The mucus layer is mainly composed of secretion products from goblet cells, with its outer layer colonized by microbial communities and its inner layer containing minimal bacteria (Tsiaoussis et al., 2015). Mucus, predominantly composed of mucin (MUC), are divided into two types: transmembrane mucin (MUC1, MUC4, MUC15, MUC16, etc.) and secretory mucin (primarily MUC2) (Chopyk and Grakoui, 2020). Microorganisms competed for attachment sites and energy for colonization by degrading the O-and N-linked glycans and glycosaminoglycans of MUC2 (Martens et al., 2009). The protective effect of mucus in MUC2-deficient mice was significantly weakened, allowing direct entry of bacteria into epithelium and crypts, thereby inducing colitis-related cytokine expression (Johansson et al., 2008). Transmembrane mucin not only protected intestinal epithelial cells and acted as a lubricant but also provided immune protection and inhibits cell apoptosis (Constantinou et al., 2011; Paone and Cani, 2020). For example, MUC1 overexpression generated anti-MUC1 antibodies that could damage colon cells through cell-dependent cytotoxicity, leading to chronic intestinal inflammation such as ulcerative colitis (UC) (Apostolopoulos et al., 2015). Preventive treatment with anti-inflammatory milk fat globule membrane (MFGM) upregulated colonic MUC2, MUC4, Reg3g, and other gene expressions in mice, enhancing mucosal barrier integrity and reducing the risk of microbial-induced intestinal inflammation and secondary liver injury (Wu et al., 2022). Fecal samples from liver cirrhosis patients showed potential pathogenic bacteria rich in sialidase (e.g., Veillonella atypica, Veillonella parvula, and Streptococcus spp.) degrading MUC2 O-glycans, leading to barrier damage (Patel et al., 2022). Additionally, isoproterenol can reduce the number of goblet cells and mucus thickness in mice, impairing the intestinal mucosal epithelial and vascular barriers, facilitating BT to the liver and exacerbating liver damage (Sorribas et al., 2020). This multifaceted dysfunction of the intestinal barrier significantly contributes to the severity and complications of liver cirrhosis.

Intestinal epithelial cells include five specialized types: stem cells, goblet cells, neuroendocrine cells, Paneth cells, and intestinal absorptive cells (Pott and Hornef, 2012). They form a protein network that mediates selective permeability through transcellular and paracellular pathways (Tsukita et al., 2001). The protein network is composed of various adhesive complexes such as desmosomes, adhesive junctions (AJs), tight junctions (TJs), and gap junctions (Groschwitz and Hogan, 2009), among which TJ is recognized as the most important. Besides, Claudins, Occludin, and cytoskeleton-connected adhesive molecules (mainly microfilaments) considered as particularly important TJs (Tsiaoussis et al., 2015). Compared to healthy individuals, the expression levels of Occludin and Claudin-1 in intestinal epithelial cells were reduced in patients with liver cirrhosis, negatively correlated with the Child-Pugh score (Assimakopoulos et al., 2012). As a dynamic permeability tight barrier, intestinal epithelial TJs could prevent potential pathogenic bacteria, toxins, and other harmful substances from invading and permit the passage of nutrients, water, and ions (Hossain and Hirata, 2008). Mutation or defects in TJs cause TJPs contraction, enlarging intercellular spaces and enabling harmful macromolecules such as bacteria and toxins to infiltrate the portal vein, promoting the occurrence and development of liver cirrhosis (Twardowska et al., 2022). Additionally, oxidative stress is a key mechanism in intestinal barrier damage (Mohamed et al., 2021; Mo et al., 2022), inducing intestinal epithelial cell apoptosis, reducing the expression of TJPs, and increasing intestinal permeability (Li et al., 2022).

