Background/Objectives: Chronic alcohol overconsumption triggers alcohol liver injury, and therapeutic strategies targeting alcohol-triggered oxidative stress and hepatic inflammatory responses represent potential approaches to ameliorating alcohol-related hepatotoxicity. This study aimed to determine the hepatoprotective activity of finger citron essential oil (FCEO) in alcoholic liver disease (ALD)-afflicted rats and explore its underlying mechanisms. In order to identify the effective components, we compared the effects of FCEO and D-limonene. Methods: The regulatory effects of FCEO on metabolic enzymes were systematically evaluated through in vitro experiments. In vivo studies were conducted to investigate and compare the hepatoprotective effects of FCEO and D-limonene. Staining methods, assay kits, and Western Blot were used to determine the roles of FCEO and D-limonene in the ALD rats. Results: We found that FCEO downregulated phase I metabolic enzymes and upregulated phase II metabolic enzymes in Buffalo Rat Liver-3A (BRL-3A) cells. FCEO and/or D-limonene intervention reduced transaminase levels in ALD rats and effectively alleviated inflammatory cell infiltration and lipid droplet accumulation in their liver tissue. Additionally, FCEO and D-limonene played a regulatory role in oxidative stress and inflammation-related pathways such as the MAPK/Nrf2 and NF-κB/AMPK pathways. FCEO was superior to D-limonene as an antioxidant in alleviating alcoholic liver injury. Conclusions: This study revealed the alleviative effects and mechanisms of FCEO on alcoholic liver injury, demonstrating better efficacy compared to its monomer, thus providing a strategy for the development and utilization of finger citron resources.

Accumulation of hydrophobic bile acids (BAs) is linked with cancer development. However, derivatives of deoxycholic acid (DCA) and lithocholic acid (LCA) produced via bacterial metabolism may mitigate the proinflammatory and cytotoxic effects of hydrophobic BAs. The impact of diet on secondary BA derivative production has not been determined.

This study aimed to study the associations between BA-modulating nutrients and the composition of secondary BAs and their derivatives.

Stool and blood were collected from 138 participants aged 45-75 y that self-identified as Black or non-Hispanic White. BAs were extracted from stool and serum and quantified using LC/ESI-MS/MS. Energy, macronutrients, micronutrients, and specific dietary nutrients were estimated from two 24-h diet recalls. The abundance of genes for microbial BA metabolism was assessed from stool metagenomes. Kendall τ correlation and regression-based modeling were performed to determine associations between BA categories, microbial genes, and select energy-adjusted dietary variables (alcohol, calcium, coffee, fiber, fat, and protein).

Participants had a mean age of 60 y and a mean BMI of 31 kg/m2. BA derivatives were present in all participant stools, with lagodeoxycholic acid being the most abundant derivative quantified. Analysis of stool microbial metagenomes revealed the presence of genes for secondary BA derivative production in all participants. Protein is positively associated with the accumulation of secondary BAs. monounsaturated fatty acids (MUFA)s were negatively associated with high abundant derivatives of DCA in regression models. Total fiber and coffee intake were positively correlated with increased conversion of BAs to derivatives. Race and smoking status were significant predictors of associations between dietary variables and BA derivatives.

Protein, MUFAs, total fiber and coffee are significantly associated with concentrations of secondary BAs and their derivatives. Future work should account for social and structural influences on dietary intake and its relationship with BA-elicited cancer risk.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition marked by excessive lipid accumulation in hepatic tissue. This disorder can lead to a range of pathological outcomes, including metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Despite extensive research, the molecular mechanisms driving MASLD initiation and progression remain incompletely understood. Oxidative stress and lipid peroxidation are pivotal in the "multiple parallel hit model", contributing to hepatic cell death and tissue damage. Gut microbiota plays a substantial role in modulating hepatic oxidative stress through multiple pathways: impairing the intestinal barrier, which results in bacterial translocation and chronic hepatic inflammation; modifying bile acid structure, which impacts signaling cascades involved in lipidic metabolism; influencing hepatocytes' ferroptosis, a form of programmed cell death; regulating trimethylamine N-oxide (TMAO) metabolism; and activating platelet function, both recently identified as pathogenetic factors in MASH progression. Moreover, various exogenous factors impact gut microbiota and its involvement in MASLD-related oxidative stress, such as air pollution, physical activity, cigarette smoke, alcohol, and dietary patterns. This manuscript aims to provide a state-of-the-art overview focused on the intricate interplay between gut microbiota, lipid peroxidation, and MASLD pathogenesis, offering insights into potential strategies to prevent disease progression and its associated complications.

