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World J Hepatol. Mar 27, 2025; 17(3): 104167
Published online Mar 27, 2025. doi: 10.4254/wjh.v17.i3.104167
Gut microbiota in the development and progression of chronic liver diseases: Gut microbiota-liver axis
Aysun Yakut, Department of Gastroenterology, İstanbul Medipol University Sefakoy Health Practice Research Center, İstanbul 38000, Türkiye
ORCID number: Aysun Yakut (0000-0001-7792-8438).
Author contributions: Yakut A designed the overall concept and outline of the manuscript, wrote and edited the manuscript, and performed the literature review.
Conflict-of-interest statement: The author reports no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Aysun Yakut, MD, Department of Gastroenterology, İstanbul Medipol University Sefakoy Health Practice Research Center, Maslak Cesme Street, Tevfikbey District, Kucukcekmece, İstanbul 38000, Türkiye. aysun.yakut@istanbul.edu.tr
Received: December 12, 2024
Revised: January 28, 2025
Accepted: February 25, 2025
Published online: March 27, 2025
Processing time: 104 Days and 10.1 Hours

Abstract

The gut microbiota (GM) is a highly dynamic ecology whose density and composition can be influenced by a wide range of internal and external factors. Thus, “How do GM, which can have commensal, pathological, and mutualistic relationships with us, affect human health?” has become the most popular research issue in recent years. Numerous studies have demonstrated that the trillions of microorganisms that inhabit the human body can alter host physiology in a variety of systems, such as metabolism, immunology, cardiovascular health, and neurons. The GM may have a role in the development of a number of clinical disorders by producing bioactive peptides, including neurotransmitters, short-chain fatty acids, branched-chain amino acids, intestinal hormones, and secondary bile acid conversion. These bioactive peptides enter the portal circulatory system through the gut-liver axis and play a role in the development of chronic liver diseases, cirrhosis, and hepatic encephalopathy. This procedure is still unclear and quite complex. In this study, we aim to discuss the contribution of GM to the development of liver diseases, its effects on the progression of existing chronic liver disease, and to address the basic mechanisms of the intestinal microbiota-liver axis in the light of recent publications that may inspire the future.

Key Words: Gut microbiota; Gut microbiota-liver axis; Liver diseases; Treatment strategies and modeling; Chronic liver diseases

Core Tip: The gut microbiota (GM) plays an active role in both physiological and pathological processes for the host. These microbiomes and their metabolites living in the intestine interact with the host metabolism and reach the liver via portal flow. This interaction creates many defined and undefined mechanisms, forming the intestinal microbiota-liver axis. GM, together with the host interaction, can play a triggering role in the development of chronic diseases in the liver, and can also cause the existing chronic liver disease to complicate. GM, surprisingly, can also contribute to the progression of cirrhosis, cirrhosis complications and hepatocellular carcinoma.



INTRODUCTION

In recent years, the increasing number of studies on gut microbiota (GM) and the existence of the relationship between the dynamic ecosystem in GM and liver disease have created the concept of the GM-liver axis. As a result of the interaction between the portal vein, biliary tract, systemic circulation, GM and host metabolism, the GM-liver axis is formed and chronic liver diseases are induced. Intestinal products such as host-microbial metabolites-microbial associated molecular patterns are transported to the liver via the portal vein and affect liver function. In parallel, the liver transports bile salts and antimicrobial molecules to the intestinal lumen via the biliary tract to maintain intestinal eubiosis by controlling unrestricted bacterial growth[1]. This interaction may lead to metabolic disorders in the liver in the presence of intestinal dysbiosis, leading to liver damage. For example, dysbiotic GM reduces the activation of nuclear bile acids (BAs) receptor farnesoid X receptor (FXR) and membrane G protein-coupled receptor Takeda G protein-coupled receptor 5 (TGR5), which leads to a decrease in the synthesis of secondary BAs, thereby contributing to bile salt retention, small intestinal translocation, and bacterial proliferation, and eventually leading to liver disease[2]. The diseased liver cannot effectively inhibit bacterial overgrowth and eliminate harmful microbial byproducts. In addition, liver damage is closely related to the severity of intestinal dysbiosis[3]. On the other hand, while drawing attention to the importance and role of the GM-liver axis in the onset and development of chronic liver disease, it is important that hepatic encephalopathy (HE), which is considered a typical GM-gut-liver-brain axis disease model, is also affected by changes and interactions in the microbiota. In this article, we wanted to present the basic mechanisms of the GM-liver axis, the important pathophysiological effects of GM in the development of liver diseases, the effects on the progression of existing chronic liver diseases, the effects of manipulations in the treatments that can be done in GM and that are about to be defined, and the studies that can inspire the future of GM in the development and progression of chronic liver diseases in the light of current studies.

PATHOPHYSIOLOGICAL MECHANISMS IN THE GM-GUT-LIVER AXIS
Pathophysiology of changes in permeability in the intestinal barrier

The intestinal barrier permits nutrients from the intestinal lumen to be transported selectively while preventing the passage of infections and harmful metabolites. Bacterial endotoxins and digestion products can enter the portal vein lumen and travel to the liver non-selectively when the intestinal barrier becomes more porous[4]. Numerous elements, such as immune cells, tight junction proteins, antimicrobial peptides, and the protective mucosal layer, influence the intestinal barrier’s permeability[5]. The mucus layer’s functions include facilitating nutrition absorption and shielding intestinal cells from the elements[6]. Defensins and immunoglobulin A are two examples of antimicrobial peptides released by Paneth cells that provide the mucus layer with antibacterial properties. The thickness and composition of the mucus layer influence the characteristics of the bacterial niche, whereas bacteria can also modify the features of the mucus layer[7]. Mucispirillum sp. bacteria seen in metabolic dysfunction-associated fatty liver disease (MAFLD) patients alter the intestinal mucosal surface[8]. Intestinal dysbiosis diminishes the synthesis of the principal intestinal mucin and the key constituent of the mucus layer by suppressing mucin 2 gene expression[7]. As the symptoms of MAFLD-related liver damage intensify, a rise in bacterial protein levels in the blood is evident due to heightened intestinal barrier permeability[9].

Conversely, intestinal endothelial cells’ junction is often closed by tight junction proteins, which stops dangerous compounds from being transported from the intestine to the portal system. It has been shown that people with MAFLD have lower amounts of several proteins. The intestinal lumen’s endotoxin levels rise as a result of dysbiosis. By activating toll-like receptor 4 (TLR4) in the liver and small intestine, lipopolysaccharide (LPS), an endotoxin of gram-negative bacteria, contributes to the development of MAFLD[10]. It has been demonstrated that as LPS stimulates the intestinal TLR4 receptor complex, the TLR4/myeloid differentiation primary response 88 signaling pathway is activated. This, in turn, activates myosin light chain kinase, increasing the permeability of intestinal tight junction proteins without changing the protein levels[11]. Other research has demonstrated that at varying LPS doses, tight junction redistribution and alteration are linked to increased gut barrier permeability[12]. Additionally, intestinal microbiota, intestinal barrier integrity, and metabolic endotoxemia are linked by the endocannabinoid system, namely intestinal cannabinoid (CB) receptors. Serum LPS levels rise and tight junction protein [zonula occludens-1 (ZO-1) and occluding] mRNA expression falls as CB1 agonists are administered, but antagonist therapy has the reverse effect[13]. It has been demonstrated that the effects of intestinal Oscillibacter and Desulfovibrio bacteria on CB1 agonist receptors are comparable[14]. The lamina propria and Peyer’s patches, on the other hand, offer tolerance to commensal microorganisms and innocuous compounds while simultaneously protecting the host immune system from dangerous substances[15]. There is a decrease in T cells in the lamina propria and an increase in proinflammatory cytokines such as IL-6, interferon-gamma, and tumor necrosis factor α in the chronic liver illness MAFLD. It’s interesting to note that MAFLD is associated with higher amounts of proinflammatory microorganisms such as Streptococcus sp. and Escherichia coli (E. coli)[16].