Following the disruption of the physical barrier structure, activation of the intestinal mucosal immune system occurs, with humoral immunity dominated by secreted immunoglobulin A (SIgA). SIgA not only prevents the recognition and uptake of bacteria, toxins, and other harmful molecules by intestinal mucosal epithelial cells (Mantis et al., 2011) but also contributes to the elimination of pathogens and toxins through intestinal mechanical peristalsis. Furthermore, it attenuates the systemic immune response and immune tolerance triggered by external antigenic stimulation and prevents the intestinal mucosal immune barrier system from eliciting an immune response to beneficial gut microbiota (Perez-Lopez et al., 2016). These intricate mechanisms involve T cells, interleukins (IL)-4, IL-6, transforming growth factor (TGF)-β, and tumor necrosis factor (TNF)-α within gut-associated lymphoid tissue (GALT) (Hooper and Macpherson, 2010). Prolonged pathogen stimulation of the immune system, coupled with inhibition of regulatory cells such as macrophages, dendritic cells, and M cells, disrupts immune homeostasis, thereby instigating intestinal inflammation. Multiple immune cells through complex interactions accelerates pro-inflammatory and fibrotic processes in the liver (Winer et al., 2016). Porowski et al. calculated the hepatic elimination ratio (LER) of IL-6, hepatocyte growth factor (HGF), TNF-α, and TGF-β introduced from the GALT and portal vein. In healthy individuals, LER values were 0.4, 0.2, 0.4, and 0.3 respectively, while in liver transplant patients, they were-0.1, −0.5, 0.1, and-0.2, respectively. Negative elimination rates indicate cytokine synthesis surpassing degradation in patients with liver cirrhosis (liver failure), with levels of these growth factors and cytokines closely related to the severity of liver cirrhosis (Porowski et al., 2015). Moreover, the severe immune deficiency induced by systemic inflammation and immune cell dysfunction in patients with liver cirrhosis plays a pivotal role in the pathogenesis of chronic acute liver failure (ACLF) (Martin-Mateos et al., 2019). In addition, endotoxins can severely damage the intestinal mucosal barrier and immune system of the body through oxidative stress (Wang and Wang, 2022). This particular subject was further elucidated in subsequent sections.

We explored the composition and changes in gut microbiota in the above discussion. Here, we delve into the interplay and mechanisms between the biological barrier, comprised of gut microbiota, and other barriers. Firstly, mucoglycans serve as nutrients for beneficial bacteria, enabling them to compete for mucosal colonization sites and inhibit pathogen colonization (Paone and Cani, 2020), thereby influencing mucus properties by interfering with glycosyltransferase expression, MUC2 glycosylation, and transmembrane mucin glycosylation (Schroeder, 2019; Pelaseyed and Hansson, 2020). Furthermore, microbial metabolites such as acetate and butyrate contribute to epithelial homeostasis by modulating goblet cells (Wrzosek et al., 2013). Lactobacillus reuteri mediates the PI3K/Akt Nrf-2/HO-1-NF-κβ and PKC-Nrf-2/HO-1-NF-κβ signaling pathways, enhancing the expression of TJPs, inhibiting TNF-induced apoptosis of intestinal epithelial cells (Zhou et al., 2022), and activating the Wnt/β-catenin pathway to stimulate the proliferation of intestinal epithelial cells, thereby regulating the physical barrier function of the intestine (Wu et al., 2020).

Microorganisms and the intestinal mucosal immune system interact with each other, jointly maintaining a symbiotic relationship between the host and microorganisms (Hooper et al., 2012). SIgA on the surface of the intestinal mucosa selectively binds to symbiotic bacteria, preventing their penetration of the epithelial barrier (Macpherson et al., 2000). Microbial colonization also facilitates the development and function of the intestinal immune system (O’Hara and Shanahan, 2006). The Toll-like receptor (TLR) family and nucleotide-binding oligomerization domain proteins Nod1 and Nod2 serve as primary receptor systems for microbial regulation of the innate immune system in the intestinal mucosa (Kelly and Conway, 2005). For example, LPS not only aids in the repair of damaged intestinal epithelium through MyD88-dependent processes (Rakoff-Nahoum and Medzhitov, 2007), but also activates the expression of the antimicrobial lectin Reg III γ, serving as an additional barrier to inhibit bacterial infiltration into the intestinal mucosa (Vaishnava et al., 2011). Therefore, excessive microbial stimulation may lead to the abnormal activation of intestinal immune cells, leading to intestinal inflammation. In summary, damages to the intestinal biological barrier inevitably affect the physical and immune barriers of the host, ultimately increasing the risk of various chronic liver diseases such as cirrhosis.