Malnutrition is prevalent, detrimental, and associated with worse outcomes, including higher rates of hospitalization, morbidity, and mortality. In this review article, we aimed to define malnutrition in patients with chronic liver disease (CLD), elucidate the pathogenesis of malnutrition, discuss the advantages and disadvantages of current screening methods, and highlight the latest evidence-based dietary recommendations. Emerging evidence suggests that CLD-specific tools such as the Liver Disease Undernutrition Screening Tool and the Royal Free Hospital-Nutritional Prioritizing Tool can accurately identify patients at high risk for malnutrition and should be used in conjunction with more standard tools such as subjective global assessments. The pathogenesis of malnutrition in CLD is multifactorial but seems to arise in large from altered metabolism, namely a reduction in protein synthesis and an increase in resting energy expenditure. However, decreased nutrient intake, impaired nutrient absorption and increased nutrient losses have also been shown to contribute. Key findings in this review argue against protein-restricted diets in patients with CLD and support the use of plant-based proteins over dairy and meat proteins for those with liver cirrhosis complicated by hepatic encephalopathy. Frequent small meals are recommended in patients with liver cirrhosis in addition to the avoidance of prolonged fasts >12 hours due to their hypercatabolic state. CLD covers a wide spectrum of diseases, and this review calls for an individualized approach to addressing the specific nutritional needs, depending on the etiology of CLD, its severity, associated complications, and comorbid conditions. This can be best achieved by close, longitudinal follow-up with a multidisciplinary team including a registered dietitian who can obtain a comprehensive, accurate nutritional assessment.

The global incidence and mortality rates of alcohol-related liver disease are on the rise, reflecting a growing health concern worldwide. Alcohol-related liver disease develops due to a complex interplay of multiple reasons, including oxidative stress generated during the metabolism of ethanol, immune response activated by immunogenic substances, and subsequent inflammatory processes. Recent research highlights the gut microbiota's significant role in the progression of alcohol-related liver disease. In patients with alcohol-related liver disease, the relative abundance of pathogenic bacteria, including Enterococcus faecalis, increases and is positively correlated with the level of severity exhibited by alcohol-related liver disease. Supplement probiotics like Lactobacillus, as well as Bifidobacterium, have been found to alleviate alcohol-related liver disease. The gut microbiota is speculated to trigger specific signaling pathways, influence metabolite profiles, and modulate immune responses in the gut and liver. This research aimed to investigate the role of gut microorganisms in the onset and advancement of alcohol-related liver disease, as well as to uncover the underlying mechanisms by which the gut microbiota may contribute to its development. This review outlines current treatments for reversing gut dysbiosis, including probiotics, fecal microbiota transplantation, and targeted phage therapy. Particularly, targeted therapy will be a vital aspect of future alcohol-related liver disease treatment. It is to be hoped that this article will prove beneficial for the treatment of alcohol-related liver disease.

The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.

Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence and severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation is a well-established key factor, recent evidence highlights the critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced liver injury. This review provides a comprehensive analysis of the complex interactions within the hepatic microenvironment in ALD. It examines the contributions of both parenchymal cells, like hepatocytes, and non-parenchymal cells, such as hepatic stellate cells, Kupffer cells, neutrophils, and liver sinusoidal endothelial cells, in driving the progression of the disease. Additionally, we explored the involvement of key mediators, including cytokines, chemokines and inflammasomes, which regulate inflammatory responses and promote liver injury and fibrosis. A particular focus has been placed on extracellular vesicles (EVs) as essential mediators of intercellular communication both within and beyond the liver. These vesicles facilitate the transfer of signalling molecules, such as microRNAs and proteins, which modulate immune responses, fibrogenesis and lipid metabolism, thereby influencing disease progression. Moreover, we underscore the importance of organ-to-organ crosstalk, particularly in the gut-liver axis, where dysbiosis and increased intestinal permeability lead to microbial translocation, exacerbating hepatic inflammation. The adipose-liver axis is also highlighted, particularly the impact of adipokines and free fatty acids from adipose tissue on hepatic steatosis and inflammation in the context of alcohol consumption.

