Guozhen Yang
Jiling Zhu†
Kai Dai- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
The gut microbiota is fundamental to human health, maintaining intricate symbiotic interactions with the host. Accumulating evidence highlights a critical association between gut microbiota dysbiosis and the initiation and progression of chronic liver diseases (CLDs). Particularly hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, alcoholic liver disease (ALD), metabolic-associated steatotic liver disease (MASLD), and cirrhosis. This microbial imbalance may contribute to the progression of CLDs primarily via the “gut-liver axis,” the mechanisms involve gut barrier dysfunction, abnormal immune regulation, and metabolic alterations. This review synthesizes cutting-edge research on the interplay between gut dysregulation and CLDs, elaborating molecular mechanistic pathways including the TLR4/NF-κB signaling pathway, AMPK pathway, and farnesoid X receptor (FXR)-mediated bile acid signaling. Additionally, it discusses clinically oriented therapeutic strategies targeting microbiota modulation, including probiotics, fecal microbiota transplantation (FMT), and personalized dietary interventions, offering innovative insights for the prevention and management of chronic liver diseases.
Introduction
The gut microbiota, a complex community of microorganisms residing in the gastrointestinal tract, plays a crucial role in maintaining human health. It is involved in essential functions such as digestion, metabolism, immune regulation, and protection against pathogens (1–3). The balance of this microbial community is vital for overall health, and its disruption, known as dysbiosis, is increasingly recognized as a contributing factor in various diseases, including chronic liver diseases (CLDs) (4). Research has shown a potential link between gut microbiota dysbiosis and the pathogenesis of CLDs. Dysbiosis can lead to increased intestinal permeability, allowing the translocation of microbial products such as lipopolysaccharides (LPS) into the bloodstream, which in turn triggers systemic inflammation and liver injury (5, 6). Furthermore, alterations in gut microbiota composition can affect liver metabolism, including lipid metabolism and bile acid synthesis, which may contribute to the progression of liver diseases (5, 7–9).
On the other hand, research suggests that the balance of the intestinal microbiota can be restored through dietary interventions, probiotic supplementation, and fecal microbiota transplantation, which in turn may alleviate chronic liver damage and reduce liver fibrosis. Therefore, it is essential to further investigate the underlying mechanisms linking intestinal microbiota dysbiosis to chronic liver diseases and to identify effective therapeutic strategies that can restore microbial equilibrium and support liver health. To ensure the comprehensiveness and rigor of this review, a systematic literature search was performed in PubMed, Embase, and Web of Science databases. Core keywords included “gut microbiota dysbiosis,” “gut-liver axis,” “chronic liver disease,” “HBV,” “HCV,” “alcoholic liver disease,” “MASLD,” “cirrhosis,” “probiotics,” “fecal microbiota transplantation,” “microbial metabolites,” and “mechanism.” Evidence priority was given to systematic reviews, Meta-analyses, and RCTs, followed by high-quality cohort studies and basic mechanistic research.
Overview of gut microbiota
The gut microbiota, a complex and dynamic ecosystem, comprises trillions of microorganisms, including bacteria, viruses, fungi, and archaea, residing in the gastrointestinal tract (10–12). This microbiota plays a crucial role in maintaining host health by participating in various physiological processes, including digestion, metabolism, immune function, and the synthesis of essential vitamins and short-chain fatty acids (SCFAs) (13–16).
Gut microbiota and dysbiosis
The gut microbiota consists predominantly of bacterial phyla such as Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, with each phylum containing various genera and species that perform specific functions (17–19). For example, Firmicutes includes beneficial species such as Lactobacillus rhamnosus, Clostridium butyricum, and Faecalibacterium prausnitzii; Bacteroidetes comprises Bacteroides fragilis and Bacteroides thetaiotaomicron, which are involved in polysaccharide fermentation; Actinobacteria includes Bifidobacterium infantis and Bifidobacterium longum; Proteobacteria includes potential pathogens such as Escherichia coli and Salmonella enterica (Table 1) (20). These microorganisms are involved in the fermentation of dietary fibers, which produces SCFAs like acetate, propionate, and butyrate, vital for colonic health and energy metabolism (21–23).
Table 1. Overview of core gut microbiota and their metabolites.
Gut microbiota dysbiosis refers to an imbalance in the microbial community, often characterized by a decrease in microbial diversity and an overgrowth of pathogenic bacteria (13, 24, 25). Several factors contribute to dysbiosis, including antibiotic use, dietary changes, infections, and environmental exposures. For instance, the overuse of antibiotics can lead to a significant reduction in microbial diversity, allowing opportunistic pathogens to flourish and disrupt the gut barrier (26). Additionally, dietary patterns high in processed foods and low in fiber can alter the composition of gut microbiota, leading to metabolic disorders such as obesity and type 2 diabetes (27). Studies have shown that the imbalance of gut microbiota is closely linked to the occurrence, development, and prognosis of several liver diseases, including acute liver injury, viral hepatitis, cirrhosis, autoimmune liver disease, alcoholic liver disease (ALD), and metabolic-associated steatotic liver disease (MASLD) (28). This dysbiosis influences the degree of hepatic steatosis, inflammation, fibrosis, and even carcinogenesis through multiple interactions with the host immune system and other cell types, which is closely associated with the occurrence of chronic liver diseases (29). Understanding the mechanisms underlying dysbiosis is crucial for developing targeted interventions, such as probiotics and dietary modifications, to restore microbial balance and promote health (30–32).
Gut microbiota dysbiosis and chronic liver diseases
The gut microbiota plays a crucial role in maintaining human health and is increasingly recognized for its involvement in various diseases, including CLDs. Dysbiosis, a state of microbial imbalance, has been linked to the pathogenesis and progression of CLDs through several mechanisms. These mechanisms mainly include impaired gut barrier function, abnormal immune regulation, and metabolic alterations (Figure 1), which collectively contribute to increased susceptibility to infections and exacerbation of liver conditions (33, 34).
Figure 1. Mechanisms such as gut barrier dysfunction, abnormal immune regulation, and metabolic alterations can lead to gut microbiota dysbiosis, which is transmitted to the liver via the gut-liver axis, thereby promoting the initiation and progression of various chronic liver diseases (CLDs) including viral hepatitis (HBV/HCV infection), ALD, MASLD, and cirrhosis; conversely, the progression of CLDs further exacerbates gut microbiota dysbiosis through the same gut-liver axis, forming a persistent vicious cycle that drives continuous disease deterioration. Created with BioRender.com.
Gut barrier dysfunction
Dysbiosis can lead to increased intestinal permeability, a condition often referred to as “leaky gut” (35). This phenomenon is mediated by downregulated expression of tight junction proteins, including zonula occludens-1 (ZO-1), Occludin, and Claudin-1, in intestinal epithelial cells. Pathogenic bacteria, notably E. coli and Klebsiella pneumoniae, secrete toxins such as cytolethal distending toxin (CDT) that induce degradation of tight junction proteins (36). Concomitantly, depletion of beneficial commensals (e.g., L. rhamnosus and F. prausnitzii) diminishes the biosynthesis of butyrate, which is an essential metabolite that sustains intestinal epithelial cell viability and preserves gut barrier integrity through activation of the AMPK signaling pathway (37).
Additionally, dysbiosis-induced inflammation downregulates the transcription of tight junction protein genes, further increasing intestinal permeability (38). This allows for the translocation of bacteria and their products, such as LPS, into the systemic circulation, which can provoke systemic inflammation and contribute to liver injury (5, 39). The disruption of the gut barrier is particularly concerning in patients with CLDs, as it can exacerbate the inflammatory response and further impair liver function. Studies have shown that alterations in gut microbiota composition, characterized by a decrease in beneficial bacteria and an increase in pathogenic strains, can lead to gut barrier dysfunction (38). This dysfunction not only facilitates the entry of harmful microbial products into the bloodstream but also contributes to the progression of liver diseases such as MASLD and ALD (40, 41).