GM-metabolic interactions and changes between host

The liver converts cholesterol into BAs. They are made up of secondary BAs such as lithocholic acid and deoxy cholic acid (DCA) as well as main BAs like CA and chenodeoxy CA (CDCA). Primary BAs build up in the gallbladder after being conjugated with taurine or glycine. In which food enters the intestine, BAs are sequestered. To create hydrophobic secondary BAs, the intestinal microbiota deconjugates, dehydroxylates, oxidizes, and desulfates primary BAs. Enterohepatic circulation reabsorbs secondary BAs in the distal ileum, and the portal vein returns them to the liver[17]. Bacteria belonging to the genera Bacillus, Staphylococcus, Bacteroides, Lactobacillus, Clostridium, and Enterococcus spp., as well as species representing Firmicutes, Proteobacteria, and Bacteroidetes spp., are involved in the deconjugation process. In primary BAs made in the liver, they generate bile salt hydrolases that deconjugate taurine and glycine groups[18]. Firmicute bacteria are crucial to the dehydroxylation process, particularly strains from the genus Clostridium. To transform primary BAs (CA and CDCA) into secondary BAs (DCA and lithocholic acid), they generate BA 7α-dehydroxylase[19]. Bacteroides, Clostridium, Eubacterium, Escherichia, Eggerthella, Peptostreptococcus, and Ruminococcus species are the primary bacteria implicated in BA oxidation. They generate the enzyme BA hydroxysteroid dehydrogenase, which changes harmful BAs into urodeoxycholic acid, which is more soluble in water and less harmful to human cells[20]. Sulfatases produced by a variety of gut bacteria, including Clostridium sp. strain S2, can enhance the desulfation of BAs. Intestinal microorganisms that desulfate BAs aid in their reabsorption. Maintaining BA homeostasis depends on it[19]. The development of MAFLD impairs the metabolism of BA, and it has been demonstrated that the liver produces more primary and secondary BA, which raises blood levels of BA. A recent meta-analysis’s findings indicate that variations in BA profiles may be influenced by geographic regions or the severity of the disease. Serum levels of taurocholic acid and glycolic acid have been found to rise, which has been identified as a significant contributing factor to severe liver fibrosis (> F2)[21]. Through the FXR and TGR5, BAs, which are signaling molecules that control glucose, lipids, and the immune system, primarily contribute to host cell metabolism[22]. Of all the main BAs, CDCA is the most effective FXR agonist. Through the stimulation of fibroblast growth factor 19, FXR activation increases the absorption of glucose by adipocytes. But FXR also suppresses the expression of sterol regulatory element binding protein 1c and activates peroxisome proliferator-activated receptor alpha, which stops fat buildup in the liver and boosts β-oxidation efficiency[23]. By inhibiting neuropeptide Y and agouti-related neuropeptide neurons in the arcuate area, TGR5 activation increases the release of glucagon-like peptide-1 (GLP-1), which in turn causes a decrease in hunger and an increase in glucose-dependent insulin secretion[24]. Additionally, it has been demonstrated that BA-induced TGR5 receptor activation in Kupffer cells inhibits LPS-induced cytokine production, indicating a possible role for BA in the immunological response[25]. By suppressing cholesterol 7α-hydroxylase expression, both receptors contribute to lowering BA secretion through a negative feedback loop[26]. Patients with MAFLD had higher triglyceride levels and lower serum FXR expression[27]. In addition, the DCA level is higher than the CDCA level. Increased lipid buildup and insulin resistance may result from the observed alterations in BA levels and composition, which may also impair the function of FXR and TGR5 receptors[21].

Conversely, choline, the main source of methyl groups, is produced in the liver by de novo synthesis as well as from food[28]. Choline is essential for the liver’s production of very low-density lipoprotein, which helps the body get rid of extra triglycerides. The intestinal bacteria in the colon partially break down choline to produce trimethylamine (TMA), which is subsequently transported to the liver through the portal circulation. TMA N-oxide (TMAO) is created as TMA undergoes oxidation in the liver. Proteobacteria (Proteus penneri and Providencia rettgeri species) and Firmicutes (Anaerococcus hydrogenis, Clostridium asparagiforme, Clostridium hathewayi, and Clostridium sporogenes) are the phyla of bacteria that are principally engaged in choline metabolism in the intestine[29]. Increased TMAO accumulation in the liver is caused by intestinal dysbiosis and a diet low in choline. Because of the reduced choline bioavailability, MAFLD may develop as a result[30]. Additionally, by inhibiting BA-mediated hepatic FXR signaling, TMAO may exacerbate liver steatosis. The intestinal fermentation of dietary fiber results in the production of short-chain fatty acids (SCFAs), which are molecules with one to eight carbon atoms and represent another metabolic pathway[31]. The main gut bacteria that produce SCFA are Bacteroides species, Anaerostipes species, and others[32]. Total SCFA levels, particularly those of acetate, propionate, and butyrate, are lower in MAFLD patients than in healthy people[33]. Intestinal epithelial cells receive nourishment by SCFAs, particularly butyrate, and decreased intestinal barrier permeability is linked to lower SCFA levels. Propionate functions as a substrate for gluconeogenesis in the liver, preventing the synthesis of cholesterol. In contrast, acetate is a substrate for the production of beta-hydroxybutyric acid, glutamine, glutamate, and long-chain fatty acids. Hepatocytes directly oxidize butyrate[31]. Additionally, LPS-induced tumor necrosis factor α release and nuclear factor-kappa B (NF-κB) activation can be inhibited by acetate and butyrate, which reduces liver inflammation[34]. By reducing the pH in the intestinal lumen, SCFAs prevent the growth of bacteria. Acetate generated by Bifidobacterium species has been demonstrated to inhibit the growth of enteropathogenic bacteria[35]. High amounts of butyrate are correlated with enhanced mucin synthesis and decreased bacterial adhesion to the intestinal epithelium. Butyrate has been shown to maintain epithelial integrity[36]. By promoting perceptions of fullness and activating hormones that control appetite, SCFAs may help prevent the onset of obesity. The capacity of SCFAs to enhance GLP-1 and peptide YY production through receptor activation on intestinal enteroendocrine L cells is one mechanism corroborating the association between SCFAs and food consumption[37]. Additionally, by promoting catabolic processes, SCFAs may lessen hepatic steatosis. Using supplements, care should be taken because high levels of SCFAs can encourage the development of hepatocellular carcinoma (HCC)[38]. Leucine, isoleucine, and valine are branched aliphatic essential amino acids, often known as branched-chain amino acids. It is believed that the bacteria Bacteroides vulgatus and Prevotella copri contribute to the development of insulin resistance[39]. Hepatic fat accumulation decreased as a result of oral branched-chain amino acid supplementation, which raised levels of healthy GM, such as Bifidobacterium sp. and Ruminococcus flavefaciens[40]. Additionally, a high concentration of Bifidobacterium sp. increased SCFAs, particularly acetate, which in turn increased GLP-1 secretion[41].

Numerous investigations have demonstrated that hepatic steatosis lowers the activity of urea cycle enzymes. As a result, the liver accumulates ammonia, which causes hematopoietic stem cells to express profibrotic genes. Ammonia is produced from amino acids by the intestinal microbiota. Therefore, the composition of the intestinal microbiota plays an important role in circulating ammonia levels. Gram (-) bacilli of the family Enterobacteriaceae and gram (+) bacteria (members of genus Clostridium) that are completely anaerobic have been demonstrated to be the main producers of ammonia[42]. Moreover, the development of MAFLD has been persistently linked to elevated levels of E. coli, a member of the Enterobacteriaceae[43]. A neurotoxic substance that easily penetrates the blood-brain barrier is ammonia. Through the gut-liver-brain axis, elevated inflammation also plays a major role in the development of HE when chronic liver disease worsens, and proper management of GM dysbiosis seems to be essential in treatment approaches[44].