Probiotics can alleviate alcoholic liver disease. However, whether inactive counterparts can produce similar outcomes requires further investigation. We investigated the effects of viable (V) and dead (D) Lactobacillus paracasei CCFM1120 on alcohol-induced ALD mice. The results showed that CCFM1120V and D ameliorated the disease symptoms and intestinal injury. Specifically, these interventions strengthened the intestinal barrier, as evidenced by the increased expression of ZO-1 (zonula occludens 1), occludin, and claudin-1 in the colon and the restored ileal microstructure, including the villi and crypts. In addition, they enhanced the antioxidant capacity of the liver by reducing the production of malondialdehyde and increasing the levels of glutathione and superoxide dismutase. The activation of Nrf2 and HO-1 may be responsible for recovering the antioxidant capacity. Interventions can decrease mouse TNF-α, IL-6 and IL-1β content in serum, probably through the TLR4/MyD88/NF-κB pathway. Furthermore, they possess the ability to restore the quantities of bacteria responsible for producing butyric acid, such as Lactobacillus, Blautia, Bifidobacterium, Ruminococcaceae, Faecalibaculum and Lachnospiraceae. Taken together, CCFM1120V and D apparently can modify the composition of the gut microbiota, foster the gastrointestinal equilibrium, fortify the intestinal barrier, augment the antioxidant capacity of the liver, and effectively shield it from ethanol-induced injury.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.

The application of rifaximin, a non-absorbable antibiotic, in hepatic encephalopathy (HE) has been well established; however, its effect on other complications in cirrhotic patients with previous gastroesophageal variceal bleeding (GEVB) remains unclear. Therefore, we performed a pilot randomized controlled trial aiming to evaluate the impact of rifaximin on cirrhosis-related complications and changes in gastric microbiota.

Eighty cirrhotic patients who received prophylactic endoscopic treatment for variceal rebleeding were randomly assigned to the control or rifaximin treatment group (rifaximin 400 mg twice daily for 8 weeks). Primary outcome was the total liver-related score, consisting of changes in cirrhosis-related complications including rebleeding, ascites, HE and portal vein thrombosis (PVT). The 16S rDNA sequencing analysis was conducted with gastric lavage fluid samples for the analysis of gastric microbiota.

During the 8-week follow-up, the total liver-related score decreased significantly upon rifaximin therapy (-0.35 ± 0.14 vs 0.05 ± 0.14, p = 0.0465) as well as serum C-reactive protein (CRP) (p = 0.019) and interleukin-8 (p = 0.025) compared with the control group. The rate of PVT recanalization was significantly higher in the rifaximin group (p = 0.012). Prominent difference in gastric microbiota between the two groups was observed, and the rifaximin group had a higher abundance of several taxa which were dysregulated in the progression of cirrhosis. CRP was correlated with several taxa including Alphaproteobacteria, Rhizobiales and Collinsella.

Rifaximin may improve cirrhosis-related complications, including PVT, in patients with previous GEVB through anti-inflammatory and microbiota-modulating functions.

NCT02991612.

Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism.

BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study.

We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia.

Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.

The gut microbiome exerts metabolic actions on distal tissues and organs outside the intestine, partly through microbial metabolites that diffuse into the circulation. The disruption of gut homeostasis results in changes to microbial metabolites, and more than half of the variance in the plasma metabolome can be explained by the gut microbiome. Ethanol is a major microbial metabolite that is produced in the intestine of nearly all individuals; however, elevated ethanol production is associated with pathological conditions such as metabolic dysfunction-associated steatotic liver disease and auto-brewery syndrome, in which the liver's capacity to metabolize ethanol is surpassed. In this Review, we describe the mechanisms underlying excessive ethanol production in the gut and the role of ethanol catabolism in mediating pathogenic effects of ethanol on the liver and host metabolism. We conclude by discussing approaches to target excessive ethanol production by gut bacteria.

Patients with cirrhosis have intestinal barrier dysfunction but the role of the individual cell types in human small intestine is unclear. We performed single-nuclear RNA sequencing (snRNAseq) in the pinch biopsies of terminal ileum of four age-matched men [56 years, healthy control, compensated, early (ascites and lactulose use) and advanced decompensated cirrhosis (ascites and rifaximin use)]. Cell type proportions, differential gene expressions, cell-type specific pathway analysis using IPA, and cellular crosstalk dynamics were compared. Stem cells, enterocytes and Paneth cells were lowest in advanced decompensation. Immune cells like naive CD4 + T cells were lowest while ITGAE + cells were highest in advanced decompensation patients. MECOM had lowest expression in stem cells in advanced decompensation. Defensin and mucin sulfation gene (PAPSS2) which can stabilize the mucus barrier expression were lowest while IL1, IL6 and TNF-related genes were significantly upregulated in the enterocytes, goblet, and Paneth cells in decompensated subjects. IPA analysis showed higher inflammatory pathways in enterocytes, stem, goblet, and Paneth cells in decompensated patients. Cellular crosstalk analysis showed that desmosome, protease-activated receptors, and cadherin-catenin complex interactions were most perturbed in decompensated patients. In summary, the snRNAseq of the human terminal ileum in 4 subjects (1 control and three cirrhosis) identified multidimensional alteration in the intestinal barrier with lower stem cells and altered gene expression focused on inflammation, mucin sulfation and cell-cell interactions with cirrhosis decompensation.