BAs originate from cholesterol oxidation in the liver through two primary pathways. Under normal conditions, cholesterol 7α-hydroxylase (CYP7A1) initiates the classical pathway to produce the majority of primary BAs. CYP7A1 regulates the overall rate of BA synthesis, while sterol 12α-hydroxylase regulates the cholic acid (CA) to chenodeoxycholic acid ratio in the BA pool. In an adaptive response, alternative pathways, initiated by sterol-27 hydroxylase, play crucial roles in intestinal metabolism, cellular signaling, and microbial composition (Li and Chiang, 2014). Intestinal microbiota modify human BAs via four mechanisms: deconjugation of glycine or taurine, dehydroxylation, dehydrogenation, and epimerization (Guzior and Quinn, 2021), further activating BAs receptors. There is a close relationship between metabolic disorders of BAs and liver cirrhosis, along with its complications and intestinal dysbiosis.

Changes in gut microbiota composition and activity due to factors such as antibiotics, diet, and exercise significantly impact BA synthesis and signal transduction (Collins et al., 2023). Bacterial bile salt hydrolase (BSH), found in various gut bacteria like Clostridium, Enterococcus, Bifidobacterium, Lactobacillus, and Bacteroidetes, catalyzes the decoupling, oxidation, and 7α-dehydroxylation of conjugated BA, regulating the production level of secondary BAs (Ridlon et al., 2016). In addition, the composition and number of Firmicutes also affect secondary BA levels by altering 7α-dehydroxylation (Lee et al., 2022). Conversely, BAs influence microbiota composition and function, playing a decisive role in both quantitative and qualitative changes, as well as metabolic activities of gut microbiota. For example, studies suggest that glycine-and taurine-preferred BSH can inhibit the growth of Clostridium difficile, possibly by increasing the concentration of microbial conjugated BA, which inhibits the germination, growth, and toxin expression of Clostridium difficile (Foley et al., 2023). Moreover, BA administration in neonatal mice could significantly drive the maturation of the intestinal microbiota, improving its diversity and richness (Van Best et al., 2020). However, BAs may also harm intestinal bacteria due to their toxic effects, mediating oxidative stress and DNA damage (Collins et al., 2023). Overall, BA metabolism intricately links gut microbiota to physiology and pathology of the liver, offering a broader perspective for the treatment of liver diseases through the modulation of gut microbiota.

FXR is a core regulatory factor in the biosynthesis of BAs and enterohepatic circulation. Dysfunction of the microbiota leads to decreased BA activity, reducing unconjugated BA and secondary BA production, weakening FXR activity, and exacerbating cirrhosis through various pathways: (1) In hepatocytes, FXR interacts with nuclear receptors such as peroxisome proliferator-activated receptors (PPAR)-α and liver X receptor (LXR)α to form heterodimers, regulating downstream target gene expression. Weakened FXR activity decreases the expression of PPAR-α and LXRα, negatively impacting liver energy metabolism (Preidis et al., 2017); (2) The inhibitory and regulatory effects on TLR4 transcription levels and NLRP3 inflammasome are weakened, promoting the production of inflammatory factors such as IL-1β and NOS2, further exacerbating the inflammatory response (Vavassori et al., 2009; Han et al., 2018); (3) Fat synthesis, high-density lipoprotein (HDL) formation, liver HDL uptake, and fatty acid β-oxidation, are affected, disrupting lipid metabolism and worsening liver steatosis and fibrosis (Ding et al., 2015); (4) Enhanced HSC activation increases collagen synthesis and deposition, accelerating liver fibrosis progression (Zhou et al., 2020). (5) Dysbiosis and the release of inflammatory markers (LPS) (Ridlon et al., 2015) further lead to BT, endotoxemia, and intestinal barrier damage, significantly correlating with liver cirrhosis progression and cognitive impairment (Zhang et al., 2022).

The main products of anaerobic fermentation in the intestine are SCFAs, with acetic acid, propionic acid, and butyric acid being the most abundant (Vallianou et al., 2021). These SCFAs help maintain energy homeostasis through multiple pathways. Firstly, SCFAs, especially butyric acid, act as preferred energy sources for intestinal epithelial cells. Upon absorption, butyric acid is converted into cellular energy, inhibiting NLRP3 inflammasome activation and autophagy, thus protecting the intestinal barrier against LPS damage and maintaining the normal cell function (Feng et al., 2018). Moreover, acetate, propionate, and butyrate contribute to glucose, cholesterol, and lipid metabolism, directly impacting hepatic energy levels (Den Besten et al., 2013). Additionally, they indirectly influence the energy metabolism of peripheral organs by affecting the activity of hormones and the nervous system (Chambers et al., 2015; Perry et al., 2016). Therefore, SCFAs play an important role in human physiology and pathology (Koh et al., 2016).