Abnormal immune regulation
The gut microbiota can mediate gut epithelial and immune cells interaction through vitamins synthesis or metabolic products. The microbiota plays a vital role in growth and development of the main components of human’s adaptive and innate immune system, while the immune system regulates host-microbe symbiosis. The gut microbiota is integral to the development and regulation of the immune system, and its disruption can lead to an imbalance between pro-inflammatory and anti-inflammatory responses (42). Mechanistically, dysbiosis-induced LPS translocation activates the TLR4/NF-κB signaling pathway in hepatic Kupffer cells and hepatic stellate cells, promoting the secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, which drive hepatic inflammation and subsequent fibrogenesis (43, 44). Meanwhile, the reduction of butyrate impairs the differentiation of Tregs (regulatory T cells) in the gut and liver, while enhancing the activation of Th17 cells and their secretion of IL-17A—further amplifying the pro-inflammatory microenvironment (45).
Additionally, gut microbiota-derived metabolites such as indole (from Proteobacteria) can modulate the function of dendritic cells, leading to abnormal activation of adaptive (46). In chronic liver disease, this imbalance can result in immune dysregulation, characterized by an overactive inflammatory response that contributes to liver damage and increases the risk of infections. For instance, the presence of certain gut bacteria can stimulate the production of inflammatory cytokines, which further exacerbate liver inflammation and damage (38, 47). In other words, negative alteration in gut microbiota composition or gut dysbiosis, can disturb immune responses, which will make the host more susceptible to infections (48). Furthermore, dysbiosis has been associated with the activation of the gut-liver axis, where gut-derived signals influence hepatic immune responses, thereby enhancing the susceptibility to infections and liver disease progression (42, 48).
Metabolic alterations
Dysbiosis also leads to significant metabolic changes that can increase the host’s susceptibility to infections and the progression of CLDs. As is well-known, The gut microbiota is responsible for the production of various metabolites, including SCFAs and bile acids, which play critical roles in maintaining gut health and regulating immune responses (5, 49). SCFAs, especially butyrate, primarily exert their effects via the AMPK signaling pathway: they suppress the expression of key hepatic lipogenic genes, including Srebp2, Fasn, Srebp-1c, Cd36, and Acc, to inhibit lipogenesis, while concomitantly activating fatty acid oxidation, thereby regulating lipid metabolism in hepatocytes and alleviating hepatic lipid accumulation (50, 51). Bile acids, as key signaling molecules, bind to FXR (farnesoid X receptor) in hepatocytes and intestinal epithelial cells to modulate glucose and lipid homeostasis, as well as regulate inflammation via the FXR-SHP pathway (52). Dysbiosis-induced reduction in SCFA production and alterations in bile acid composition (e.g., increased primary/secondary bile acid ratio) disrupt these metabolic pathways, leading to hepatic steatosis and metabolic dysfunction (53). Additionally, dysbiosis increases the production of microbial-derived ethanol and acetaldehyde, which directly induce hepatocyte injury in ALD and MASLD (54, 55).
Alterations in the composition of gut microbiota can disrupt the production of these metabolites, leading to an increased risk of metabolic disorders and liver disease (38, 47). For example, reduced levels of SCFAs due to dysbiosis have been linked to impaired gut barrier function and increased inflammation, both of which can exacerbate liver disease and increase susceptibility to infections (38). Moreover, changes in bile acid metabolism due to dysbiosis can further influence liver function and the risk of chronic liver disease (40). In summary, dysbiosis of gut microbiota significantly influences the pathogenesis of chronic liver diseases through mechanisms involving gut barrier dysfunction, abnormal immune regulation, and metabolic alterations (39, 47, 48). Understanding these mechanisms is essential for developing targeted therapeutic strategies aimed at restoring gut microbiota balance and improving liver health.
Detection techniques and factors influencing microbiota research results
The inconsistency of gut microbiota research results in CLDs is partly attributed to differences in detection techniques and research factors. 16S rRNA sequencing can identify microbial taxa at the phylum and genus levels with high throughput but has limitations in species-level resolution (e.g., distinguishing E. coli from E. fergusonii) and functional annotation (56). By contrast, metagenomics sequencing research has accelerated the accumulation of genomic sequences of microbial species that had been inaccessible before. Analysis of the metagenomic sequencing data can reveal not only the species but also the functional composition of microbial communities, providing comprehensive information on microbial genes and functional pathways, enabling accurate species identification and prediction of metabolic potential, but this approach is constrained by high costs and computational complexity (57). Bioinformatics analysis pipelines also affect outcomes: QIIME2 is superior for 16S data analysis, while MetaPhlAn3 and HUMAnN3 are more suitable for taxonomic assignment and metagenomic functional annotation (58).
Additionally, geographic and dietary differences lead to variations in baseline gut microbiota composition (59)—Asian populations have higher abundance of Bacteroidetes due to high-fiber diets, while Western populations have higher Firmicutes. In cirrhotic patients, decompensated status is associated with more severe dysbiosis compared to compensated status (60). Studies have demonstrated that the abundance of Enterobacteriaceae, and Proteobacteria is increased in decompensated cirrhotic patients who eventually succumb to the disease (61). For HBV/HCV patients, antiviral therapy (e.g., entecavir for HBV, glecaprevir/pibrentasvir for HCV) can partially reverse gut microbiota dysbiosis by reducing hepatic inflammation, which should be considered when interpreting study results (62).
Gut microbiota changes in chronic liver diseases
Chronic liver diseases are consistently associated with significant alterations in gut microbiota composition and function, a phenomenon that critically influences disease progression and clinical outcomes. Substantial heterogeneity exists in microbial dysbiosis patterns across distinct CLD etiologies—including viral hepatitis (HBV/HCV infection), MASLD, ALD, and cirrhosis—reflecting disease-specific host-microbiota interactions (Table 2). Key alterations encompass reduced microbial alpha-diversity, depletion of commensal taxa, and enrichment of pathobionts, collectively disrupting gut barrier integrity and promoting microbial translocation via the gut-liver axis (63). These perturbations drive hepatic inflammation, fibrogenesis, and metabolic dysregulation through mechanisms involving endotoxemia, bile acid metabolism impairment, and short-chain fatty acid depletion (64). A comprehensive understanding of etiology-specific microbial signatures is therefore essential for developing targeted therapeutic strategies aimed at restoring eubiosis, thereby mitigating liver injury and improving patient prognosis.
Table 2. Alterations in gut microbiota in different etiologies of chronic liver diseases.
Gut microbiota changes in viral hepatitis (HBV/HVC infection)
Viral hepatitis, particularly caused by HBV and HCV, has been linked to significant dysbiosis in the gut microbiota (65). Studies have shown that patients with chronic HBV and HCV infections exhibit a decrease in microbial diversity, which is often accompanied by an increase in pathogenic bacteria such as Proteobacteria and a reduction in beneficial taxa like Firmicutes and Bacteroidetes (65–67). Confounding factors such as prolonged antibiotic use and PPI (proton pump inhibitor) administration can further alter the composition of gut microbiota, a phenomenon that is prevalent in viral hepatitis patients complicated with spontaneous bacterial peritonitis and gastroesophageal reflux disease. PPIs reduce gastric acid secretion, leading to the overgrowth of oral bacteria (e.g., Streptococcus salivarius) in the gut, which in turn exacerbates microbial translocation and hepatic inflammation (68, 69). Additionally, viral replication itself modulates gut microbiota by inducing systemic inflammation, which suppresses beneficial bacteria growth (70).
The gut microbiota’s composition can influence the severity of liver inflammation and fibrosis, as certain microbial profiles have been associated with increased liver damage and disease progression (71, 72). For instance, specific bacterial genera such as Escherichia and Shigella have been identified as potential markers for predicting the risk of developing severe liver disease in these patients (73, 74). Furthermore, the dysbiosis observed in viral hepatitis may exacerbate systemic inflammation, leading to further liver injury through mechanisms involving microbial translocation and immune activation (75). Thus, the interplay between gut microbiota and liver health in viral hepatitis underscores the potential for microbiome-targeted therapies to mitigate liver damage and improve clinical outcomes.