Minimal hepatic encephalopathy (MHE) negatively affects the prognosis of cirrhosis, but treatment is not standard. Rifamycin SV MMX (RiVM) is a nonabsorbable rifampin derivative with colonic action.

In a phase 2 placebo-controlled, double-blind randomized clinical trial patients with MHE were randomized to RiVM or placebo for 30 days with a 7-day follow-up. The primary endpoint was a change in stool cirrhosis dysbiosis ratio. Gut-brain (cognition, stool/salivary microbiome, ammonia, brain magnetic resonance spectroscopy), inflammation (stool calprotectin/serum cytokines), patient-reported outcomes (sickness impact profile: total/physical/psychosocial, high = worse), and sarcopenia (handgrip, bioelectric impedance) were secondary. Between/within groups and delta (post-pre) comparisons were performed.

Thirty patients (15/group) were randomized and completed the study without safety concerns. While cirrhosis dysbiosis ratio was statistically similar on repeated measures ANOVA (95% CI: -0.70 to 3.5), ammonia significantly reduced (95% CI: 4.4-29.6) in RiVM with changes in stool microbial α/β-diversity. MHE status was unchanged but only serial dotting (which tests motor strength) improved in RiVM-assigned patients. Delta physical sickness impact profile (95% CI: 0.33 = 8.5), lean mass (95% CI: -3.3 to -0.9), and handgrip strength (95% CI: -8.1 to -1.0) improved in RiVM versus placebo. Stool short-chain fatty acids (propionate, acetate, and butyrate) increased post-RiVM. Serum, urine, and stool bile acid profile changed to nontoxic bile acids (higher hyocholate/ursodeoxycholate and lower deoxycholate/lithocholate) post-RiVM. Serum IL-1β and stool calprotectin decreased while brain magnetic resonance spectroscopy showed higher glutathione concentrations in RiVM.

RiVM is well tolerated in patients with MHE with changes in stool microbial composition and function, ammonia, inflammation, brain oxidative stress, and sarcopenia-related parameters without improvement in cognition. RiVM modulates the gut-brain axis and gut-muscle axis in cirrhosis.

The gut-liver axis refers to the intimate relationship and rigorous interaction between the gut and the liver. The intestinal barrier's integrity is critical for maintaining liver homeostasis. The liver operates as a second firewall in this interaction, limiting the movement of potentially dangerous compounds from the gut and, as a result, contributing in barrier management. An increasing amount of evidence shows that increased intestinal permeability and subsequent bacterial translocation play a role in liver damage development. The major pathogenic causes in cirrhotic individuals include poor intestinal permeability, nutrition, and intestinal flora dysbiosis. Portal hypertension promotes intestinal permeability and bacterial translocation in advanced liver disease, increasing liver damage. Bacterial dysbiosis is closely related to the development of cirrhosis and its related complications. This article describes the potential mechanisms of dysbiosis in liver cirrhosis and related complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma, using dysbiosis of the intestinal flora as an entry point.

The gut microbiome and its metabolites are involved in developing and progressing liver disease. Various liver illnesses, such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis C, and hepatocellular carcinoma, are made worse and have worse prognoses with aging. Dysbiosis, which occurs when the symbiosis between the microbiota and the host is disrupted, can significantly negatively impact health. Liver disease is linked to qualitative changes, such as an increase in hazardous bacteria and a decrease in good bacteria, as well as quantitative changes in the overall amount of bacteria (overgrowth). Intestinal gut microbiota and their metabolites may lead to chronic liver disease development through various mechanisms, such as increasing gut permeability, persistent systemic inflammation, production of SCFA, bile acids, and alteration in metabolism. Age-related gut dysbiosis can disrupt the communication between gut microbiota and the host, impacting the host's health and lifespan. With aging, a gradual loss of the ability to maintain homeostasis because of structural alteration and gut dysbiosis leads to the disease progression in end-stage liver disease. Recently chronic liver disease has been identified as a global problem. A large number of patients are receiving liver transplants yearly. Thereby gut microbiome ecology is changing in the patients of the gut due to the changes in pathophysiology during the preoperative stage. The present review summarises the age-associated dysbiosis of gut microbial composition and its contribution to chronic liver disease. This review also provides information about the impact of liver transplant on the gut microbiome and possible disadvantageous effects of alteration in gut microbiota.