SCFAs are closely related to the occurrence and severity of liver cirrhosis (Cao et al., 2023). There is a correlation between a decrease in the number of SCFA-producing bacteria compared with compensated patients and the occurrence of decompensated events (Bajaj et al., 2023). Reduced SCFA levels, particularly butyric acid, have been observed in fecal samples from cirrhotic patients, positively correlating with Child-Pugh classification (Jin et al., 2019). Furthermore, abnormal SCFA production correlates with liver cirrhosis severity. Diminished levels of beneficial bacteria such as Lachnospiraceae, Roseburia, Blautia, and Ruminococcaceae lead to decreased butyrate levels, impacting TJ and mucin (MUC) expression and altering intestinal barrier function and permeability. Consequently, pro-inflammatory cytokines were released into the liver (Woodhouse et al., 2018), affecting NF-κB signaling pathways and histone deacetylase inhibition (Neis et al., 2016). SCFAs have demonstrated an important role in regulating endothelial function, immune response, and vascular tone. The imbalance in SCFA production due to dysbiosis of the flora, particularly decreased Bacteroidetes abundance, disrupt these regulatory mechanisms, contributing to portal hypertension (Toshida et al., 2023).

Endotoxins, a component of LPS, constitute the outermost layer of Gram-negative bacteria cell walls, exerting diverse biological effects on ALD, viral hepatitis, cirrhosis, and its complications (Porras et al., 2017; Sehgal et al., 2020). Alcohol consumption and HFD-induced dysbiosis trigger potential pathogen translocation through the disrupted intestinal barriers. LPS binds to TLR4, stimulating Kupffer cells in the liver and the NF-κB pathway and promoting the expression of inflammatory factors, such as TNF-α, IL-1, and IL-6. On the other hand, LPS-TLR4 can increase the permeability of intestinal TJs and activate HSC, leading to inflammatory reactions in the intestine and liver. Besides, it also promotes the excessive secretion and deposition of collagen and other extracellular matrix proteins, ultimately leading to the development of liver cirrhosis (Roderburg and Luedde, 2014). Interestingly, LPS in activating immune signal transduction through TLR4-related pathways and affecting liver physiological functions is structurally dependent, indicating that a few LPS may act as antagonists to inhibit the occurrence of inflammatory responses (Di Lorenzo et al., 2019). In the gut microbiota of patients diagnosed with liver cirrhosis, increased abundance of the Enterobacteriaceae family, encoding heptyltransferase I (HpeI), a key enzyme involved in LPS synthesis, were observed and categorized into seven clusters. Specifically, the first cluster of HpeI serves as a biomarker for liver cirrhosis, offering diagnostic and treatment guidance from the perspective of gut microbiota (Lin et al., 2021).

Oxidative stress plays a crucial role in the progression of chronic liver disease to cirrhosis and its complications (Assimakopoulos et al., 2011). Liver damage weakens antioxidant effects, elevating oxidative stress and the production of reactive oxygen species (ROS), which subsequently harm the intestinal mucosa (Moustafa et al., 2009). It is specifically characterized by high levels of lipid peroxidation, protein oxidation, and an imbalance in glutathione redox status (Spahr et al., 2007). Damaged intestinal mucosa enhances permeability, promotes BT, coupled with collateral circulation and liver damage, finally leading to endotoxemia. The ensuing cycle exacerbates oxidative stress, intestinal barrier dysfunction, and organ damage (Liu et al., 2023), underscoring a significant correlation between liver cirrhosis, endotoxemia, and oxidative stress. Cheon et al. found that elevated endotoxin levels and subsequent increased ammonia levels activate the NLRP3 inflammasome through mitochondrial oxidative stress, resulting in neuroinflammation, brain edema, and the development of HE (Bajaj, 2014; Cheon et al., 2023). In addition, entero-derived endotoxins and oxidative stress are important factors in triggering portal hypertension in decompensated cirrhosis (Tripathi et al., 2018; Liu et al., 2023). Alterations in specific gut microbiota (Corynebacterium, Lautropia) and their excessive accumulation of metabolites, particularly LPS, are strongly associated with sepsis and related events in patients with decompensated cirrhosis (Philips et al., 2023). In addition, Sandler et al. proposed that LPS-induced inflammatory response and oxidative stress are predictive of progression to early compensated cirrhosis and end-stage liver failure in patients with chronic HBV or HCV infection (Sandler et al., 2011). Therefore, the exploration of drugs that target the regulation of LPS and its producing bacteria is expected to provide a therapeutic strategy for liver cirrhosis at different stages of progression.