Gut microbiota changes in MASLD and ALD
Metabolic liver diseases, such as MASLD, and ALD are characterized by distinct alterations in gut microbiota composition (76). In ALD, chronic alcohol consumption leads to dysbiosis, with a notable increase in pathogenic bacteria and a decrease in beneficial microbes. Phenomena such as antibiotic use and malnutrition also commonly occur in patients with ALD, and these confounding factors can exacerbate dysbiosis. Long-term antibiotic exposure significantly reduces microbial diversity, while a low-protein diet further impairs the growth of beneficial bacteria (e.g., Bifidobacterium) (54, 77). In addition, alcohol-induced intestinal epithelial injury directly alters the microbiota composition by creating a pro-inflammatory microenvironment that favors pathogenic bacteria (17, 78). Studies have reported a significant reduction in the abundance of Lactobacillus and Bifidobacterium species in patients with ALD, which correlates with increased intestinal permeability and systemic inflammation. Large amounts of endotoxins translocated from the gut strongly activate Toll-like receptor 4 in the liver and play an important role in the progression of ALD, especially in severe alcoholic liver injury (17, 54). Similarly, in MASLD, the gut microbiota shows a shift towards a more pro-inflammatory profile, with increased levels of Firmicutes and a decrease in Bacteroidetes, which is associated with the progression from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis (79). In fact, gut dysbiosis is closely associated with hepatic steatosis and metabolic syndrome. The dysbiosis in these conditions is thought to contribute to the pathogenesis of liver disease through mechanisms such as altered bile acid metabolism, increased LPS translocation, and modulation of host immune responses (53, 80). Therefore, interventions aimed at restoring gut microbiota balance, such as dietary modifications, probiotics, and fecal microbiota transplantation, hold promise for improving metabolic liver disease outcomes.
Gut microbiota changes in cirrhosis
Liver cirrhosis is one of the chronic liver diseases that can be complicated by episodes of decompensation such as variceal bleeding, hepatic encephalopathy (HE), ascites, and jaundice, with subsequent increased mortality. Infection remains one of the most frequent complications in patients with liver cirrhosis, with spontaneous bacterial peritonitis (SBP) being the most prevalent type. SBP is mainly induced by Gram-negative bacteria living in the intestinal tract, and translocating through the intestinal barrier, which in cirrhotic patients is defective and more permeable. Confounding factors such as long-term use of antibiotics (e.g., rifaximin), lactulose, and PPIs significantly affect the gut microbiota composition in patients with liver cirrhosis. For instance, rifaximin, which is used for the treatment of complications in cirrhotic patients, can markedly reduce the abundance of Enterobacteriaceae, but it may also lead to a decrease in beneficial bacteria (e.g., Lactobacillus); lactulose promotes the growth of Bifidobacterium and Lactobacillus through fermentation in the colon, thereby increasing the production of short-chain fatty acids (81, 82). Notably, decompensated cirrhosis is associated with more severe dysbiosis compared to compensated cirrhosis, including further reduction in microbial diversity and increased abundance of pathobionts (e.g., Enterobacteriaceae, Streptococcaceae) (60). Additionally, hepatic dysfunction itself also alters gut microbiota by reducing bile acid secretion, which is essential for maintaining microbial balance (40, 83). This dysbiosis is characterized by an overgrowth of pathogenic bacteria, including Enterobacteriaceae and a decrease in protective species, leading to increased susceptibility to infection (84, 85). The presence of SBP significantly worsens the clinical course of cirrhosis, contributing to acute-on-chronic liver failure and increased mortality rates (86). Mechanistically, the dysbiosis in cirrhotic patients not only facilitates bacterial translocation but also triggers systemic inflammation, exacerbating liver dysfunction and promoting further complications (60, 79). Consequently, strategies aimed at restoring gut microbiota balance, such as antibiotic prophylaxis and probiotics, are critical in managing the risk of infections in cirrhotic patients.
Treatment of chronic liver diseases
The pivotal role of the gut-liver axis in CLDs has unveiled novel therapeutic avenues for their prevention and treatment. Specifically, interventions targeting the intestinal microbiome offer promising strategies to mitigate and repair hepatic injury while improving patient prognosis. Future research directions may emphasize the development of personalized therapeutic regimens incorporating dietary modifications, microbiota-targeted interventions, and advanced techniques including fecal microbiota transplantation (FMT), probiotics, and prebiotics (Table 3). This integrated approach seeks to reestablish intestinal microbial homeostasis, promote hepatic repair, and ultimately enhance the quality of life for patients with chronic liver diseases.
Table 3. Summary of microbiota-targeted therapeutic strategies for chronic liver diseases.
Microbial therapies: probiotics, prebiotics, and synbiotics
Microbial therapy, encompassing probiotics, prebiotics, and synbiotics, represents a promising therapeutic approach to restore gut microbiota homeostasis and mitigate bacterial infection risk in patients with chronic liver disease (87).
Probiotics, as active beneficial microorganisms, mitigate microbial imbalances in liver diseases by replenishing beneficial gut bacteria and strengthening intestinal barrier function. A randomized controlled trial (RCT) involving 67 patients with HBV-related liver cirrhosis demonstrated that 12-week supplementation with Bifidobacterium infantis and Clostridium butyricum led to significant enrichment of dominant bacteria (Clostridium cluster I and Bifidobacterium) and marked reduction in Enterococcus and Enterobacteriaceae in the probiotic group. In addition, the indicators of intestinal mucosal barrier function were significantly improved after probiotic treatment, which may have contributed to the enhancement of cognitive function and the reduction of ammonia levels. The research demonstrates treatment with probiotics containing C. butyricum and B. infantis represents a new adjuvant therapy for the management of MHE in patients with HBV-induced cirrhosis (88). Probiotic application is associated with improvement in conditions such as minimal hepatic encephalopathy (MHE), highlighting their potential in the management of chronic liver diseases (66). Another RCT found that ALD mice diet with BL21 exhibited a significant reduction in hepatic oxidative stress, along with increased concentrations of superoxide dismutase, catalase and glutathione in the liver. Gut microbiota analysis revealed that BL21 intervention increased the relative abundance of Bifidobacterium and Akkermansia compared with the ALD group, this indicates that dietary supplementation with BL21 can ameliorate ALD by enhancing hepatic antioxidant capacity and modulating gut microbiota, and thus holds promise as a potential strategy for the prevention and treatment of this disease (89).
Prebiotics act as metabolic substrates for beneficial gut microbiota, enhancing their proliferation and metabolic activity. Their fermentation by intestinal commensals generates short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate—key metabolites that improve the gut barrier integrity and function, and modulate gut microbiota, glucose and lipid metabolism, as well as the inflammatory response and immune system, thereby contributing to gut-liver axis homeostasis and host metabolism (90). For instance, lactulose serves not only as a first-line treatment for HE but also functions as a prebiotic. A multi-center randomized controlled trial in China revealed that lactulose suppresses the growth of ammonia-producing bacteria such as Streptococcus salivarius, reduces ammonia production and absorption, and concurrently stimulates the proliferation of beneficial sugar-fermenting bacteria like Bifidobacterium and Lactobacillus (81, 91). Furthermore, numerous studies indicate that lactulose alleviates cognitive impairment in patients with chronic liver disease by inhibiting small intestinal bacterial overgrowth (SIBO) and bacterial translocation, as well as lowering serum levels of tumor necrosis factor-α (TNF-α), interleukins (ILs), and endotoxins (92).
