our understanding of the role of the gut microbiota in liver diseases. 16S rRNA sequencing enables the identification and quantification of bacterial taxa, providing valuable insights into microbial diversity and shifts associated with liver pathology. Metagenomics expands on this by analyzing the complete genetic material within a sample, uncovering not only the microbial composition but also the functional capabilities of the gut microbiota. Through this approach researchers have identified alterations in metabolic pathways, such as increased ethanol production and endotoxin biosynthesis, that contribute to systemic inflammation[59,60].

These technologies support a move toward personalized medicine in which treatments can be tailored to an individual’s specific dysbiosis patterns. For instance, probiotics can be selected to promote the growth of beneficial SCFA-producing bacteria, often diminished in cirrhosis and MASLD. Similarly, prebiotics may be used to nurture these beneficial microbes while targeted antibiotics can help reduce harmful bacterial populations. Additionally, postbiotics offer promising anti-inflammatory and gut barrier-supporting effects. Altogether, the ability to precisely characterize the gut microbiota opens new avenues for individualized therapeutic strategies, aiming to correct microbial imbalances and improve clinical outcomes in liver disease[61,62].

Variations in treatment response to rifaximin and other therapies in HE is closely linked to differences in gut microbiota composition and the presence of conditions such as metabolic syndrome. Studies have shown that patients with cirrhosis and HE possess distinct microbial signatures that can influence how they respond to treatment. Individuals with metabolic syndrome tend to have a poorer response to rifaximin when managing MHE. This finding underscores the importance of considering comorbidities like metabolic syndrome when stratifying patients for more personalized therapeutic strategies[63].

Additionally, the broader microbiome, including bacterial and viral components such as bacteriophages, also impacts disease progression and treatment efficacy. Alterations in the phage-bacterial network have been documented in patients with cirrhosis and HE, and rifaximin has been shown to modulate these interactions. These observations suggest that microbiota-based profiling could be instrumental in predicting treatment outcomes and optimizing therapy choices[64].

For patients who are refractory to standard treatments like rifaximin and lactulose, FMT has emerged as a promising alternative. By restoring gut microbial balance, FMT offers a targeted approach to improving outcomes in HE, particularly for those who do not benefit from conventional therapies[36].

Next-generation probiotics (NGPs) represent a promising advancement in the treatment of liver diseases, offering potential benefits beyond those of conventional probiotics. Unlike traditional formulations, NGPs are carefully selected or bioengineered to target specific disease mechanisms with improved stability and viability. Utilizing tools from synthetic biology and bioinformatics, these probiotics can be tailored to address pathological conditions, including hepatic disorders, thereby enabling more precise therapeutic interventions. Engineered as live biotherapeutic agents, NGPs can be designed to carry out targeted functions such as suppressing pathogenic microbes or modulating immune activity, both of which are relevant to maintaining liver health. Despite their potential, the clinical application of NGPs remains under investigation, and further research is essential to refine their efficacy and establish safety profiles for broader therapeutic use[65].

Challenges and opportunities in gut microbiota research

The considerable interindividual variability in gut microbiota composition poses a major obstacle to the development of standardized therapeutic strategies, particularly in the context of NGPs for liver disease. This heterogeneity is shaped by a range of factors, such as host genetics, dietary habits, and environmental exposures, leading to highly personalized microbial profiles. As a result the efficacy of probiotic interventions can differ markedly between individuals, depending on their baseline microbiota and its metabolic capacity, making it challenging to identify universally effective strains or formulations[66,67]. In addition, the influence of the gut microbiome on drug metabolism and host physiological responses further complicates the standardization of microbiota-based therapies. Given the central role of the liver in pharmacokinetics, variations in microbial communities may significantly impact drug bioavailability and efficacy in patients with liver disorders. These complexities highlight the need for personalized or stratified treatment approaches that consider individual microbiome characteristics to improve clinical outcomes[68].

To address these challenges strategies such as pooled microbiome therapeutics have emerged in which microbiota from multiple donors are combined to create a more stable and functionally diverse therapeutic product. Preclinical studies have demonstrated that this approach can enhance efficacy and reduce variability in treatment responses. Nonetheless, successful clinical translation will depend on a deeper understanding of host-microbiome-drug interactions, alongside the advancement of reliable microbiome profiling techniques and targeted intervention frameworks[69].

Emerging technologies such as artificial intelligence and systems biology are reshaping the future of microbiota-based therapies in liver disease. These innovations offer powerful tools for improving predictive modeling and designing more precise interventions, including FMT and engineered probiotics. Artificial intelligence and machine learning can integrate and analyze complex multi-omics datasets, such as metagenomics, metabolomics, transcriptomics, and proteomics, to uncover the intricate relationships between gut microbes and host physiology. This enables the identification of microbial biomarkers associated with disease progression and therapeutic responsiveness, supporting the development of personalized treatment strategies[70].

In parallel, systems and synthetic biology approaches allow for the rational design of microbial communities with therapeutic potential. For example, technologies like CRISPR/Cas9 and metabolic engineering are being leveraged to construct next-generation probiotics with specific functions, such as producing anti-inflammatory metabolites or restoring metabolic balance in the gut-liver axis. The integration of artificial intelligence with genome-scale metabolic models further enhances this process by predicting microbial behavior and interactions within host environments, informing the design of tailored microbial consortia.

Together, these technological innovations provide a powerful framework for advancing microbiota-based therapies. By enabling the development of personalized, functionally targeted interventions, they hold promises for improving clinical outcomes in liver diseases characterized by gut dysbiosis and immune dysregulation[71-73].

CONCLUSION

The gut microbiota has emerged as a central player in the pathophysiology of liver diseases through its influence on ammonia production, systemic inflammation, and neurocognitive dysfunction. This complex gut-liver-brain axis highlights the importance of considering microbial composition and function in the clinical management of liver disorders. Traditional therapeutic options, such as non-absorbable disaccharides, rifaximin, and probiotics, remain vital tools, but they are now being complemented by a new generation of microbiota-targeted strategies, including postbiotics, synbiotics, FMT, and small molecule modulators, that aim to restore microbial balance and enhance host-microbe interactions. Moreover, the therapeutic implications of gut microbiota modulation extend beyond HE to conditions such as MASLD and cirrhosis, suggesting a broader role for microbiome-based interventions in hepatology. As research progresses, a more nuanced understanding of microbial metabolites, bile acid signaling, and host immune responses will be essential to refine these therapies and identify patient subgroups most likely to benefit. Ultimately, incorporating microbiota-directed strategies into a personalized medicine framework holds the potential to revolutionize liver disease management, improve quality of life, and reduce the burden of complications associated with chronic liver conditions.