Indole can be produced by various gut microbiota such as Escherichia coli, Clostridium, and Bacteroidetes (Lee et al., 2015). Studies have found that indole can alter the composition of gut microbiota and increase gene expression of TJPs and mucins between epithelial cells, indicating enhanced intestinal epithelial barrier (Shimada et al., 2013). Moreover, indole can reduce TNF-α-mediated activation of NF-κβ, inhibit the expression of pro-inflammatory chemokine IL-8, and increase the expression of anti-inflammatory cytokine IL-10. Furthermore, it confers resistance to pathogen colonization, particularly against Escherichia coli, thereby attenuating intestinal inflammation (Bansal et al., 2010). Zhao et al. observed that indole intervention in HFD-treated rats resulted in significant downregulation of genes related to liver fibrosis and collagen synthesis (Zhao et al., 2019). However, subsequent studies have shown that indole or its metabolites do not consistently exhibit a beneficial role in liver disease. Liu et al. found that indole-3-propionic acid (IPA) could reduce the gap in gut microbiota diversity between CCl4-induced mice and healthy counterparts, activated HSCs and the TGF-β1/Smads signaling pathway, leading to hepatocyte apoptosis, increased expression of extracellular matrix components such as collagen I and α-SMA, ultimately promoting liver fibrosis (Liu et al., 2021). These contrasting findings underscore the necessity for thorough validation and consideration when evaluating the therapeutic potential of IPA in managing liver cirrhosis. Nevertheless, Li et al. analyzed 560 metabolites in serum metabolomics of patients with cirrhosis at different stages and found that IPA was the most significant indicator of decompensated metabolic biomarker reduction, suggesting that IPA can help accurately predict the stage of cirrhosis (Li et al., 2024).

Gut microbiota metabolism involves the conversion of choline into TMA, which is absorbed by the host and subsequently converted into trimethylamine N-oxide (TMAO) in the liver (Arias et al., 2020). Imbalances in gut microbiota reduce the bioavailability of choline and increase portal venous influx of TMA, both implicated in metabolic abnormalities associated with liver cirrhosis (Albillos et al., 2020). Mourier et al. established a fatty liver model using a methionine/choline-deficient diet, revealing downregulation of the Wnt/β-catenin pathway in mice, leading to disruption of the intestinal vascular barrier (Mouries et al., 2019). Sawada et al. observed reduced expression of TJPs like ZO-1 in choline-deficient rats compared to controls, resulting in intestinal endotoxin accumulation in the portal vein, triggering liver inflammation and oxidative stress (Sawada et al., 2019). In addition, deficiencies in methionine and choline promote the accumulation of cholesterol and fat in the liver by inhibiting the assembly/export of very low-density lipoprotein (Simon et al., 2020). Excessive fat deposition in liver cells is the main cause of liver inflammation, implicating its role in diverse liver diseases (Li et al., 2023).

In fact, Enterobacteriaceae and Klebsiella pneumoniae in the gut produce endogenous ethanol through the fermentation of carbohydrates, and ethanol metabolism produces toxic acetaldehyde (Salaspuro, 1997). Numerous studies have proved that when alcohol accumulates in the intestine due to long-term drinking, obesity and other factors, it will increase the expression of inflammatory cytokines to disrupt intestinal homeostasis, resulting in portal endotoxemia (Sheth et al., 2007; Kwon et al., 2014). In addition, ROS and ammonia produced by ethanol metabolism may cause oxidative stress and hepatocyte necrosis (Lieber, 1999). What’s more, its metabolite acetaldehyde may damage TJs of intestinal epithelial cells, destroy the intestinal barrier, cause pathological BT and intestinal leakage, and promote the progression of cirrhosis (Yan et al., 2023). In conclusion, endogenous ethanol can worsen liver inflammation through multiple pathways and has a significant effect on fibrosis.