Synbiotics, defined as combinations of probiotics and prebiotics, demonstrate a synergistic effect in modulating the composition and functionality of the intestinal microbiota. Clinical evidence indicates that synbiotic interventions significantly enhance liver function parameters, reduce systemic inflammation, and decrease infection incidence, particularly in patients with liver cirrhosis and hepatic encephalopathy (21). Patients with liver cirrhosis exhibit marked abnormalities in their intestinal microecosystem, characterized by the overgrowth of potentially pathogenic E. coli and Staphylococcus in feces. A clinical trial involving 97 consecutive cirrhotic patients with MHE but no overt hepatic encephalopathy demonstrated that synbiotic therapy significantly increased the fecal abundance of non-urease-producing Lactobacillus species at the expense of these other bacterial taxa. Modulation of the gut microbiota was associated with a significant reduction in blood ammonia levels and reversal of MHE in 50% of patients. Synbiotic therapy also led to a substantial reduction in endotoxemia. Improvements in the CTP (child-turcotte-pugh) functional class were observed in nearly 50% of cases (93). Furthermore, a synbiotic consisting of Bifidobacterium longum and fructooligosaccharides reduces blood ammonia levels and improves cognitive function in MHE patients (94). A systematic review shows that synbiotic supplementation reduces SIBO, promotes the proliferation of beneficial bacteria, decreases serum endotoxin levels, and alleviates hepatic encephalopathy symptoms in patients with liver cirrhosis (95). Moreover, the application of commensal bacteria such as Lactobacillus and Bifidobacterium effectively lowers blood ammonia and endotoxin levels and reduces the risk of MHE recurrence, which confers greater benefits on patients’ long-term prognosis. (95).
Microbial therapy not only demonstrates substantial benefits in the treatment of hepatic encephalopathy but also holds promise for intervening in metabolic liver diseases. A meta-analysis involving 11 RCTs and 741 patients with MASLD reveals that supplementation with probiotics, prebiotics, or synbiotics can enhance glucose homeostasis, reduce lipid levels, normalize liver enzyme profiles, and alleviate hepatic steatosis. Furthermore, the analysis indicates that in Caucasian populations, probiotics are more effective in improving MASLD compared to prebiotics or synbiotics administered in Asian or European populations (96). With advancing research on the gut-liver axis mechanism, integrating these microbiota-targeted therapeutic strategies into clinical practice is anticipated to offer novel approaches for promoting liver health and preventing infections.
Fecal microbiota transplantation therapy
Fecal Microbiota Transplantation (FMT), as an emerging therapeutic strategy, has garnered increasing attention in the management of patients with chronic liver diseases complicated by recurrent infections. This therapeutic approach aims to restore intestinal microecological balance by transferring fecal material from healthy donors into recipients, thereby enhancing their overall health status (29). The transplanted fecal material comprises approximately 55% microbial communities and 24% soluble components, such as mucus, fat, protein, small molecules, and short-chain fatty acids (97). Compared with the targeted eradication of pathogenic bacteria through antibiotic therapy or the administration of specific probiotics, FMT enables the transplantation of a more comprehensive and stable intestinal microbiota system (98). In recent years, accumulating evidence has demonstrated that FMT can significantly reduce the risk of infection recurrence, particularly in cases of recurrent Clostridioides difficile infection (CDI), which is frequently observed in patients with liver disease who experience intestinal dysbiosis due to prolonged antibiotic use. Furthermore, FMT has demonstrated potential in ameliorating HE. As one of the most severe complications of liver cirrhosis, recurrent HE represents a significant cause of rehospitalization, neurological impairment, and mortality, often precipitated by upper gastrointestinal bleeding or severe infections. Although conventional antibiotic therapy can effectively control infections, it may further compromise the intestinal microbiota barrier and exacerbate HE progression. By restoring microbial diversity and enhancing intestinal barrier integrity, FMT offers a novel therapeutic strategy to address this challenge. Bajaj et al. (99) performed an open-label randomized clinical trial comparing the efficacy and safety of FMT from screened donors with standard of care (SOC) in patients with recurrent HE and liver cirrhosis. The results indicated that the FMT group not only exhibited significantly lower rates of adverse events and HE recurrence compared to the SOC group, but also demonstrated substantial improvements in cognitive function. Additionally, FMT conferred protective effects against hepatic necrosis and intestinal mucosal barrier injury.
The efficacy of FMT in these contexts demonstrates its potential as a therapeutic strategy for addressing complications associated with chronic liver disease. However, concerns surrounding safety and standardization persist. Adverse events, such as gastrointestinal discomfort and rare cases of multidrug-resistant organism transmission, underscore the need for stringent donor screening protocols. Addressing challenges in donor selection, regulatory oversight, and personalized approaches will be critical to optimizing FMT as a safe and effective therapeutic strategy (100). Additional investigations are required to optimize donor selection criteria, standardize procedural protocols, and evaluate long-term outcomes in order to fully harness the benefits of FMT within this patient population.
Dietary interventions therapy
Dietary intervention represents a key strategy for modulating intestinal flora and reducing infection risk in patients with chronic liver diseases (101). Dietary composition significantly influences the diversity and functional capacity of gut microbiota, thereby regulating host metabolic processes and immune responses. Research indicates that diets abundant in dietary fiber (eggs, fruits, vegetables, and whole grains) promote the proliferation of beneficial bacteria, enhance SCFA production, and contribute to intestinal health maintenance (102). In patients with MASLD and cirrhosis, caloric restriction combined with high-protein regimens has been shown to increase microbial gene richness and improve clinical phenotypes (103). Conversely, high-fat and high-sugar dietary patterns tend to induce dysbiosis, characterized by reduced microbial diversity and heightened inflammatory responses. Findings from a cross-sectional analysis involving 450 adults diagnosed with MASLD revealed that greater adherence to the MIND diet was correlated with improved liver function, reduced systemic inflammation, enhanced metabolic health, as well as more favorable indicators of gut microbiome composition in MASLD patients. At the core of the MIND dietary pattern are polyphenol-rich foods (e.g., berries, leafy green vegetables), dietary fiber (whole grains, legumes), and unsaturated fats (nuts, olive oil) (104). Additionally, Clinical evidences demonstrate that targeted dietary interventions can substantially improve intestinal homeostasis, enhance hepatic function, and reduce infection incidence in chronic liver disease patients (105).
Notably, dietary interventions should be individualized based on disease severity: decompensated cirrhotic patients require moderate protein intake to avoid hyperammonemia, while MASLD patients benefit from low-fat, high-fiber diets with reduced added sugars. Future research should focus on identifying specific dietary patterns and components that effectively optimize gut microbial structure and function, thereby developing practical and effective strategies for infection prevention and health management in this patient population.
Personalized treatment strategies
In the clinical management of chronic liver diseases, personalized treatment strategies are receiving increasing emphasis. This trend arises from a deepening understanding of the gut-liver axis and intestinal microbiota’s role in disease pathogenesis. Precision medicine focuses on designing targeted interventions based on individual patient characteristics, including genetic profile, microbiota composition, and disease phenotype, to enhance therapeutic outcomes and minimize adverse effects. For example, through microbiota analysis, clinicians can identify patient populations most likely to benefit from targeted dietary modifications, probiotic interventions, or fecal microbiota transplantation (106). Furthermore, the integration of artificial intelligence and machine learning algorithms for multi-source data analysis enables the development of predictive models, facilitating the formulation of more precise therapeutic regimens for chronic liver disease patients and further optimizing clinical outcomes (107). As research continues to elucidate the complexity of the gut microbiome and its intricate interactions with hepatic health, the implementation of personalized treatment strategies holds promise for substantially improving quality of life and long-term prognosis in patients with chronic liver diseases.
Challenges and future perspectives
Despite significant progress in understanding the gut-microbiota-liver axis, several challenges remain in translating this knowledge into clinical practice. First, individual variability in gut microbiota: Gut microbial composition is influenced by genetics, diet, lifestyle, and disease status, leading to significant inter-individual differences. This variability makes it difficult to identify universal microbial signatures for CLDs, and may explain the inconsistent efficacy of microbiota-targeted therapies (108). Second, causal relationship vs correlation: Most studies have reported correlative associations between gut microbiota dysbiosis and CLDs, but the causal relationships remain unclear. Future studies using germ-free mice, microbial transplantation are needed to confirm the causal role of specific microbial taxa and metabolites. Third, lack of standardized detection methods: Current methods for gut microbiota analysis (16S rRNA sequencing, metagenomic sequencing) vary in accuracy and reproducibility, and there is no consensus on standardized sampling, processing, and analytical pipelines (56, 57). Fourth, limited long-term safety and efficacy data: Most clinical trials of microbiota-targeted therapies are small-scale and short-term, and long-term safety (e.g., risk of infection, immune disorders) and efficacy (e.g., prevention of disease progression to hepatocellular carcinoma) need to be evaluated in large-scale RCTs.