Alcoholic liver disease (ALD) is the leading cause of liver-related deaths worldwide. Kefir has been studied for its properties of anti-obesity, rebuilding intestinal homeostasis, and alleviating non-alcoholic fatty liver disease. However, the possible role of kefir in the prevention or treatment of ALD has not been carefully considered. Here, it evaluated the protective effects of kefir supplementation on alcohol-induced liver injury.

C57BL/6J mice are fed to Lieber-DeCarli liquid diet containing alcohol to build ALD mouse model, followed by oral administration with kefir. Results indicate that kefir treatment improves liver pathological changes, decreases the expression levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and inflammatory markers, and increases antioxidant levels. Kefir supplementation also restores the intestinal barrier and altered microbial composition, indicates as increases of Blautia, Bacteroides, and Parasutterella and decreases in the Firmicutes/Bacteroidetes (F/B) ratio and populations of Psychrobacter, Bacillus, and Monoglobus. Moreover, kefir supplementation decreases the levels of total bile acids (BAs) and primary BAs and increases the secondary/primary BA ratio. Gut microbes play a key role in the conversion of primary to secondary fecal BAs.

Kefir can ameliorate ALD through regulating the composition of the gut microbiota.

Alcoholic liver disease (ALD) has a multifaceted development, progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis, irreversible liver damage that can even result in hepatocellular carcinoma. The prevalence of ALD is increasing globally, particularly among middle-aged adults. Gender-based studies have revealed that ALD affects more men; however, disease progression differs between men and women. Despite this, the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism, particularly with estrogen and estrogen receptors (ERs) in ALD, remains poor. This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs. Chronic alcohol consumption affects the immune response, and whether estrogen has any contributory effect remains inadequately studied. This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling. The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD, the development of effective therapeutic approaches, and better disease management in both men and women, as ALD remains a major public health concern.

Alcoholic liver disease (ALD) is characterized by the disturbance of bile acids homeostasis, which further deteriorates ALD. Bile acid metabolism and its related signal molecules have become new therapeutic targets for alcoholic liver disease. This study aimed to investigate the impact of kaempferol (KAE) on ALD and elucidate its underlying mechanisms.

C57BL/6 N mice were utilized to establish Binge-on-Chronic alcohol exposure mice model. KAE was administered as an interventional drug to chronic alcohol-fed mice for four weeks to assess its effects on liver damage and bile acid metabolism. And Z-Guggulsterone (Z-Gu), a global FXR inhibitor, was used to investigate the impact of intestinal FXR-FGF15 signal in ALD mice. Additionally, intestinal epithelial cells were exposed to alcohol or specific bile acid to induce the damage of FXR activity in vitro. The dual luciferase activity assay was employed to ascertain the interplay between KAE and FXR activity.

The results indicated that KAE treatment exhibited a significant hepatoprotective effect against chronic alcohol-fed mice. Accompanied by the intestinal FXR activation, the administration of KAE suppressed hepatic bile acid synthesis and promoted intestinal bile acid excretion in chronic ALD mice. And the notable alterations in total bile acid levels and composition were observed in mice after chronic alcohol feeding, which were reversed by KAE supplementation. And more, the protective effects of KAE on ALD mice were deprived by the inhibition of intestinal FXR activation. In vitro experiments demonstrated that KAE effectively activated FXR-FGF15 signaling, mitigated the damage to FXR activity in intestinal epithelial cells caused by alcohol or specific bile acids. Additionally, luciferase activity assays revealed that KAE directly promoted FXR expression, thereby enhancing FXR activity.

KAE treatment inhibited hepatic bile acids synthesis, maintained bile acids homeostasis in ALD mice by directly activating intestinal FXR-FGF15 signaling, which effectively alleviated liver injury induced by chronic alcohol consumption.

Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several underlying mechanisms that contribute to the development of AH, including metabolic alterations, immune stimulation, and intestinal dysbiosis. These pathological changes intricately intertwine during the progression of AH. Notably, recent studies have increasingly highlighted the pivotal role of alterations in the intestinal microbiota in the pathogenesis of AH. Consequently, future investigations should place significant emphasis on exploring the dynamics of intestinal microbiota. In this comprehensive review, we consolidate the primary causes of AH while underscoring the influence of gut microbes. Furthermore, by examining AH treatment strategies, we delineate the potential therapeutic value of interventions targeting the gut microbiota. Given the existing limitations in AH treatment options, we anticipate that this review will contribute to forthcoming research endeavors aimed at advancing AH treatment modalities.