Resveratrol (RSV) is primarily derived from natural plants such as Polygonum cuspidatum, Cassia seed, and grapes (Zhang et al., 2021). RSV has various pharmacological activities, including anti-inflammatory, antioxidant, anti-lipogenic, and anti-tumor effects, which could be closely related to its capacity for modulating gut microbiota, thereby ameliorating liver cirrhosis (Kim et al., 2011; Gambini et al., 2015). Recently, Li et al. found that in a CCl4-induced liver fibrosis rat model, RSV reversed the reduced expression of ZO-1, Occludin, and other proteins and mRNA induced by CCl4, accelerating the repair of damaged intestinal mucosal barriers. Moreover, while Staphylococcus xylosus and Staphylococcus lentus accelerate BT and enhance intestinal permeability, RSV inhibits the excessive proliferation of Staphylococcus lentus by inhibiting its biofilm formation, leading to the regulation of intestinal flora imbalance, adjustment of gut microbiota balance, and substantial amelioration of liver fibrosis (Li et al., 2022).

Berberine (BBR) a quaternary ammonium alkaloid derived from Rhizoma coptidis, has become a novel therapeutic approach in recent years (Song et al., 2020). It relies on its antibacterial, anti-inflammatory, anti-fibrotic, and anti-hyperlipidemic activities to target the regulation of gut microbiota in the treatment of liver diseases. BBR can enhance intestinal anaerobic bacteria to stimulate butyrate production, elevate the levels of beneficial bacteria (especially Clostridium) in the intestines, thereby reducing host liver inflammation, regulating lipid metabolism, and improving liver fibrosis. Additionally, BBR serves as an FXR and TGR5 agonist, pivotal in modulating the metabolic homeostasis of BAs, thereby intervening in liver cirrhosis by mediating the crosstalk between BAs metabolism and gut microbiota (Liu et al., 2022). However, studies have indicated that BBR itself can induce dysbiosis of the microbiota, leading to mild diarrhea in the host (Yue et al., 2019). Therefore, in future, special attention should be paid to the adverse reactions or intolerance of BBR in the drug development.

Corydalis saxicola Bunting (CSB) has significant therapeutic benefits in various liver diseases (Qin et al., 2023). Recently, Qin et al. demonstrated for the first time that palmitine (PAL) is the main active component of CSB and plays a pivotal role, particularly in conferring anti-fibrotic attributes. Further analysis using metagenomic sequencing methods revealed that the anti-fibrotic properties of PAL depended on the gut microbiota and could significantly reverse the decrease in the abundance of s_Lactobacillus_reuteri, s_Lactobacillus_murinus and s_Lactobacillus_johnsonii induced by CCL4. These three bacteria were directly negatively correlated with the degree of liver fibrosis. In addition, the levels of LPS, TNF-α, IL-6 and IL-1β in the liver of mice were reduced to varying degrees after PAL treatment, repair the intestinal barrier, and increase the immune response of intestinal epithelial cells against inflammatory stimuli, thereby elucidating the specific mechanism underlying PAL’s hepatoprotective effects (Qin et al., 2023).

Curcumol (CU), a sesquiterpenoid compound extracted from turmeric, has garnered attention for its crucial anti-inflammatory, anti-fibrotic, and immunomodulatory roles in liver and intestinal diseases (Liu et al., 2019; Yang et al., 2020). Recent CU can effectively alleviate liver cirrhosis (Zhang et al., 2024), alter the fecal microbiota composition in rats afflicted with liver fibrosis, reduce the abundance of Bacteroidetes, increase the abundance of Firmicutes and Proteobacteria, and inhibit the activity of TLR4/NF-κβ signaling pathway, leading to reduced expression of inflammatory factors (IL-6, TNF-α, IL-8) (Zheng et al., 2022). These findings suggest that CU has a potential as an alternative therapeutic drug targeting the liver and intestine.