However, cirrhosis, HCC, and chronic liver disease are also influenced by the GM’s endogenous ethanol production. The gut’s production of ethanol stimulates NF-κB signaling molecules, which have the potential to harm tissue. Intestinal permeability may rise as a result of this injury, raising LPS levels in the hepatic portal system. Liver inflammation can result from elevated LPS levels activating TLR4 and the inflammasome. The process of endogenous alcohol production involves bacteria associated to the Gammaproteobacteria class, including E. coli, Klebsiella pneumoniae, and other members of the Enterobacteriaceae family[45]. Patients with MAFLD may experience impaired ethanol metabolism and higher blood ethanol levels as a result of changes in alcohol dehydrogenase activity in the liver caused by defects in insulin signaling[46].

Intestinal L cells, which are more prevalent from the duodenum to the colon, produce GLP-1 into the portal circulation. Nutrients, neurons, and endocrine systems all stimulate L cells. In addition, the GM and its metabolites, including SCFAs, increase GLP-1 production[47]. Because GLP-1 is an incretin, it lowers glycemia by increasing insulin production in a glucose-dependent way. The upper intestine’s K cells secrete gastric inhibitory polypeptide, another peptide in the incretin family that stimulates postprandial insulin secretion. GLP-1 has a number of regulatory and protective functions in addition to its insulinotropic actions. GLP-1 enhances satiety, decreases acid secretion and motility, and inhibits gastric emptying. In addition, GLP-1’s effects on the brainstem and hypothalamus result in decreased food consumption. The liver, brain, heart, adipose tissue, muscles, bones, kidneys, and lungs are among the tissues where GLP-1 has protective and regulating actions[48]. The primary processes by which GLP-1 reduces the hepatic steatosis, inflammation, and fibrosis seen in MAFLD are body weight loss and insulin resistance. By controlling Kupffer cell activity in the liver and preventing their activation in hematopoietic stem cells, among other anti-fibrotic actions, GLP-1 may potentially have anti-inflammatory effects[49]. The activity and expression of GLP-1 receptors in liver tissue, as well as their ability to diminish steatosis, are not well supported by data[50]. The function of GLP-2, which is co-secreted and comes from the same gene as GLP-1, is intestinal lining repair. It increases intestinal cell proliferation, decreases intestinal permeability, and enhances food absorption[51]. Fuchs et al[52] reported that GLP-2 treatment attenuated the activation of hematopoietic stem cells. GLP-2 is also thought to contribute to its hepatoprotective and antifibrotic effects.

GM-LIVER AXIS IN THE DEVELOPMENT OF CHRONIC LIVER DISEASES
MAFLD

The chronic liver disease known as MAFLD can lead to cirrhosis, fibrosis, steatosis, steatohepatitis, and HCC. Type-2 diabetes, obesity, hyperlipidemia, hypertension, and metabolic syndrome are all strongly linked to the development of MAFLD[53]. It is currently thought that a number of detrimental factors, such as insulin resistance, oxidative stress, altered lipid metabolism, release of inflammatory cytokines, endoplasmic reticulum stress, intestinal dysbiosis or gut-liver axis activation, genetic, and epigenetic factors, combine to cause the most significant triggers in the pathogenesis of MAFLD. According to Boursier et al[54], intestinal dysbiosis and modifications in the intestinal microbiota’s metabolic activity are linked to the severity of MAFLD. Changes in intestinal permeability, elevated low-grade inflammatory response, control of dietary choline metabolism, alterations in BA metabolism, and endogenous ethanol production resulting in alterations in intestinal microbiota are some of the mechanisms that have been identified as potentially causing fat accumulation in the liver (Figure 1)[55]. In addition to these processes, it has also been documented that GM contributes to the neuroendocrine control of lipid metabolism. Furthermore, ammonia and metabolites of the GM may result in neurotoxic damage linked to cognitive impairment in MAFLD; nonetheless, more investigation is required to completely comprehend the mechanism behind the functional alterations brought on by cognitive impairment in MAFLD. Mouries et al[56] recently discovered that the impairment of the intestinal epithelial barrier and intestinal vascular barrier are initial occurrences in the development of MAFLD, and that high-fat diet (HFD) mice experience damage to the intestinal vascular barrier and bacterial translocation within just one week. Thus, the intestinal barrier is crucial in MAFLD in addition to the significant role played by the intestinal microbiota and its byproducts.

Figure 1
Figure 1 Diagrammatic illustration of the role the gut microbiota plays in the onset of non-alcoholic fatty liver disease. The gut-liver axis components are operating normally in the left panel. In the right panel, non-alcoholic fatty liver disease (NAFLD) is shown. The translocation of certain bacterial products into the portal vein is facilitated by the dysbiotic microbiota and the altered intestinal barrier brought on by tight junction dysfunction. These bacterial products cause inflammation and the development of NAFLD by interacting with toll-like receptors on the surface of the liver cells. TMA: Trimethylamine; SCF: Short-chain fatty acid; BA: Bile acid; LPS: Lipopolysaccharide; TLR: Toll-like receptor. Citation: Joon A, Sharma A, Jalandra R, Bayal N, Dhar R, Karmakar S. Nonalcoholic Fatty Liver Disease and Gut-liver Axis: Role of Intestinal Microbiota and Therapeutic Mechanisms. J Transl Gastroenterol 2024; 2: 38-51. Copyright © 2024 Author(s). Xia & He Publishing Inc[55].

The GM has been a target in the treatment of MAFLD in recent years because to research on the microbiota-gut-liver axis. The first-line treatment for MAFLD is diet and exercise. The diversity and makeup of GM are significantly impacted by a Mediterranean-style diet high in monounsaturated fatty acids. Its polyphenols can boost Bifidobacteria, whereas its high dietary fiber content can boost Bacteroides and inhibit Firmicutes[57]. Furthermore, exercise can successfully balance intestinal dysbiosis in HFD mice, reducing intestine-liver axis imbalance and enhancing BA homeostasis, both of which aid in regulating the development of MAFLD. The use of probiotics to control GM is another promising regulation in the treatment of MAFLD. The probiotic Lactobacillus rhamnosus GG (LGG) lowers liver inflammation and steatosis, improves intestinal barrier function, and increases the number of beneficial bacteria in the distal small intestine. However, the study by Naudin et al[58] discovered that dietary supplementation of Lactococcus lactis subspecies cremoris was more effective than dietary supplementation of LGG in lowering liver fat and the development of inflammation in female mice fed a high-fat, high-carbohydrate diet. Furthermore, a randomized clinical experiment revealed that children’s MAFLD might be considerably improved by taking VSL#3 supplements for four months, which may be due to an increase in GLP-1[59]. For the first time, a highly effective multi-strain probiotic was shown in another randomized clinical trial to dramatically ameliorate cytokines and liver histology in adult patients with MAFLD[60]. Fecal microbiota transplantation (FMT), which has shown promise in treating MAFLD, has only been used in a few clinical trials and animal research. In HFD animals with steatohepatitis, FMT has been demonstrated to ameliorate intestinal dysbiosis, raise cecal butyrate and small intestine tight junction protein ZO-1 concentrations, and decrease endotoxin and inflammatory factor production[61]. FMT can result in the transfer of metabolic phenotypes in HFD mice, according to a recent study by Porras et al[62]. However, after 6 weeks of allogeneic FMT, clinical trials have demonstrated that aberrant permeability of the small intestine was considerably reduced in patients with MAFLD[63]. Large-scale FMT investigations are required to assess the impact of MAFLD, despite the optimistic outcomes of the existing trials.