Future research directions should focus on the following aspects: (1) Precision medicine: Using multiomics technologies (metagenomics, transcriptomics, metabolomics, proteomics) to identify personalized microbial signatures and develop targeted therapies for different CLDs subtypes and patient populations. (2) Mechanistic exploration: Elucidating the molecular mechanisms of gut-microbiota-liver crosstalk at the single-cell and spatial levels, such as the interaction between specific microbial metabolites and hepatic immune cells or hematopoietic stem cells. (3) Novel therapeutic development: Developing next-generation probiotics (engineered bacteria producing therapeutic molecules), bacteriophages targeting pathogenic bacteria, and microbial metabolite analogs with enhanced stability and bioavailability. (4) Clinical translation: Establishing standardized gut microbiota detection platforms and therapeutic guidelines, and exploring the combination of microbiota-targeted therapies with traditional treatments (e.g., lipid lowering drugs, antiviral therapy) to improve clinical outcomes. (5) Prevention strategies: Identifying early microbial biomarkers for CLDs and developing dietary and lifestyle interventions to prevent gut microbiota dysbiosis and liver disease initiation.
Conclusion
Dysbiosis of the gut microbiota and chronic liver diseases, particularly in the context of co-infection, represent a growing area of scientific inquiry. This review seeks to elucidate the intricate relationship between intestinal microbial composition and the progression of chronic liver diseases (HBV/HCV infection, MASLD, and cirrhosis), which holds significant implications for developing novel diagnostic and therapeutic approaches while improving patient outcomes. Gut microbiota dysbiosis can exacerbate hepatic inflammation, fibrosis, and overall disease advancement. The gut-liver axis serves as a critical pathway, mediating hepatic dysfunction and disease severity through microbial metabolites and inflammatory signaling (e.g., TLR4/NF-κB, AMPK pathways). This mechanistic understanding not only deepens insights into the pathogenesis of chronic liver diseases but also identifies promising intervention targets. Furthermore, the gut microbiota has emerged as a compelling therapeutic focus, with interventions including probiotic and prebiotic supplementation, alongside dietary modifications, and FMT, demonstrating potential for restoring microbial homeostasis and promoting hepatic health. However, a key challenge remains in optimizing intervention strategies to enable precise applications tailored to individual microbiota profiles and clinical presentations. The advancement of personalized medicine in this domain necessitates rigorous clinical investigations to establish the efficacy and safety profiles of various interventions. The integration of advanced technologies such as metagenomics and metabolomics will further elucidate the microbiome’s role in liver pathologies and provide a foundation for refining therapeutic strategies. In terms of treatment safety, microbiota-targeted therapies carry certain risks that require clinical attention. Probiotics are generally safe, but in cirrhotic patients with immunodeficiency, the risk of sepsis should be vigilantly monitored. FMT has the potential risk of transmitting infectious diseases and inducing adverse reactions, which can be mitigated through rigorous donor screening and standardized procedures. Dietary interventions should avoid extreme diets (e.g., excessive protein intake in patients with decompensated cirrhosis may trigger hepatic encephalopathy), and the dosage should be adjusted based on the patient’s tolerance and nutritional status. Prior to initiating microbiota-targeted therapy, clinicians should conduct an individualized risk-benefit assessment, closely monitor patients for adverse events during treatment, and administer timely symptomatic management.
In conclusion, the intimate relationship between intestinal microbiota dysbiosis and chronic liver diseases, particularly under infectious conditions, establishes a promising avenue for future scientific exploration. Recognizing the central role of intestinal microecological regulation in therapeutic approaches will facilitate the development of innovative strategies that not only ameliorate hepatic health but also significantly enhance patients’ overall quality of life.
Author contributions
GY: Writing – original draft. JZ: Writing – review & editing. MW: Writing – review & editing. SS: Writing – review & editing. KD: Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work supported by the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCFZ-2022-028).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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References
1. Zhou Z, Chen X, Sheng H, Shen X, Sun X, Yan Y, et al. Engineering probiotics as living diagnostics and therapeutics for improving human health. Microb Cell Fact. (2020) 19:56. doi: 10.1186/s12934-020-01318-z
2. Tustumi F, Arienzo VP, Sunye IR, Lucas PFS, Colonno BB, Quintas JG, et al. Esophageal dysbiosis in achalasia and Cancer development: a critical review. Genes. (2023) 14:1521. doi: 10.3390/genes14081521
3. Dóra D, Kovács T, Nagy N. [The role of intestinal macrophages and the enteric nervous system in gut neuroimmunology. basic science and clinical implications]. Orv Hetil. (2020) 161:771–9. doi: 10.1556/650.2020.31685
4. Duan Y, Llorente C, Lang S, Brandl K, Chu H, Jiang L, et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. (2019) 575:505–11. doi: 10.1038/s41586-019-1742-x
5. Adhikary S, Esmeeta A, Dey A, Banerjee A, Saha B, Gopan P, et al. Impacts of gut microbiota alteration on age-related chronic liver diseases. Dig Liver Dis. (2024) 56:112–22. doi: 10.1016/j.dld.2023.06.017
6. Christensen E. [The gut microbiome is important in chronic liver disease]. Ugeskr Laeger. (2019) 181:V07180485.
7. Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev. (2014) 66:948–83. doi: 10.1124/pr.113.008201
8. Chiang JYL, Ferrell JM. Discovery of farnesoid X receptor and its role in bile acid metabolism. Mol Cell Endocrinol. (2022) 548:111618. doi: 10.1016/j.mce.2022.111618
9. Chiang JYL, Ferrell JM. Bile acid metabolism in liver pathobiology. Gene Expr. (2018) 18:71–87. doi: 10.3727/105221618X15156018385515
10. Abenavoli L, Procopio AC, Scarpellini E, Polimeni N, Aquila I, Larussa T, et al. Gut microbiota and non-alcoholic fatty liver disease. Minerva Gastroenterol. (2021) 67:339–47. doi: 10.23736/S2724-5985.21.02896-5
11. Bonde A, Daly S, Kirsten J, Kondapaneni S, Mellnick V, Menias CO, et al. Human gut microbiota-associated gastrointestinal malignancies: a comprehensive review. Radiographics. (2021) 41:1103–22. doi: 10.1148/rg.2021200168
12. Salami M. Interplay of good bacteria and central nervous system: cognitive aspects and mechanistic considerations. Front Neurosci. (2021) 15:613120. doi: 10.3389/fnins.2021.613120
13. Jiang S, Shen B. [Research progress on the relationship between gut microbiota dysbiosis and osteoarthritis]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. (2023) 37:371–6. doi: 10.7507/1002-1892.202212037