Ginkgolide A (GA), a diterpenoid compound extracted from the roots and leaves of Ginkgo biloba trees, has been widely used in clinical practice to treat cardiovascular and neurological disorders (Wang et al., 2023). However, recent studies have found that GA has great potential in managing liver diseases (Ye et al., 2016; Jeong et al., 2017). Enterococcus and Bacteroides, but not Lactobacillus, were involved in GA regulation of intestinal flora imbalance in cirrhotic mice. It can also activate the progesterone X receptor (PXR), a potential therapeutic target for liver cirrhosis, thereby upregulating the expression of PXR in the liver and intestines. By improving the expression of TJPs such as ZO-1 and Occludin, inhibiting pathological translocation of intestinal bacteria, and regulating the inflammatory cytokine environment within the liver, GA plays an important role in maintaining the balance of the gut-liver axis during the treatment of liver cirrhosis (Mohandas and Vairappan, 2020a,b).

Glaucocalyxin A (GLA), a natural n-pentane diterpene isolated from the aerial parts of Rabdosia japonica (Chen et al., 2021), has recently been implicated in improve gut microbiota dysbiosis in a mouse model of liver fibrosis. GLA treatment could decrease the Bacteroidetes to Firmicutes ratio. At the class level, it decreased abundance of Clostridia and increased availability of Bacteroidia. At the order level, the abundance of Erysipelotrichales decreased, while that of Bacteroidia increased. At the family level, Lachnospiraceae became less abundant in the GLA group, whereas the presence of Muribaculaceae and Bacteroidaceae increased. GLA can also reduce the levels of inflammatory factors that are closely related to the gut microbiota, such as TNF-α, TGF-β, and ROS, thereby reducing the extent of liver fibrosis and addressing the imbalance of intestinal flora caused by liver diseases (Qu et al., 2023).

In addition, Yang et al. explored the synergistic effect of a blend of triterpenoids extracted from E. fukienensis Hsu. (EFT) and phenolic acids derived from the roots of S. miltiorrhiza Bge (SMP) on liver fibrosis. Their findings underscored a significant reduction in the Firmicutes/Bacteroidetes ratio in the EFT+SMP group compared to the model group, concomitant with a decrease in the levels of gut microbiota metabolites lysophosphatidylethanolamine (LysoPE) and lysophosphatidylcholine (LysoPC), both of which have pro-fibrotic effects, thereby inhibiting the activation of Kupffer cells. These findings suggest that the potential association between EFT+SMP and gut microbiota may serve as a mechanism for the management of liver fibrosis (Tan et al., 2020).

Artesunate (AS) is synthesized based on dihydroartemisinin, a derivative of artemisinin, and is mainly used for malaria treatment (Rueangweerayut et al., 2012). AS has beneficial therapeutic effects on liver diseases (Kong et al., 2019). Chen et al. found that AS intervention group exhibited a significant increase in intestinal microbial diversity (primarily Lactobacillus), compared to the cirrhosis model group, and resulted in a deceased incidence and quantity of BT, contributing to the protection of the intestinal barrier, reduction of inflammation, and mitigation of liver injury. These findings demonstrated that AS effectively reduced the prevalence of liver cirrhosis induced by variouspathogenic factors, such as CCl4, alcohol, and HFDs (Chen et al., 2016).

Previous studies have underscored the significant anti-liver fibrosis activity and “probiotic-like effect” of the ethyl acetate extract of Cichorium pumilum Jacq (CGEA) (Qin et al., 2014; Lee et al., 2015). Therefore, building upon the gut-liver axis concept, Chang et al. further explored the effects of CGEA on the gut microbiota and intestinal barrier and discovered that CGEA promoted the growth of Bifidobacteria, increased the abundance of Ruminococcus, and consequently improved the homeostasis of the gut-liver axis. It is essential to highlight that lactate, the main compound in CGEA, is significant for the anti-inflammatory process. By inhibiting the phosphorylation of mitogen-activated protein kinase (MAPK) and Akt signaling pathways triggered by LPS, CGEA can effectively suppress the expression of inflammatory factors such as IL-6 and NO, thereby alleviating the liver’s inflammatory response (Han et al., 2021).