The association between liver fibrosis and oral or gut microbiota has been studied before. However, epidemiological studies in the general population are limited owing to the difficulty of noninvasive liver-fibrosis assessment. FibroScan-asparate aminotransferase (FAST) scores can be used to accurately and non-invasively evaluate liver fibrosis. This study aimed to determine the association between liver fibrosis and oral or gut microbiota using the FAST score in the general population. After propensity score matching of 1059 participants based on sex, age, body mass index, homeostasis model assessment of insulin resistance, and triglyceride levels, 125 (non-liver-fibrosis group, 100; liver fibrosis group, 25) were included. The diversity of gut microbiota differed significantly between the two groups; however, no significant differences were noted in their oral microbiota. The liver fibrosis group showed an increase in the relative abundance of Fusobacteria strains and a decrease in the relative abundance of Faecalibacterium, with the presence of Fusicatenibacter in the gut microbiota. Feacalibacterium was not identified as an independent factor of liver fibrosis in adjusting the fatty liver index. In the general population, gut microbiota may be more involved in liver fibrosis than oral microbiota.

Alcoholic liver disease (ALD)-one of the most common liver diseases - involves a wide range of disorders, including asymptomatic hepatic steatosis, alcoholic hepatitis (AH), liver fibrosis, and cirrhosis. Alcohol consumption induces a weakened gut barrier and changes in the composition of the gut microbiota. The presence of CYP2E1 and its elevated levels in the gastrointestinal tract after alcohol exposure lead to elevated levels of ROS and acetaldehyde, inducing inflammation and oxidative damage in the gut. At the same time, the influx of harmful molecules such as the bacterial endotoxin LPS and peptidogly from gut dysbiosis can induce intestinal inflammation and oxidative damage, further compromising the intestinal mucosal barrier. In this process, various oxidative stress-mediated post-translational modifications (PTMs) play an important role in the integrity of the barrier, eg, the presence of acetaldehyde will result in the sustained phosphorylation of several paracellular proteins (occludin and zona occludens-1), which can lead to intestinal leakage. Eventually, persistent oxidative stress, LPS infiltration and hepatocyte damage through the enterohepatic circulation will lead to hepatic stellate cell activation and hepatic fibrosis. In addition, probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), bioengineered bacteria, gut-restricted FXR agonists and others are promising therapeutic approaches that can alter gut microbiota composition to improve ALD. In the future, there will be new challenges to study the interactions between the genetics of individuals with ALD and their gut microbiome, to provide personalized interventions targeting the gut-liver axis, and to develop better techniques to measure microbial communities and metabolites in the body.

Alcohol-related liver disease (ALD) from excessive alcohol intake has a unique gut microbiota profile. The disease progression-free survival in ALD patients has been associated with the degree of gut dysbiosis. The vicious cycles between gut dysbiosis and the disease progression in ALD including: an increase of acetaldehyde production and bile acid secretion, impaired gut barrier, enrichment of circulating microbiota, toxicities of microbiota metabolites, a cascade of pro-inflammatory chemokines or cytokines, and augmentation in the generation of reactive oxygen species. The aforementioned pathophysiology process plays an important role in different disease stages with a spectrum of alcohol hepatitis, ALD cirrhosis, neurological dysfunction, and hepatocellular carcinoma. This review aims to illustrate the pathophysiology of gut microbiota and clarify the gut-brain crosstalk in ALD, which may provide the opportunity of identifying target points for future therapeutic intervention in ALD.

Alterations in plasma and intestinal metabolites contribute to the pathogenesis and progression of alcohol-related liver cirrhosis (ALC).

To explore the common and different metabolites in the plasma and feces of patients with ALC and evaluate their clinical implications.

According to the inclusion and exclusion criteria, 27 patients with ALC and 24 healthy controls (HCs) were selected, and plasma and feces samples were collected. Liver function, blood routine, and other indicators were detected with automatic biochemical and blood routine analyzers. Liquid chromatography-mass spectrometry was used to detect the plasma and feces metabolites of the two groups and the metabolomics of plasma and feces. Also, the correlation between metabolites and clinical features was analyzed.