Numerous studies on the use of herbal remedies to treat MAFLD are now underway. It has been demonstrated that the Chinese herbal remedy Dachaihu decoction helps treat MAFLD. The mechanism has been described as the partial control of liver function, lipid metabolism, and intestinal mucosal barrier. Furthermore, it has been demonstrated that Shenling Baizhu powder, which is made from ten distinct traditional Chinese medicinal herbs, improves liver function, lowers serum endotoxin and inflammatory factors, lowers LPS levels, and increases the relative abundance of beneficial bacteria (Bifidobacterium and Anaerostipes)[64]. In the research of Feng et al[65], the traditional Chinese medicine Qushi Huayu decoction decreased liver lipid synthesis, improved the liver’s antioxidant system, and encouraged the development of regulatory T cell-mediated microbiota in the intestine. The significance of polyphenols and their impact on intestinal microbiota have been assembled in light of recent developments in the treatment of MAFLD. According to these animal studies, the polyphenol in Raw Bowl Tea not only decreased the amount of Firmicutes in the feces of mice with MAFLD, but it also raised the minimum amounts of Bacteroides and Akkermansia, decreased the production of inflammatory factors, and lessened the pathological damage to the tissues of the liver and small intestine[66]. It has been demonstrated that the green tea polyphenol (epigallocatechin-3-gallate) affects the BA metabolism and the GM composition of HFD-fed animals[67]. As to these studies, polyphenol may be a very effective treatment for MAFLD patients.

Alcoholic liver disease

The spectrum of alcoholic liver disease (ALD) is extremely complicated. With prolonged exposure, this chronic liver disease develops into cirrhosis, fibrosis, simple steatosis, alcoholic hepatitis, and HCC. Research has concentrated on the role of oxidative stress in the disease’s pathophysiology[68]. The gut-liver axis problem is believed to be mostly caused by ALD intestinal microbiota alterations and GM’s role in bacterial ethanol generation. The direct transfer of products resulting from the interaction between the gut and its microbiota to the liver through the portal vein, as well as the feedback mechanism of bile and antibody secretion to the gut and liver, is known as the gut-liver axis. Through a number of methods, including enhanced liver lipid metabolism, increased alcohol generation, increased intestinal permeability, bacterial translocation, intestinal bacterial proliferation, intestinal microbiota imbalance, and decreased bile output, the GM influences the liver. Cirrhosis, alcoholic hepatitis, and eventually alcohol-related harm can be brought on by pathological events involving the microbiota, especially BA metabolism. Furthermore, the relationship between the GM and alcohol dependency is caused by certain alterations in the gut-liver-brain axis, and changes in the microbiota may also affect brain function. The GM may also raise the likelihood of major alcohol-related illness, while also positively influencing the development of alcohol-dependent psychotic symptoms.

Alcohol abstinence and lifestyle modifications should be the main interventions for ALD. Even in the later stages of the disease, a substantial reversal and long-lasting improvement in prognosis require complete abstinence from alcohol[69]. Godlewski et al[70] recently demonstrated that peripherally restricted medications that block CB1 receptors can lower mice’s consumption of ethanol, making therapy safer. Altering the GM is a further therapy option for ALD. By improving intestinal FXR/fibroblast growth factor 15 signaling pathway-mediated regulation of de novo production of BAs, LGG, probiotic supplementation can decrease hepatic BAs and enhance BA excretion, according to a recent study. In mice, this stops fibrosis and liver damage brought on by too much BAs[71]. Furthermore, alcohol consumption decreases the number of Akkermansia muciniphila in both human and mouse intestines. Yet, this gram-negative intestinal commensal increases mucus production to support barrier function[72]. Thus, the strain of Akkermansia muciniphila may be beneficial for patients with ALD. In order to lower ammonia levels by correcting intestinal microbiota imbalances, efforts have been attempted to boost populations of beneficial bacteria like Bifidobacteria and Lactobacillus when ALD develops into alcoholic cirrhosis[73]. However, according to the initial findings of a randomized clinical trial evaluating the effectiveness of FMT and steroids for treating severe alcoholic hepatitis, patients who received FMT fared better in terms of survival than those who received steroids[74]. This implies that FMT might be a viable alcoholic hepatitis therapy option. Additionally, following antibiotic pretreatment, FMT capsules were safe and well tolerated for cirrhotic and recurrent HE patients, according to recent research by Bajaj et al[75]. To assess the function and proven effectiveness of FMT in ALD, more investigation is necessary. Additional studies on the therapy of ALD by Duan et al[76] demonstrated that bacteriophages might eradicate alcohol-induced liver damage in mice and selectively target cytolytic Enterococcus faecalis. But additional patient testing and the assessment of bacteriophage safety are being looked into[77]. Chronic alcohol use caused dysbiosis in mice and reduced antimicrobial peptides-α-defensins in Paneth cells, according to a study by Zhong et al[78]. It has been demonstrated that functional α-defensin knockout increases the translocation of pathogen-associated molecular patterns and causes liver damage by interacting with alcohol interference in the intestinal barrier and bacterial composition. As synthetic human α-defensin 5 is administered, the composition of cecal microbes is efficiently altered. In instance, it reverses the negative effects of alcohol and boosts certain gut microorganisms. Thus, human α-defensin 5, which requires more research, might be a novel and promising treatment for alcoholic hepatitis. Furthermore, Chu et al[79] demonstrated that the polypeptide toxin candidalysin, which is released by the symbiotic intestinal fungus Candida albicans, may cause hepatocyte injury and raise proinflammatory cytokine levels in mice’s livers following ethanol treatment. Candidalysin-induced hepatocyte death could result directly from this. Additionally, they discovered that in patients with alcoholic hepatitis, candidalysin was linked to the severity and death of liver disease. Therefore, it was also believed that by lowering the inflammatory response, blocking the production of candidalysin could ameliorate ALD illness. Even though there are treatment models based on the liver-intestinal microbiota axis, they require more research to be useful in modern therapy.

Primary biliary cirrhosis and primary sclerosing cholangitis

Hepatic portal inflammation, which progressively advances to obliterative fibrosis and ultimately liver cirrhosis, is a hallmark of chronic cholestatic liver disorders, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)[80]. Biliary dysbiosis in PSC patients is accompanied by elevated levels of taurolithocholic acid, a pro-inflammatory and possibly carcinogenic toxin[81]. Furthermore, compared to inflammatory bowel disease patients without concurrent PSC, PSC and inflammatory bowel disease patients show distinct microbiota and microbiota-fecal BA associations[82]. For instance, PSC patients have lower levels of Clostridiales II relative abundance and overall bacterial diversity than both ulcerative colitis patients and control subjects[83]. As a result, host metabolism is probably changed by microbial changes of BAs, which could change immunological signaling through BA receptors and immune responses. Because both illnesses are caused by microbial causes, altered BA composition in PBC and PSC may potentially enable uncommon bacteria to proliferate and maintain ascending infections inside the biliary tree[84]. Thus, there is proof that the pathophysiology of PBC and PSC involves microbial agents, modifications to the gut/biliary tract microbiota, and a changed metabolite profile that includes BAs. Since pathogenic bacteria can use the biliary tree as a route for infection and ursodeoxycholic acid is currently the only Food and Drug Administration-approved drug available for the treatment of PBC, its mechanism of action may involve antimicrobial effects, as recently demonstrated for Clostridium difficile infections[85]. Whether antibiotic administration could be a novel and alternative therapeutic option for the treatment of these devastating diseases should be addressed in future studies.