Sodium alginate (SA), a natural polysaccharide extracted from seaweed or Sargassum of brown algae post-iodine and mannitol extraction, has emerged as a potential drug for liver protection and regeneration promotion (Li et al., 2022; Xia et al., 2023). Chen et al. underscored that liver fibrosis resulted in reduced gut microbiota diversity in rats, elevated colonization of harmful bacteria (such as Erysipelotrichaceae, Helicobacter, and Monolobus), and compromised the intestinal barrier. SA intervention remedied these pathological changes and increase the abundance of beneficial bacteria (such as Lactobacillus, Lachnospiraceae, and Eubacteria), thus improving liver fibrosis and inflammatory responses by restoring the stability of gut microbiota (He et al., 2023).

Lycium barbarum L. oligosaccharides (LBO) are oligosaccharides derived from Lycium barbarum. CCl4-induced liver fibrosis in mice results in increased ROS expression and mitochondrial dysfunction (Bi et al., 2024). Zhang et al. conducted further research and discovered a potential association between the pathological changes observed in liver fibrosis and dysbiosis of the gut microbiota. LBO could effectively treat liver fibrosis, mainly due to the restoration of gut microbiota, significantly increasing the enrichment of commensal bacteria Bacillus, Tyzzerella, Fournierella and Coriobacteriaceae UCG-002, further improves metabolic disorders caused by bacterial dysbiosis, repairs intestinal mucosal damage, regulates colonic epithelial permeability, and enhances mitochondrial function (Zhang et al., 2023).

Dendrobium officinale polysaccharide (DOP) have been previously shown to have anti-inflammatory, anti-oxidative, immune, hypoglycemic and other pharmacological properties (Liu et al., 2021; Wang et al., 2022; Chen et al., 2023), and play a significant therapeutic effect on acetaminophen induced liver injury by targeting the intestinal mucosal barrier (Lin et al., 2018). Subsequently, Wang et al. further explored and found that the mechanism of DOP in maintaining intestinal balance involved regulating the expression levels of TJPs such as occludin, claudin-1, ZO-1 and caspase-3 proteins, inhibiting the activation of LPS-TLR4-NF-κB signaling pathway, and reducing the content of inflammatory factors TGF-β and TNF-α, increasing the expression of anti-inflammatory factor IL-10, which significantly reduces the expression of α-SMA and collagen I, thereby reducing hepatocyte apoptosis and liver fibrosis (Wang et al., 2020).

Garlic, which is commonly used as a food spice, is also one of the traditional Chinese medicines and can be widely used in the treatment of cancer, nervous system and various metabolic diseases (Zhang et al., 2020; Tedeschi et al., 2022). In an experimental study on alcoholic liver fibrosis (ALF), garlic polysaccharide (GP) reversed the negative effects of changes in intestinal dominant flora on ALF, enriched Lachnospiraceae and Lactobacillus again, and reduced the diversity of potential pathogenic bacteria (Firmicute and Facklamia). It also regulates the protein expression of TGF-β1 (a key pro-fibrotic factor), TNF-α, and decorin (an anti-fibrotic agent), inhibits HSCs activation and reduces extracellular matrix (ECM) accumulation, ultimately demonstrating its hepatoprotective activity (Wang et al., 2018).

FTA is a glycoside compound extracted from the dried fruit of Forsythia suspensa and serves as a natural hepatoprotective agent (Gong et al., 2023). Fu et al. found that FTA not only restored the disrupted structure of intestinal microbiota, specifically, Ace index increased significantly, Shannon index decreased significantly, Lachnospiraceae_NK4A136_group, Ruminococcaceae_UCG-014, Lactobacillus、Bacteroides, Prevotellaceae_UCG-001, Helicobacter and Alloprevotellabut were adjusted to benefit the health of the host, also promoted the production of SCFA (particularly butyric acid). Furthermore, FTA reduced the levels of inflammatory factors such as LPS and TNF-α in serum, upregulated the mRNA expression of ZO-1, Claudin-1, and Occludin in a dose-dependent manner, thereby mitigating intestinal permeability. Meanwhile, FTA regulates the expression of genes related to BAs metabolism (such as FXR, CYP7A1.), thereby facilitating the communication between gut microbiota and the liver, underscoring its hepatoprotective and anti-fibrotic properties (Fu et al., 2022).