14. Luo P, Lednovich K, Xu K, Nnyamah C, Layden BT, Xu P. Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis. Transl Res. (2022) 248:128–50. doi: 10.1016/j.trsl.2022.06.003
15. Macfarlane GT, Macfarlane S. Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics. J Clin Gastroenterol. (2011) 45:S120–7. doi: 10.1097/MCG.0b013e31822fecfe
16. Joyce SA, Clarke DJ. Microbial metabolites as modulators of host physiology. Adv Microb Physiol. (2024) 84:83–133. doi: 10.1016/bs.ampbs.2023.12.001
17. Yang F, Wei J, Shen M, Ding Y, Lu Y, Ishaq HM, et al. Integrated analyses of the gut microbiota, intestinal permeability, and serum metabolome phenotype in rats with alcohol withdrawal syndrome. Appl Environ Microbiol. (2021) 87:e0083421. doi: 10.1128/AEM.00834-21
18. Lemon KP, Klepac-Ceraj V, Schiffer HK, Brodie EL, Lynch SV, Kolter R. Comparative analyses of the bacterial microbiota of the human nostril and oropharynx. mBio. (2010) 1:e00129-10. doi: 10.1128/mBio.00129-10
19. Liu B, Song C, Gao Q, Liu B, Zhou Q, Sun C, et al. Maternal and environmental microbes dominate offspring microbial colonization in the giant freshwater prawn Macrobrachium rosenbergii. Sci Total Environ. (2021) 790:148062. doi: 10.1016/j.scitotenv.2021.148062
20. Gomaa EZ. Human gut microbiota/microbiome in health and diseases: a review. Antonie Van Leeuwenhoek. (2020) 113:2019–40. doi: 10.1007/s10482-020-01474-7
21. Luo M, Xin RJ, Hu FR, Yao L, Hu SJ, Bai FH. Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis. World J Gastroenterol. (2023) 29:144–56. doi: 10.3748/wjg.v29.i1.144
22. Facchin S, Bertin L, Bonazzi E, Lorenzon G, De Barba C, Barberio B, et al. Short-Chain fatty acids and human health: from metabolic pathways to current therapeutic implications. Life. (2024) 14:559. doi: 10.3390/life14050559
23. Duan H, Wang L, Huangfu M, Li H. The impact of microbiota-derived short-chain fatty acids on macrophage activities in disease: mechanisms and therapeutic potentials. Biomed Pharmacother. (2023) 165:115276. doi: 10.1016/j.biopha.2023.115276
24. Ke S, Yu Y, Xu Q, Zhang B, Wang S, Jin W, et al. Composition-Activity relationships of polysaccharides from Saccharina japonica in regulating gut microbiota in short-term high-fat diet-fed mice. J Agric Food Chem. (2021) 69:11121–30. doi: 10.1021/acs.jafc.1c04490
25. Martin AJM, Serebrinsky-Duek K, Riquelme E, Saa PA, Garrido D. Microbial interactions and the homeostasis of the gut microbiome: the role of Bifidobacterium. Microbiome Res Rep. (2023) 2:17. doi: 10.20517/mrr.2023.10
26. Zhang Z, Xue C, Ju M, Guo J, Wang M, Yi S, et al. Maternal gut dysbiosis alters offspring microbiota and social interactions. Microorganisms. (2021) 9:1742. doi: 10.3390/microorganisms9081742
27. Bhardwaj M, Mazumder PM. The gut-liver axis: emerging mechanisms and therapeutic approaches for nonalcoholic fatty liver disease and type 2 diabetes mellitus. Naunyn Schmiedebergs Arch Pharmacol. (2024) 397:8421–43. doi: 10.1007/s00210-024-03204-6
28. Betrapally NS, Gillevet PM, Bajaj JS. Gut microbiome and liver disease. Transl Res. (2017) 179:49–59. doi: 10.1016/j.trsl.2016.07.005
29. Gu X, Lu Q, Zhang C, Tang Z, Chu L. Clinical application and progress of fecal microbiota transplantation in liver diseases: a review. Semin Liver Dis. (2021) 41:495–506. doi: 10.1055/s-0041-1732319
30. Caley LR, White H, de Goffau MC, Floto RA, Parkhill J, Marsland B, et al. Cystic fibrosis-related gut dysbiosis: a systematic review. Dig Dis Sci. (2023) 68:1797–814. doi: 10.1007/s10620-022-07812-1
31. Bulnes R, Utay NS. Therapeutic microbiome modulation: new frontiers in HIV treatment. Curr Opin HIV AIDS. (2024) 19:268–75. doi: 10.1097/COH.0000000000000864
32. Yaghmaei H, Bahanesteh A, Soltanipur M, Takaloo S, Rezaei M, Siadat SD. The role of gut microbiota modification in nonalcoholic fatty liver disease treatment strategies. Int J Hepatol. (2024) 2024:4183880. doi: 10.1155/2024/4183880
33. Arab JP, Martin-Mateos RM, Shah VH. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg. Hepatol Int. (2018) 12:24–33. doi: 10.1007/s12072-017-9798-x
34. Calleja-Conde J, Echeverry-Alzate V, Bühler KM, Durán-González P, Morales-García JÁ, Segovia-Rodríguez L, et al. The immune system through the lens of alcohol intake and gut microbiota. Int J Mol Sci. (2021) 22:7485. doi: 10.3390/ijms22147485
35. Di Vincenzo F, Del Gaudio A, Petito V, Lopetuso LR, Scaldaferri F. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Intern Emerg Med. (2024) 19:275–93. doi: 10.1007/s11739-023-03374-w
36. Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. (2019) 68:1516–26. doi: 10.1136/gutjnl-2019-318427
37. Bakshi J, Mishra KP. Sodium butyrate prevents lipopolysaccharide induced inflammation and restores the expression of tight junction protein in human epithelial Caco-2 cells. Cell Immunol. (2025) 408:104912. doi: 10.1016/j.cellimm.2024.104912
38. Mendez-Sanchez N, Coronel-Castillo CE, Cordova-Gallardo J, Qi X. Antibiotics in chronic liver disease and their effects on gut microbiota. Antibiotics. (2023) 12:1475. doi: 10.3390/antibiotics12101475
39. Konturek PC, Harsch IA, Konturek K, Schink M, Konturek T, Neurath MF, et al. Gut-Liver axis: how do gut bacteria influence the liver? Med Sci. (2018) 6:79. doi: 10.3390/medsci6030079
40. Li M, Liu T, Yang T, Zhu J, Zhou Y, Wang M, et al. Gut microbiota dysbiosis involves in host non-alcoholic fatty liver disease upon pyrethroid pesticide exposure. Environ Sci Ecotechnol. (2022) 11:100185. doi: 10.1016/j.ese.2022.100185
41. Staufer K, Stauber RE. Steatotic liver disease: metabolic dysfunction, alcohol, or both? Biomedicines. (2023) 11:2108. doi: 10.3390/biomedicines11082108
42. Yang M, Massad K, Kimchi ET, Staveley-O’Carroll KF, Li G. Gut microbiota and metabolite interface-mediated hepatic inflammation. Immunometabolism. (2024) 6:e00037. doi: 10.1097/IN9.0000000000000037
43. Abdelmageed ME, Abdelrahman RS. Canagliflozin attenuates thioacetamide-induced liver injury through modulation of HMGB1/RAGE/TLR4 signaling pathways. Life Sci. (2023) 322:121654. doi: 10.1016/j.lfs.2023.121654
44. Wang Z, Gao W, Cheng X, Zhang N, Lu W, Li Y, et al. Vitamin D3 attenuates hepatic inflammation in primary biliary cholangitis by inhibiting TLR4/NF-κB mediated M1 macrophage polarization. Sci Rep. (2025) 15:44345. doi: 10.1038/s41598-025-27911-z
45. McBride DA, Dorn NC, Yao M, Johnson WT, Wang W, Bottini N, et al. Short-chain fatty acid-mediated epigenetic modulation of inflammatory T cells in vitro. Drug Deliv Transl Res. (2023) 13:1912–24. doi: 10.1007/s13346-022-01284-6
46. Martirosyan A, Pérez-Gutierrez C, Banchereau R, Dutartre H, Lecine P, Dullaers M, et al. Brucella β 1,2 cyclic glucan is an activator of human and mouse dendritic cells. PLoS Pathog. (2012) 8:e1002983. doi: 10.1371/journal.ppat.1002983
47. Bae HR, Shin SK, Yoo JH, Kim S, Young HA, Kwon EY. Chronic inflammation in high-fat diet-fed mice: unveiling the early pathogenic connection between liver and adipose tissue. J Autoimmun. (2023) 139:103091. doi: 10.1016/j.jaut.2023.103091
48. Al-Rashidi HE. Gut microbiota and immunity relevance in eubiosis and dysbiosis. Saudi J Biol Sci. (2022) 29:1628–43. doi: 10.1016/j.sjbs.2021.10.068
49. Chen CY, Ho HC. Roles of gut microbes in metabolic-associated fatty liver disease. Tzu Chi Med J. (2023) 35:279–89. doi: 10.4103/tcmj.tcmj_86_23