Cirrhosis and HE

The final stage of several chronic liver disorders is cirrhosis. Reduced liver function and portal hypertension are its clinical markers. Jaundice, variceal hemorrhage, ascites, or HE are among the consequences that are linked to decompensated cirrhosis[86]. The pathophysiology of HE, spontaneous bacterial peritonitis, and other infections is significantly influenced by GM, endotoxins, and metabolites that facilitate bacterial translocation. GM has been linked to the worsening of decompensation and the advancement of chronic liver disease[87]. A helpful quantitative measure to characterize alterations in the microbiome that coincide with the advancement of cirrhosis could be the cirrhosis dysbiosis ratio. Interestingly, a recent study found that the existence of dysbiosis in cirrhosis patients is correlated with the diversity of bacteria in their circulation. Also, in cirrhosis-associated brain dysfunction, certain taxa of gut bacteria are linked to alterations in neurons and astrocytes. Ahluwalia et al[88] studied 187 patients, 40 controls and 147 cirrhotic patients, and evaluated systemic inflammatory assessment, cognitive testing, fecal microbiota analysis and brain magnetic resonance imaging analysis. Diffusion tensor imaging revealed edema and alterations in neuronal integrity, while hyperammonemia-associated astrocytic abnormalities were linked to increased glutamate/glutamine, decreased myo-inositol, and choline magnetic resonance spectroscopy modifications. Magnetic resonance spectroscopy and astrocytic alterations linked to hyperammonemia were coupled with certain microbial families (autochthonous taxa negative and Enterobacteriaceae positive). Porphyromonadaceae, on the other hand, showed no correlation with ammonia and only with neuronal alterations on diffusion tensor imaging. It was determined that specific gut microbial taxa were linked to the astrocytic and neurological effects of brain dysfunction brought on by cirrhosis. Additionally, they discovered that HE patients had considerably lower cognitive function, systemic inflammation, dysbiosis, and hyperammonemia than controls and cirrhotics without HE when evaluating the relationships between cognition, magnetic resonance imaging parameters, and GM between groups. Thus, alterations in the gut-liver-brain-microbiota axis are intimately linked to the development of cirrhosis and HE. From preclinical alterations to coma, HE can present as neurological or behavioral disorders[89]. Increases in the toxic microbial byproducts ammonia, indole, oxindole, and endotoxin are linked to the development of HE. Significant pathophysiological events are caused by the rise in the concentration of these harmful metabolites and the diseased liver’s incapacity to eliminate these products. The pathophysiology of HE also involves bacterial translocation, inflammation, leaky gut, and small intestine bacterial overgrowth.

The gut, microbiota, liver, and their interactions are among the several systems linked to the triggering factors for the development of HE in cirrhotic patients. Constipation, systemic infections, alterations in the intestinal flora, and spontaneous and/or therapeutic shunts all raise the chance of developing HE[87]. The abundance of intestinal microbiota with and without HE has been assessed in numerous studies published in the literature. But it’s interesting to point out that, using specific procedures, it has been demonstrated that the mucosa’s microbiome may differ significantly from the host’s feces. Examining the intestinal mucosa and feces, same difference was also observed between the HE and HE-free groups. There were notable differences in the fecal microbiome, which corresponds to the mucosal microbiome makeup in the entire population[90]. Interestingly, the majority of the bacteria found in higher abundance in feces were Firmicutes (Leuconostoc, Roseburia, Veillonella, and Incertae Sedis XI), while the important bacterial genera found in higher abundance in the mucosa belonged to Firmicutes (Blautia, Incertae Sedis XI), actinobacteria (Propionibacterium and Streptomyces), and Proteobacteria (Vibrio). The evaluation of the HE and HE-free groups revealed these differences as well. In both HE and non-HE patients, it was discovered that the mucosa had a considerably higher concentration of Propionibacterium and Vibrio species than the feces. There were notable variations in the mucosal microbiome between HE and non-HE patients, but not noticeable alterations in the fecal microbiota.

Roseburia was more prevalent in the HE-free group, whereas Firmicutes species, particularly those belonging to the genera Veillonella, Megasphaera, Bifidobacterium, and Enterococcus, were more prevalent in the HE group[90]. However, the ammonia pathway plays a significant role in HE, and the GM also plays a role in the development of HE through ammonia synthesis. Zhang et al[91] discovered that the sole urease-gene-rich bacteria in the minimum HE-specific gut microbial module was Streptococcus salivarius (S. salivarius), represented by OTU151. S. salivarius bacteria can use ammonium produced from urea through urease activity as the only nitrogen source for colonization in the human body. Two ureolytic stains, JIM8777 and 57.I, have a lot of urea catabolism genes and express urease activity in the normal human mouth. According to these experiments, intestinal colonization by S. salivarius, which is represented by the mouth-derived OTU151 that exhibits urease activity, may be a factor in the buildup of ammonia in individuals with minimal HE (MHE). Although no sequences from the urease-containing bacteria Proteus or Helicobacter were detected in the MHE patient, only one from the urease-containing bacterium Klebsiella was; yet, the presence of MHE may be related to the vital functions of these three bacteria[91]. Furthermore, cirrhotic individuals with MHE had a considerably higher abundance of S. salivarius than those without MHE. So, the sequence similarity between urease-positive S. salivarius in feces and oral saliva suggested that this bacterium might raise intestinal ammonia production and cause HE in liver cirrhosis patients[91]. Disease progression is believed to be prevented by the efficacy of GM-focused therapy in the treatment of advanced liver cirrhosis and HE. In order to control the intestinal environment, diet is crucial. Limiting protein consumption in HE patients was formerly advised because protein catabolism raises ammonia levels. However, recent research has demonstrated that HE patients can tolerate a typical protein consumption. It’s interesting to note that a diet heavy in casein and veggies can lower blood ammonia levels in HE patients considerably while also improving mental health. Branched-chain amino acid supplements taken orally can effectively lower the chance of a HE recurrence. For HE, non-absorbable disaccharides such lactol and lactulose are advised as first-line treatment. In addition to being useful in treating overt HE, lutein also helps to ameliorate MHE[92]. Non-absorbable disaccharides work as prebiotics to control the gut flora, have a laxative impact, and lower ammonia production. Furthermore, research on animals has demonstrated that lactulose may change cognitive performance by promoting neuroplasticity. According to recent research, probiotics can decrease harmful bacteria and boost healthy flora. Furthermore, research on animals have demonstrated that VSL#3 has strong anti-inflammatory properties that can both increase BA synthesis in the liver of mice and prevent mesenteric artery endothelial dysfunction[93]. According to clinical research, consuming VSL#3 can improve end-stage liver disease and Child-Turcotte-Pugh scores while also considerably lowering the chance of hospitalization for HE[94]. Rifaximin, on the other hand, is an antibiotic that cannot be absorbed. In addition to lowering blood soluble CD163 and mannose receptor levels and decreasing intestinal ammonia production by upregulating intestinal glutaminase expression, it also has therapeutic benefits by partially modifying the intestinal microbiota to lower endotoxemia[95]. According to Bajaj et al[96], FMT and rifaximin can also enhance MHE’s cognitive performance. The impact of FMT on HE and advanced cirrhosis is becoming increasingly apparent. According to clinical research, FMT can enhance intestinal dysbiosis and cognition while lowering the hospitalization rate for patients with cirrhosis and recurrent HE[97]. Additionally, FMT has demonstrated the ability to restore the alterations in BAs, SCFAs, and microbial diversity brought on by antibiotic use[98].

HCC

The effectiveness of immunotherapy against malignancies is known to be impacted by GM. Additionally, there is proof that intestinal microbiota and BAs encourage the development of hepatic and intestinal cancer. Because of their ability to convert primary BAs into secondary BAs through 7-α-dehydroxylation, members of the genus Clostridiales are frequently implicated in these activities[99]. It is hypothesized that a taurine-rich animal diet raises taurocholic acid levels in the liver and intestine, which in turn raises DCA levels in the intestine compared to a plant-based diet. This is because increased bile secretion from higher fat consumption causes taurocholic acid metabolism to rise. Taurocholic acid is metabolized by Bilophila wadsworthia to the genotoxin hydrogen sulfide and by Clostridium scindens to the tumor promoter DCA. A plant-based diet deficient in taurine results in lower fecal DCA levels and genotoxic hydrogen sulfide taurine metabolism[99].