More than 300 common metabolites were identified in the plasma and feces of patients with ALC. Pathway analysis showed that these metabolites are enriched in bile acid and amino acid metabolic pathways. Compared to HCs, patients with ALC had a higher level of glycocholic acid (GCA) and taurocholic acid (TCA) in plasma and a lower level of deoxycholic acid (DCA) in the feces, while L-threonine, L-phenylalanine, and L-tyrosine increased simultaneously in plasma and feces. GCA, TCA, L-methionine, L-phenylalanine, and L-tyrosine in plasma were positively correlated with total bilirubin (TBil), prothrombin time (PT), and maddrey discriminant function score (MDF) and negatively correlated with cholinesterase (CHE) and albumin (ALB). The DCA in feces was negatively correlated with TBil, MDF, and PT and positively correlated with CHE and ALB. Moreover, we established a P/S BA ratio of plasma primary bile acid (GCA and TCA) to fecal secondary bile acid (DCA), which was relevant to TBil, PT, and MDF score.

The enrichment of GCA, TCA, L-phenylalanine, L-tyrosine, and L-methionine in the plasma of patients with ALC and the reduction of DCA in feces were related to the severity of ALC. These metabolites may be used as indicators to evaluate the progression of alcohol-related liver cirrhosis.

Impaired metabolic functions of gut microbiota have been demonstrated in alcohol-related liver disease (ALD), but little is known about changes in phenylalanine metabolism.

Bacterial genomics and fecal metabolomics analysis were used to recognize the changes of phenylalanine metabolism and its relationship with intestinal flora. Intestinal barrier function was detected by intestinal alkaline phosphatase (IAP) activity, levels of tight junction protein expression, colonic inflammation and levels of serum LPS. Lactobacillus acidophilus was chosen to correct phenylalanine metabolism of ALD mice by redundancy analysis and Pearson correlation analysis.

Using 16S rRNA sequencing and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods, we identified elevated levels of phenylalanine and its' metabolites in the gut of alcohol-fed mice compared to control mice and were negatively correlated with the abundance of Lactobacillus, which mainly metabolized phenylalanine. The intestinal phenylalanine level was positively correlated with the colon inflammatory factors TNF-α and IL-6, and negatively correlated with ZO-1 and Occludin. While intestinal alkaline phosphatase (IAP) activity was negatively correlated with the colon inflammatory factors TNF-α, IL-6 and MCP-1, and positively correlated with ZO-1 and Occludin. Increased phenylalanine inhibited IAP activity, blocked LPS dephosphorylation, increased colonic inflammation and bacterial translocation. Phenylalanine supplementation aggravated alcohol-induced liver injury and intestinal barrier dysfunction. Among the 37 Lactobacillus species, the abundance of Lactobacillus acidophilus was most significantly decreased in ALD mice. Supplementation with L. acidophilus recovered phenylalanine metabolism and protected mice from alcohol-induced steatohepatitis.

Recovery of phenylalanine metabolism through the oral supplementation of L. acidophilus boosted intestinal barrier integrity and ameliorated experimental ALD.

Alcoholic liver damage is caused by long-term drinking, and it further develops into alcoholic liver diseases. In this study, we prepared a probiotic fermentation product of Grifola frondosa total active components (PFGF) by fermentation with Lactobacillus acidophilus, Lactobacillus rhamnosus, and Pediococcus acidilactici. After fermentation, the total sugar and protein content in the PFGF significantly decreased, while the lactic acid level and antioxidant activity of the PFGF increased. Afterward, we investigated the alleviating effect of PFGF on alcoholic liver injury in alcohol-fed mice. The results showed that the PFGF intervention reduced the necrosis of the liver cells, attenuated the inflammation of the liver and intestines, restored the liver function, increased the antioxidant factors of the liver, and maintained the cecum tissue barrier. Additionally, the results of the 16S rRNA sequencing analysis indicated that the PFGF intervention increased the relative abundance of beneficial bacteria, such as Lactobacillus, Ruminococcaceae, Parabacteroids, Parasutterella, and Alistipes, to attenuate intestinal inflammation. These results demonstrate that PFGF can potentially alleviate alcoholic liver damage by restoring the intestinal barrier and regulating the intestinal microflora.

Antrodia camphorata is a genus of wood-rot basidiomycete in the family Fomitopsidaceae. It is a valuable medicinal fungus in China that contains more than 78 kinds of active compounds. A. camphorata has good protection effects on the liver, especially on alcoholic liver injury (ALI).