50. Li T, Wu J, Xia S, Yang H, Mu H, Zhu Y, et al. Lactiplantibacillus plantarum BD7807 ameliorates high-fat diet-induced lipid metabolic disorders and intestinal dysfunction via SCFAs-GPR43 pathway. Food Res Int. (2025) 220:117108. doi: 10.1016/j.foodres.2025.117108
51. Liu L, Fu C, Li F. Acetate affects the process of lipid metabolism in rabbit liver. skeletal muscle and adipose tissue. Animals. (2019) 9:799. doi: 10.3390/ani9100799
52. Mori H, Svegliati Baroni G, Marzioni M, Di Nicola F, Santori P, Maroni L, et al. Farnesoid X receptor, bile acid metabolism, and gut microbiota. Metabolites. (2022) 12:647. doi: 10.3390/metabo12070647
53. Park JW, Kim SE, Lee NY, Kim JH, Jung JH, Jang MK, et al. Role of microbiota-derived metabolites in alcoholic and non-alcoholic fatty liver diseases. Int J Mol Sci. (2021) 23:426. doi: 10.3390/ijms23010426
54. Fukui H. Gut microbiota and host reaction in liver diseases. Microorganisms. (2015) 3:759–91. doi: 10.3390/microorganisms3040759
55. Ganesan R, Gupta H, Jeong JJ, Sharma SP, Won SM, Oh KK, et al. Characteristics of microbiome-derived metabolomics according to the progression of alcoholic liver disease. Hepatol Int. (2024) 18:486–99. doi: 10.1007/s12072-023-10518-9
56. Hoffman C, Siddiqui NY, Fields I, Gregory WT, Simon HM, Mooney MA, et al. Species-Level resolution of female bladder microbiota from 16S rRNA amplicon sequencing. mSystems. (2021) 6:e0051821. doi: 10.1128/mSystems.00518-21
57. Sharifi F, Ye Y. From gene annotation to function prediction for metagenomics. Methods Mol Biol. (2017) 1611:27–34. doi: 10.1007/978-1-4939-7015-5_3
58. Noel S, Patel SK, White J, Verma D, Menez S, Raj D, et al. Metagenomic profiling of gut microbiota in kidney precision medicine project participants with CKD and AKI. Compr Physiol. (2025) 15:e70058. doi: 10.1002/cph4.70058
59. Daunizeau C, Franck M, Boutin A, Ruel M, Poliakova N, Ayotte P, et al. The gut microbiota of Indigenous populations in the context of dietary westernization: a systematic review and meta-analysis. Front Nutr. (2025) 12:1652598. doi: 10.3389/fnut.2025.1652598
60. Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol. (2021) 75:S67–81. doi: 10.1016/j.jhep.2020.11.013
61. Maslennikov R, Ivashkin V, Efremova I, Alieva A, Kashuh E, Tsvetaeva E, et al. Gut dysbiosis is associated with poorer long-term prognosis in cirrhosis. World J Hepatol. (2021) 13:557–70. doi: 10.4254/wjh.v13.i5.557
62. Laivacuma S, Oblate O, Derovs A. Gut microbiota and the gut-liver axis in liver disease: from chronic viral hepatitis to cirrhosis, hepatocellular carcinoma, and microbiome-based therapies. Microorganisms. (2025) 13:1053. doi: 10.3390/microorganisms13051053
63. Hrncir T, Hrncirova L, Kverka M, Tlaskalova-Hogenova H. The role of gut microbiota in intestinal and liver diseases. Lab Anim. (2019) 53:271–80. doi: 10.1177/0023677218818605
64. Yakut A. Gut microbiota in the development and progression of chronic liver diseases: gut microbiota-liver axis. World J Hepatol. (2025) 17:104167. doi: 10.4254/wjh.v17.i3.104167
65. Padilha MDM, Melo FTV, Laurentino RV, da Silva ANMR, Feitosa RNM. Dysregulation in the microbiota by HBV and HCV infection induces an altered cytokine profile in the pathobiome of infection. Braz J Infect Dis. (2025) 29:104468. doi: 10.1016/j.bjid.2024.104468
66. Ling H, Lin Y, Bao W, Xu N, Chen L, Zhao L, et al. Erythropoietin-mediated IL-17 F attenuates sepsis-induced gut microbiota dysbiosis and barrier dysfunction. Biomed Pharmacother. (2023) 165:115072. doi: 10.1016/j.biopha.2023.115072
67. Jinato T, Anuntakarun S, Satthawiwat N, Chuaypen N, Tangkijvanich P. Distinct alterations of gut microbiota between viral- and non-viral-related hepatocellular carcinoma. Appl Microbiol Biotechnol. (2024) 108:34. doi: 10.1007/s00253-023-12845-1
68. Fossmark R, Olaisen M. Changes in the gastrointestinal microbiota induced by proton pump inhibitors-a review of findings from experimental trials. Microorganisms. (2024) 12:1110. doi: 10.3390/microorganisms12061110
69. Horvath A, Rainer F, Bashir M, Leber B, Schmerboeck B, Klymiuk I, et al. Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis. Sci Rep. (2019) 9:12000. doi: 10.1038/s41598-019-48352-5
70. Gavkare AM, Nanaware NL, Sonar MN, Dhotre SV, Mumbre SS, Nagoba BS. Gut microbiome and viral infections: a hidden nexus for immune protection. World J Virol. (2025) 14:111912. doi: 10.5501/wjv.v14.i3.111912
71. Zheng H, You Y, Hua M, Wu P, Liu Y, Chen Z, et al. Chlorophyllin modulates gut microbiota and inhibits intestinal inflammation to ameliorate hepatic fibrosis in mice. Front Physiol. (2018) 9:1671. doi: 10.3389/fphys.2018.01671
72. Wang C, Ma C, Fu K, Gong LH, Zhang YF, Zhou HL, et al. Phillygenin attenuates carbon tetrachloride-induced liver fibrosis via modulating inflammation and gut microbiota. Front Pharmacol. (2021) 12:756924. doi: 10.3389/fphar.2021.756924
73. Sharma G, Biswas SS, Mishra J, Navik U, Kandimalla R, Reddy PH, et al. Gut microbiota dysbiosis and Huntington’s disease: exploring the gut-brain axis and novel microbiota-based interventions. Life Sci. (2023) 328:121882. doi: 10.1016/j.lfs.2023.121882
74. Gedgaudas R, Bajaj JS, Skieceviciene J, Varkalaite G, Jurkeviciute G, Gelman S, et al. Circulating microbiome in patients with portal hypertension. Gut Microbes. (2022) 14:2029674. doi: 10.1080/19490976.2022.2029674
75. Lee CC, Chiu CH. Link between gut microbiota and neonatal sepsis. J Formos Med Assoc. (2024) 123:638–46. doi: 10.1016/j.jfma.2023.09.019
76. Lemmer P, Manka P, Best J, Kahraman A, Kälsch J, Vilchez-Vargas R, et al. Effects of moderate alcohol consumption in non-alcoholic fatty liver disease. J Clin Med. (2022) 11:890. doi: 10.3390/jcm11030890
77. Busnelli M, Manzini S, Jablaoui A, Bruneau A, Kriaa A, Philippe C, et al. Fat-Shaped microbiota affects lipid metabolism, liver steatosis, and intestinal homeostasis in mice fed a low-protein diet. Mol Nutr Food Res. (2020) 64:e1900835. doi: 10.1002/mnfr.201900835
78. Chen P, Stärkel P, Turner JR, Ho SB, Schnabl B. Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice. Hepatology. (2015) 61:883–94. doi: 10.1002/hep.27489
79. John N, Ibrahim B, Ebaid M, Saab S. Outcomes in patients with liver dysfunction post SARS-CoV-2 infection: what should we measure? Hepat Med. (2023) 15:185–93. doi: 10.2147/HMER.S371507
80. Scarpellini E, Scarcella M, Tack JF, Scarlata GGM, Zanetti M, Abenavoli L. Gut microbiota and metabolic dysfunction-associated steatotic liver disease. Antioxidants. (2024) 13:1386. doi: 10.3390/antiox13111386
81. Wang JY, Bajaj JS, Wang JB, Shang J, Zhou XM, Guo XL, et al. Lactulose improves cognition, quality of life, and gut microbiota in minimal hepatic encephalopathy: a multicenter, randomized controlled trial. J Dig Dis. (2019) 20:547–56. doi: 10.1111/1751-2980.12816
82. Bajaj JS, Khoruts A. Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. J Hepatol. (2020) 72:1003–27. doi: 10.1016/j.jhep.2020.01.017
83. Wu Z, Zhou H, Liu D, Deng F. Alterations in the gut microbiota and the efficacy of adjuvant probiotic therapy in liver cirrhosis. Front Cell Infect Microbiol. (2023) 13:1218552. doi: 10.3389/fcimb.2023.1218552
84. Perdikis KC, Goossens N, Carballo S. [Bacterial infections in the context of chronic liver disease]. Rev Med Suisse. (2020) 16:1965–9.