Cholecystectomy may result in GM dysbiosis and changes the enterohepatic circulation of BAs and bile flow into the colon[100]. Intestinal dysbiosis is exacerbated by the absence of surfactant protein D, which is produced in the gallbladder[101]. Accordingly, the development of HCC in mice and nonalcoholic steatohepatitis patients has been linked to alterations in the makeup of GM implicated in BA metabolism. By analyzing stool and serum samples from patients with non-alcoholic steatohepatitis (NASH) non-HCC and NASH-HCC as well as healthy volunteers, Sydor et al[102] examined the GM and mediators of BA signaling in the presence or absence of cirrhosis. According to their findings, several bacterial taxa are involved in 7-dehydroxylation, oxidation/epimerization, and BA deconjugation. These groupings comprise the genera Bacteroides, Bifidobacterium, Lactobacillus, Ruminococcus, Clostridium, and Escherichia/Shighella that were found during microbiome investigation. While Bacteroides abundance was lowest in NASH-HCC without cirrhosis, Bifidobacterium and Bacteroides abundances were lower in NASH-non-HCC and NASH-HCC when compared to controls. The quantity of Lactobacillus increased gradually from controls to NASH-HCC with cirrhosis. In NASH-HCC without cirrhosis, the abundance of Ruminococcus rose, but that of Clostridium and Escherichia/Shighella did not alter.

CHANGES IN THE GM-LIVER AXIS IN THE LAST YEAR AND PUBLICATIONS THAT WILL INSPIRE THE FUTURE

Even though we briefly discussed the fundamental mechanisms, we are always learning more about the connection between the GM and liver axis. Plenty of investigation has been made possible by technological advancements, the growth of artificial intelligence modules, and our increasing body of knowledge. Between 2024 and 2025, 1376 papers, reviews, and meta-analyses on the topic of “gut microbiota and liver disease” were published in PubMed. Thirteen research explicitly contributed to the literature on the “gut microbiota and liver axis”, out of the 439 papers that were reported on the topic. While the studies focused more on animal experiments, the effects on MAFLD and the possible contribution of probiotics to treatment were reported. We wanted to briefly mention that these publications will have great significance in the future as hypotheses. In a mouse experimental study, Nie et al[103] created an enrichment strategy based on click chemistry. They discovered a number of BAs derived from microorganisms, such as the hitherto unidentified 3-succinylated CA (3-sucCA), which was negatively associated with liver damage in patients with mouse liver tissue biopsy-proven MAFLD. They discovered that strains of Bacteroides uniformis were strong makers of 3-sucCA both in vitro and in vivo by screening human bacterial isolates. Through activity-based protein purification and characterization, they discovered an enzyme in Bacteroides uniformis called β-lactamase that is in charge of 3-sucCA production. Additionally, they discovered that 3-sucCA is a lumen-restricted metabolite that, by encouraging the growth of Akkermansia muciniphila, reduces steatohepatitis linked to metabolic dysfunction. These findings offer fresh perspectives on the relationship between the GM and the liver that may help treat steatohepatitis brought on by metabolic imbalance (Figure 2).

Figure 2
Figure 2 The bile acid 3-succinylated cholic acid, which is produced from microorganisms, is identified via a click chemistry approach. The production of 3-succinylated cholic acid (3-sucCA) is mediated by Bacteroides uniformis-expressed bile acid acyl synthetase for succinyl. In patients with metabolic dysfunction-associated fatty liver disease, 3-sucCA has a negative correlation with liver damage 3-sucCA reduces metabolic dysfunction-associated steatohepatitis in mice by encouraging the growth of Akkermansia muciniphila. 3-sucCA: 3-succinylated cholic acid; BAS-suc: Bile acid acyl synthetase for succinyl; MAFLD: Metabolic dysfunction-associated fatty liver disease; MASH: Metabolic dysfunction-associated steatohepatitis. Citation: Nie Q, Luo X, Wang K, Ding Y, Jia S, Zhao Q, Li M, Zhang J, Zhuo Y, Lin J, Guo C, Zhang Z, Liu H, Zeng G, You J, Sun L, Lu H, Ma M, Jia Y, Zheng MH, Pang Y, Qiao J, Jiang C. Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway. Cell 2024; 187: 2717-2734.e33. Copyright © 2024 The Authors. Published by Elsevier Inc.

Yu et al’s study[104] added to the body of knowledge by indicating that altered GM may damage the intestinal barrier and cause inflammatory cytokines; that direct or indirect inhibition of the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation may reduce the inflammatory response in MASLD. And that modifying the gut-microbiota-liver axis through the NLRP3 inflammasome may be a novel therapeutic strategy for MASLD patients. Searching at this information in a broader sense, pathogen-associated molecular patterns and damage-associated molecular patterns can communicate danger signals that activate the NLRP3 inflammasome, a well-known member of the pattern recognition receptor family. The inflammatory cytokines IL-1β and IL-18 are produced when MASLD activates the NLRP3 inflammasome pathway. Changes in the GM’s composition and metabolites occur in MASLD, and the disturbed GM may also release the inflammatory cytokines IL-1β and IL-18, which worsen MASLD by rupturing the intestinal barrier and negatively regulating the liver through the gut-liver axis. Changes in the GM’s composition and metabolites occur in MASLD, and the disturbed GM may also release the inflammatory cytokines IL-1β and IL-18, which worsen MASLD by rupturing the intestinal barrier and negatively regulating the liver through the gut-liver axis. Consequently, a novel therapeutic strategy for MASLD patients may involve NLRP3 inflammasome-mediated modulation of the gut-microbiota-liver axis. The inflammatory cytokines IL-1β and IL-18 are produced when MASLD activates the NLRP3 inflammasome pathway. Changes in intestinal microbiota composition and metabolites occur in MASLD, and the disturbed microbiota can also produce inflammatory cytokines, such as IL-1β and IL-18, which can damage the intestinal barrier, negatively regulate the liver through the gut-liver axis, and exacerbate MASLD. Herbal extracts are currently the most effective medicinal ingredients utilized in studies examining how GM regulates the NLRP3 inflammasome response. These studies mostly concentrate on the in vitro and animal model phases and lack enough clinical efficacy data. Furthermore, because of the variability of metabolic syndrome and variations in research methodologies and data processing, alterations in the intestinal microbiota of MASLD patients continue to be somewhat disputed. Additionally, attention and research on the NLRP3 inflammasome, intestinal microbiota, and metabolites are necessary because the intestinal microbiota of MASLD model animal groups is susceptible to external environmental influences and the structure of the intestinal microbiota regulated by the NLRP3 inflammasome has not been fully characterized. It can further strengthen the gut-microbiota-liver balance, which is suitable for the prevention and treatment of MASLD, by establishing appropriate therapeutic measures, such as dietary modification, probiotic-prebiotic-synbiotic modulation, healthy FMT, and the use of small molecule compounds to restore GM diversity. Clarifying the interactions and cross-talks between the GM and the NLRP3 inflammasome in MASLD is therefore essential. The GM-liver-brain axis refers to the reciprocal relationship between the gut and GM, the liver, and the central nervous system. Indeed, GM impacts not only intestinal homeostasis but also the liver, brain, and other organs both inside and outside the gastrointestinal tract.

In a multidisciplinary animal investigation, Giommi et al[105] included data from metagenomic and metabolomic analysis, immunohistopathological and histopathology examinations, and both male and female zebrafish. In addition, they analyzed the potential beneficial effects of probiotics on mitigating these harmful effects and improving overall organismal health. They noted the detrimental impacts of bisphenol A (BPA) on organismal health and underlined the pressing need to develop novel approaches to both lessen the toxicant’s presence and mitigate its negative consequences. Given that they support organismal well-being, probiotics have become a viable tool in this regard. This transdisciplinary study uses zebrafish as a model to examine the effects of SLAB51 food treatment to reverse BPA toxicity. During the 28-day exposure to an environmentally appropriate BPA dose (10 μg/L, BPA) through water, a food treated with SLAB51 (109 CFU/g body weight, P), and a co-treatment with BPA and SLAB51 (BPA + P), adult males and females were housed under standard conditions (control group, C). Both males and females experienced architectural changes in their intestines as a result of BPA exposure. Pathogenic bacterial species were also more prevalent in females. As BPA and P were administered together, the natural intestinal architecture was restored, the colonization of helpful bacteria was encouraged, and the number of harmful species was decreased. Co-administration of SLAB51 partly mitigated the steatosis and glycogen depletion in the liver produced by male BPA exposure. On the other hand, the absence of steatosis and increased glycogen depletion in females exposed to BPA indicated a rise in energy demand that was corroborated by the metabolomic phenotype. The opposite effect of BPA-induced brain histopathological damage may be explained by the higher anserine and lower glutamine levels found in the liver metabolites of BPA + P males. In BPA + P females, a decrease in retinoic acid was found in the liver, suggesting an increase in retinoids responsible for BPA detoxification. All things considered, these findings showed that SLAB51 efficiently lowers the pleiotropic toxicity of BPA and has positive effects on the GM-brain-liver axis via many molecular pathways.

A substantial portion of the worldwide burden of non-viral liver disease is caused by alcoholic liver injury (ALI). Research on using fruit flavonoids as a treatment is accelerating in the absence of specific medications. Chen et al[106] examined the hepatoprotective properties of four fruits that are rich in structurally diverse flavonoids in a mouse experimental study: Turnjujube (Hovenia dulcis Thunb.), mulberry (Morus alba L.), apple (Malus domestica Borkh.), and ougan (Citrus reticulatacv. Suavissima). Utilizing ultra-performance liquid chromatography analysis, they discovered a dihydroflavonol, three polymethoxyflavones, two anthocyanins, a flavonol glycoside, and a total flavanone glycoside. For three weeks, C57BL/6J mice were administered 200 mg/kg bodyweight/day of several fruit extracts in a mouse model of acute ethanol-induced ALI. Based on the study’s findings, the four extracts demonstrated encouraging advantages in reducing oxidative stress, iron excess, and problems of lipid metabolism. The results of reverse transcription-polymerase chain reaction and Western blot studies, the possible mechanism may be partly explained by the suppression of ferroptosis pathways and the stimulation of the nuclear factor-erythroid 2 related factor 2-mediated antioxidant response. Additionally, when fruit extracts were administered, beneficial bacteria including Dubosiella, Lactobacillus, and Bifidobacterium increased, indicating a particular regulatory role in intestinal microecology. Strong relationships between intestinal flora, lipid metabolism, and iron homeostasis were found by Spearman correlation analysis, suggesting that the fruit extracts decreased ALI through the GM-liver axis. In vitro tests demonstrated the beneficial benefits of flavonoid components and confirmed the efficacy against ethanol-induced oxidative damage. These results provided credence to the potential use of ougan, mulberry, apple, and turnjujube as dietary supplements or innovative ALI therapies. The primary way that fruit extracts from ougan, mulberry, and apple may lessen alcoholic liver damage is by activating ferroptosis resistance and nuclear factor-erythroid 2 related factor 2-mediated antioxidant responses. They can also alter the composition and function of intestinal microbiota, and flavonoids may be a key component of these extracts’ therapeutic potential.

Qi et al[107] investigated the effects of Cistanche tubulosa (CPhGs) on the “gut-liver axis” in rats by looking at intestinal microbiota, intestinal barrier, and systemic LPS levels in order to elucidate their roles in liver fibrosis. This study examined the impact of phenylethanol glycoside derived from CPhGs on preventing rats from developing hepatic fibrosis brought on by bovine serum albumin. The impact of CPhGs on “gut-liver” regulation, which includes intestinal microbiota, intestinal barrier, systemic LPS concentration, and LPS-related signaling pathway, has been the focus of research into the mechanisms underlying the anti-hepatic fibrosis effect. The findings demonstrated that in fibrotic rats, CPhGs improved the relative abundance of Bacteroidetes, lowered the relative abundance of Firmicutes and Proteobacteria, and restored the variety of intestinal microbiota. Additionally, in the intestines of these rats, CPhGs encouraged the enrichment of probiotics like Blautia, Oscillospira, Ruminococcus, Odoribacter, Bacteroides, and Parabacteroides. Furthermore, by boosting the expression of ZO-1, occludin, and E-cadherin, CPhGs have been demonstrated to lessen histological damage in the intestine and repair the tight junctions of the intestine. The LPS-TLR4/myeloid differentiation primary response 88/NF-κB pathway, which was linked to liver protein expression, was demonstrated to be inhibited by CPhGs, which also successfully decreased blood LPS and liver LPS binding protein levels. While LPS and harmful bacteria were positively related with liver damage, correlation analysis verified that these helpful bacteria were adversely connected with pathological damage. The GM has a significant role in the development of the disease, and CPhGs are helpful in the prevention and management of hepatic fibrosis, according to FMT experience. They showed that control of the “gut-liver” axis mediates the anti-hepatic fibrosis mechanism of CPhGs. This result may stimulate research into their potential for clinical use.

Yang et al[108] showed that the machine learning model based on the alcohol-GM-liver axis is a useful tool for the diagnosis, identification and prognosis of HCC compared to traditional models in predicting the occurrence of early-stage HCC. As early-stage HCC is hard to predict, eight machine learning models based on this axis were used to increase its accuracy. Models for predictions were created using machine learning techniques. Eight machine learning models were developed using the GM-liver axis, alcohol consumption, alcohol consumption, “Genus: Enterococcus”, “Genus: Erysipelatoclostridium”, “Genus: Lactobacillus”, “Genus: Catenibacterium”, “Genus: Tyzzerella_4”, “Genus: Enterococcus_faecium”, “Family: Enterococcaceae”, and “Family: Leuconostocaceae”. The levels of “Species_Lactobacillus” and “Species_Tyzzerella_4” in the human body were created to forecast the occurrence of early-stage HCC. The prediction performance of all machine learning models ranged from mediocre to outstanding. The XGBoost model was thoroughly explained using the Shapley additive explanations model, which demonstrated the primary influence of Genus Erysipelatoclostridium on this high-performing prediction model. The association between alcohol use and the development of early-stage HCC was revealed to be partially mediated by “Genus_Catenibacterium”, “Genus_Tyzzerella_4”, and “Species_Tyzzerella_4” by mediation effect analysis. It was demonstrated that the alcohol drinking-GM-liver axis has a major role in predicting the occurrence of early-stage HCC by integrating clinical risk factors with the axis found by univariate/multivariate logistic analysis.

In the review by Kandalgaonkar et al[109], the liver is described as an “organ within an organ” because it is supported by the GM and is physiologically and pathologically affected by the metabolic effects of the microbiota. The liver receives all nutrients that have been absorbed by the small intestine for additional processing. The GM further breaks down undigested food as it enters the colon, creating secondary metabolites that are taken up by the portal circulation and eventually make their way to the liver. Ammonia, hydrogen sulfide, SCFAs, secondary BAs, and TMAO are some of the metabolites and co-metabolites that are produced by the microbiota. Furthermore, the liver generates a number of substances, including BAs, which can change the makeup of gut microbes and hence impact liver function. Liver diseases such cirrhosis, MAFLD, GM dysbiosis, and portosystemic shunt frequently upset the symbiosis. A shift in BA levels or profiles as well as notable alterations in the mix of gut microbes can occur from the consequent decline in liver function. This could exacerbate liver damage and drastically change the equilibrium of secondary metabolites arising from the gut flora. As a result, a popular theory in recent years is that resolving dysbiosis could reduce liver damage and boost the synthesis of beneficial metabolites. Though the importance of a healthy microbiota for health has been acknowledged by numerous studies, it is unclear what makes up this “perfect microbiome” and it has been proposed that it varies from person to person. Dietary modifications, probiotic and prebiotic use, and FMT can all alter the GM. A customized GM and altered nutrition may result in intestinal eubiosis and, thus, an improved quality of life. To characterize the intricate relationship between the GM and the liver’s metabolism of metabolites and to create therapies for liver illness, more thorough research is necessary. In mice with autoimmune hepatitis, Kang et al[110] demonstrated that synbiotics might reduce pyroptosis and inflammation in the liver, improving liver function and mitigating liver damage. They demonstrated that synbiotics preserved the integrity of the intestinal barrier while also reversing intestinal dysbiosis by boosting helpful bacteria and lowering gram-negative bacteria that contain LPSs. By blocking the TLR4/NF-κB/NLRP3/pyroptosis signaling pathway in the liver, the underlying mechanism was linked to altering the composition of the intestinal microbiota and the function of the intestinal barrier.