85. Maccauro V, Airola C, Santopaolo F, Gasbarrini A, Ponziani FR, Pompili M. Gut microbiota and infectious complications in advanced chronic liver disease: focus on spontaneous bacterial peritonitis. Life. (2023) 13:991. doi: 10.3390/life13040991
86. Kanda T, Sasaki R, Masuzaki R, Takahashi H, Mizutani T, Matsumoto N, et al. Co-Occurrence of hepatitis a infection and chronic liver disease. Int J Mol Sci. (2020) 21:6384. doi: 10.3390/ijms21176384
87. Kaufmann B, Seyfried N, Hartmann D, Hartmann P. Probiotics, prebiotics, and synbiotics in nonalcoholic fatty liver disease and alcohol-associated liver disease. Am J Physiol Gastrointest Liver Physiol. (2023) 325:G42–61. doi: 10.1152/ajpgi.00017.2023
88. Xia X, Chen J, Xia J, Wang B, Liu H, Yang L, et al. Role of probiotics in the treatment of minimal hepatic encephalopathy in patients with HBV-induced liver cirrhosis. J Int Med Res. (2018) 46:3596–604. doi: 10.1177/0300060518776064
89. Dong Y, Wu Z, Gai Z, Han M. Bifidobacterium longum subsp. longum BL21 ameliorates alcoholic liver disease in mice through enhancement of the hepatic antioxidant capacity and modulation of the gut microbiota. J Appl Microbiol. (2023) 134:lxad251. doi: 10.1093/jambio/lxad251
90. Esgalhado M, Kemp JA, Damasceno NR, Fouque D, Mafra D. Short-chain fatty acids: a link between prebiotics and microbiota in chronic kidney disease. Future Microbiol. (2017) 12:1413–25. doi: 10.2217/fmb-2017-0059
91. Yuan Q, Xin L, Han S, Su Y, Wu R, Liu X, et al. Lactulose improves neurological outcomes by repressing harmful bacteria and regulating inflammatory reactions in mice after stroke. Front Cell Infect Microbiol. (2021) 11:644448. doi: 10.3389/fcimb.2021.644448
92. Moratalla A, Ampuero J, Bellot P, Gallego-Durán R, Zapater P, Roger M, et al. Lactulose reduces bacterial DNA translocation, which worsens neurocognitive shape in cirrhotic patients with minimal hepatic encephalopathy. Liver Int. (2017) 37:212–23. doi: 10.1111/liv.13200
93. Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology. (2004) 39:1441–9. doi: 10.1002/hep.20194
94. Malaguarnera M, Greco F, Barone G, Gargante MP, Malaguarnera M, Toscano MA. Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci. (2007) 52:3259–65. doi: 10.1007/s10620-006-9687-y
95. Viramontes Hörner D, Avery A, Stow R. The effects of probiotics and symbiotics on risk factors for hepatic encephalopathy: a systematic review. J Clin Gastroenterol. (2017) 51:312–23. doi: 10.1097/MCG.0000000000000789
96. Xing W, Gao W, Lv X, Zhao Z, Mao G, Dong X, et al. The effects of supplementation of probiotics, prebiotics, or synbiotics on patients with non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Front Nutr. (2022) 9:1024678. doi: 10.3389/fnut.2022.1024678
97. Bojanova DP, Bordenstein SR. Fecal transplants: what is being transferred? PLoS Biol. (2016) 14:e1002503. doi: 10.1371/journal.pbio.1002503
98. Biazzo M, Deidda G. Fecal microbiota transplantation as new therapeutic avenue for human diseases. J Clin Med. (2022) 11:4119. doi: 10.3390/jcm11144119
99. Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology. (2017) 66:1727–38. doi: 10.1002/hep.29306
100. Elendu C, Omeludike EK, Aregbesola ET, Mordi P, Blewusi GS, Ogidan AO, et al. Fecal microbiota transplantation as a therapeutic modality for recurrent Clostridioides difficile infection: reviewing efficacy, safety, mechanisms of action, and outcomes. Ann Med Surg. (2025) 87:5829–50. doi: 10.1097/MS9.0000000000003649
101. Eom JA, Kwon GH, Kim NY, Park EJ, Won SM, Jeong JJ, et al. Diet-Regulating microbiota and host immune system in liver disease. Int J Mol Sci. (2021) 22:6326. doi: 10.3390/ijms22126326
102. Sharma AK, Sharma A, Lal S, Kumar A, Yadav NK, Tabassum F, et al. Dysbiosis versus diabesity: pathological signaling and promising therapeutic strategies. Drug Discov Today. (2023) 28:103558. doi: 10.1016/j.drudis.2023.103558
103. Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, et al. Dietary intervention impact on gut microbial gene richness. Nature. (2013) 500:585–8. doi: 10.1038/nature12480
104. Yang S, Zhang L, Hu M, He W. MIND diet score and its association with metabolic dysfunction-associated steatotic liver disease and gut microbiota profiles: a cross-sectional study. Front Nutr. (2025) 12:1637572. doi: 10.3389/fnut.2025.1637572
105. Takahashi K, Morita N, Tamano R, Gao P, Iida N, Andoh A, et al. Mouse IgA modulates human gut microbiota with inflammatory bowel disease patients. J Gastroenterol. (2024) 59:812–24. doi: 10.1007/s00535-024-02121-y
106. Ganesan R, Thirumurugan D, Vinayagam S, Kim DJ, Suk KT, Iyer M, et al. A critical review of microbiome-derived metabolic functions and translational research in liver diseases. Front Cell Infect Microbiol. (2025) 15:1488874. doi: 10.3389/fcimb.2025.1488874
107. Dhieb D, Mustafa D, Hassiba M, Alasmar M, Elsayed MH, Musa A, et al. Harnessing pharmacomultiomics for precision medicine in diabetes: a comprehensive review. Biomedicines. (2025) 13:447. doi: 10.3390/biomedicines13020447
Keywords: alcoholic liver disease, chronic liver disease, cirrhosis, gut microbiota dysbiosis, gut-liver axis, viral hepatitis, metabolic-associated steatotic liver disease, mechanism
Citation: Yang G, Zhu J, Wang M, She S and Dai K (2026) Research advances on gut microbiota dysbiosis and chronic liver diseases: a review. Front. Med. 13:1765047. doi: 10.3389/fmed.2026.1765047
Received: 10 December 2025; Revised: 05 January 2026; Accepted: 12 January 2026;
Published: 28 January 2026.
Edited by:
Giuseppe Guido Maria Scarlata, University “Magna Graecia” of Catanzaro, ItalyReviewed by:
Kartik Chandra Guchhait, Debra Thana Sahid Kshudiram Smriti Mahavidyalaya, IndiaSniedze Laivacuma, Riga Stradinš University, Latvia
Copyright © 2026 Yang, Zhu, Wang, She and Dai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sha She, cm0wMDMyMThAd2h1LmRldS5jbg==; Kai Dai, ZGFpa2FpQHdodS5lZHUuY24=
†These authors have contributed equally to this work and share first authorship