Lamas-Paz et al[111] assessed the gut-liver axis’s sex-specific effects of alcohol exposure and the GM’s function in regulating sex-specific reactions to alcohol intake in a mouse study. Male and female C57BL/6 mice aged 52 weeks were given a single oral dosage of ethanol (6 g/kg) after they had fasted for 12 hours. Instead, 52-week-old male mice from age-matched female donors underwent FMT. Age-matched female mice displayed increased intestinal permeability but partially preserved intestinal barrier integrity, while middle-aged male mice exposed to ethanol demonstrated a significant increase in intestinal permeability in the large intestine as measured by the fluorescein isothiocyanate-dextran assay and ZO-1, occludin, and mucin 2 immunostaining when compared to phosphate buffered saline-treated animals. Additionally, TLRs and indicators of hepatocellular damage, cell death (aspartate aminotransferase, TUNEL-positive cells), and lipid accumulation (oil red O) were significantly upregulated in male mice following ethanol exposure. It's interesting to note that FMT from female donors to male mice decreased middle-aged mice’s aging phenotype, intestinal leakage, altered GM composition, liver damage and inflammation, and TLR activation. This study demonstrated how gender plays a significant role in the gut-liver axis in middle-aged people who have consumed alcohol. The study also showed that gender-specific microbiota transplantation might be a viable treatment for aging-related alcohol-related problems.

The food business uses a lot of pesticides these days to boost and simplify production. These medications have effects on the GM and GM-liver axis in addition to their beneficial effects. Through the gut-liver axis, Li et al[112] examined how exposure to the herbicide/pesticide terbuthylazine damages intestinal flora and exacerbates mitochondrial quality control and panapoptosis in hepatocytes. They demonstrated that exposure to terbuthylazine damages the jejunal barrier significantly by reducing the expression of ZO-1 and occludin. Additionally, they demonstrated that terbuthylazine disrupts the GM, as seen by an increase in Nitrospirota, Chloroflexi, Desulfobacterota, Crenarchaeota, Myxococcota, and Planctomycetota and a decrease in Firmicutes. According to RNA-seq study, intestinal microbiota disorders impacted hepatocyte cell proliferation and death as well as lipid metabolism. Furthermore, terbuthylazine may cause an imbalance in the quality control of the mitochondria, which could include redox disorders, decreased activity of mitochondrial fusion and biogenesis, and an increase in mitophagy. Terbuthylazine was then found to dramatically raise the expression levels of proteins linked to necroptosis, apoptosis, and pyroptosis. All things considered, these findings point to the fundamental processes by which terbuthylazine causes hepatotoxicity through the gut-liver axis and can be used to examine how other pesticides affect GM and the gut-liver axis. The inhibitory impact of berberine alkaloid, which is present in many plants, on HCC in mice was examined by Shou et al[113]. This study is the first to show that berberine’s anti-HCC action is mediated by the liver-GM-peroxisome proliferator-activated receptors delta triad. They demonstrated that berberine stimulates the synthesis of BA generated from GM in addition to directly activating peroxisome proliferator-activated receptors delta to cause apoptotic death.

In order to successfully treat ALD, Yin et al[114] used probiotic-postbiotic intervention techniques to preserve intestinal homeostasis in a mouse trial. Here, mice models of ALD were used to show how well heat-killed Lactobacillus johnsonii (L. johnsonii) reduced ALI. One important mechanism for L. johnsonii’s protective actions against ALD was shown to be the gut-liver axis. In particular, it was shown that heat-killed L. johnsonii activates the innate immune axis of nucleotide-binding oligomerization domain 2, IL-23 and IL-22 via upregulating the expression of intestinal lysozymes, which in turn increases the generation of immune regulatory chemicals from intestinal bacteria. By stimulating the liver’s signal transducer and activator of transcription 3 pathway, elevated IL-22 promoted the production of antimicrobial peptides to preserve intestinal homeostasis and aid in the healing of liver damage. The reduction of ethanol-induced butyrate-producing bacteria (like Faecalibaculum rodentium) and the spread of opportunistic pathogens (like Helicobacter sp. and Pichia kudriavzevii) were both reversed by heat-killed L. johnsonii-induced immunity, which they found helped correct GM dysbiosis. These results offer fresh perspectives on the gut-liver axis that may help treat ALD more effectively.

This study assessed GM’s role in the onset of liver disorders and its impact on the advancement of pre-existing chronic liver disease from a variety of angles and presented the results clearly. The relationship between intestinal health and liver function is highlighted by the gut-liver axis. Changes in GM can impact a variety of liver illnesses, including as MAFLD, ALD, HE, and HCC. Clinical applications that enhance diagnosis, prognosis, and treatment aim to target this axis. The processes and phenotypes of liver disease are revealed via GM analysis. Human-sourced probiotics, synbiotics, and food supplements that include alkaloid-like compounds have the potential to be used as therapies via altering BA signaling and fecal transit[115]. Despite inspiring the future, there is still a lack of safety evaluation evidence for these therapy approaches. In order to bridge the gap between clinical application and animal models and stop the course of early liver disease, more research is required to guarantee their safety and effectiveness. The most important limiting factors in our review are the existence of unknown mechanisms and interactions, even if the existing data in the literature and new data are synthesized. We know that GM is affected by the environment, bacterial metabolism, host metabolism, host chronic diseases, drugs, water and many other conditions. Although we know that these unidentified interactions exist, original multi-center studies and meta-analyses are needed to define them.

CONCLUSION

In the pathophysiology of chronic liver disease, despite all the unknowns, the interaction between microbiota and host, including microbiota, metabolites, and host metabolism, has proven to have a strong connection and the existence of the GM-liver axis. In addition, many animal and human experiments have suggested that antibiotics, FMT, probiotics, BA sequestrants, and selectively increasing and decreasing certain microbiota, which may have a positive effect on this complex pathophysiological process, may be an alternative treatment approach. However, most of the current studies have a very low level of evidence due to the unknown level of microbial species abundance, their roles in maintaining immune tolerance, as well as drug selection, duration of use, bile permeability, and availability not yet being well understood in these treatment models. Therefore, it is obvious that with the increase in technology and cumulative knowledge, various artificial intelligence modules can be integrated into studies to determine the pathophysiological mechanisms and undiscovered elements of therapeutic models resulting from the interaction between GM and the host, and clinical research can be improved and personalized treatment algorithms and models can be created.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Corresponding Author's Membership in Professional Societies: Turkish Society of Gastroenterology.

Specialty type: Gastroenterology and hepatology

Country of origin: Türkiye

Peer-review report’s classification

Scientific Quality: Grade A, Grade C, Grade C, Grade D

Novelty: Grade B, Grade B, Grade C, Grade C

Creativity or Innovation: Grade B, Grade B, Grade C, Grade C

Scientific Significance: Grade B, Grade B, Grade B, Grade C

P-Reviewer: Ma JY; Maslennikov R; He JJ S-Editor: Wei YF L-Editor: A P-Editor: Zhao YQ

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