This paper summarizes the complex occurrence and development of alcoholic liver disease (ALD). In addition, the effect of ALD on the intestine through the gut-liver axis is summarized. The protective mechanism of A. camphorata on ALI is reviewed to reveal its therapeutic potential, offering insights into future research.

A comprehensive search in the literature was obtained from books and online databases such as Web of Science, Google Scholar, PubMed, Scopus, Science direct, ACS Publications and Baidu Scholar.

The pathogenesis of ALD mainly includes oxidative stress injury, intestinal microflora imbalance, inflammatory mediator injury and nutritional imbalance. A. camphorata contains rich active components (e.g. polysaccharides, triterpenoids, maleic and succinic acid derivatives, amino acids, superoxide dismutase, vitamins, lignin and sterols). These components have good antioxidant, anti-inflammatory and intestinal protection activities. Therefore, A. camphorata has a wide application in the prevention and treatment of ALI.

ALD develops from a mild disease to alcoholic hepatitis and cirrhosis, which is the main reason of global morbidity and mortality. At present, there is no effective drug for the treatment of ALD. A. camphorata, as a valuable medicinal fungus unique to Taiwan, has a great protective effect on the liver. It is expected to be an effective drug for ALI treatment. Although many studies have performed the protective effects of A. camphorata on ALI, its regulatory effects on the gut-liver axis of ALD patients need to be further explored.

Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, alcohol per-capita consumption rose from 5.5 litres in 2005 to 6.4 litres in 2016 and is projected to increase further to 7.6 litres in 2030. In 2019, an estimated 25% of global cirrhosis deaths were associated with alcohol. The global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 population, with the highest and lowest ASDR in Africa and the Western Pacific, respectively. The annual incidence of hepatocellular carcinoma (HCC) among patients with alcohol-associated cirrhosis ranged from 0.9% to 5.6%. Alcohol was associated with approximately one-fifth of global HCC-related deaths in 2019. Between 2012 and 2017, the global estimated ASDR for alcohol-associated cirrhosis declined, but the ASDR for alcohol-associated liver cancer increased. Measures are required to curb heavy alcohol consumption to reduce the burden of alcohol-associated cirrhosis and HCC. Degree of alcohol intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis and genetic variants are key factors in the development of alcohol-associated cirrhosis and HCC. In this Review, we discuss the global epidemiology, projections and risk factors for alcohol-associated cirrhosis and HCC.

Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Alcohol use disorder is a major cause of morbidity, which requires newer treatment approaches. We previously showed in a randomized clinical trial that alcohol craving and consumption reduces after fecal transplantation. Here, to determine if this could be transmitted through microbial transfer, germ-free male C57BL/6 mice received stool or sterile supernatants collected from the trial participants pre-/post-fecal transplant. We found that mice colonized with post-fecal transplant stool but not supernatants reduced ethanol acceptance, intake and preference versus pre-fecal transplant colonized mice. Microbial taxa that were higher in post-fecal transplant humans were also associated with lower murine alcohol intake and preference. A majority of the differentially expressed genes (immune response, inflammation, oxidative stress response, and epithelial cell proliferation) occurred in the intestine rather than the liver and prefrontal cortex. These findings suggest a potential for therapeutically targeting gut microbiota and the microbial-intestinal interface to alter gut-liver-brain axis and reduce alcohol consumption in humans.

Changes in gut microbiota (GM) may be associated with the causation and progression of multiple liver diseases such as metabolic-associated liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), primary biliary cholangitis, primary sclerosing cholangitis, autoimmune liver disease, and most importantly, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infection, and hepatocellular carcinoma. ALD includes simple steatosis, steatohepatitis, AH, cirrhosis, and acute-on-chronic liver failure. Alcohol consumption is associated with GM changes even before ALD development, and continued alcohol intake results in progressive dysbiosis and development of clinical events such as AH, infection, and HE. The composition and function of GM, specific changes in bacterial communities, and the functional metabolism of GM are affected in the spectrum of ALD, as revealed using high-throughput sequencing. It was reported in preliminary studies that modulation of disrupted GM improves adverse clinical events and ameliorates disease progression in ALD. In this review, we exhaustively discuss the preclinical and clinical studies on GM in ALD and critically discuss GM modulation and its effects based on various human and animal models of ALD.

Cholestasis is a key causative factor in alcohol-related liver disease (ALD) and variable degrees of cholestasis occur in all stages of ALD. However, the pathogenetic mechanisms and biomarkers associated with cholestasis are not well characterized. Cholestatic disease is marked by the disruption of bile acids (BA) transport and homeostasis. Consequently, in both human and experimental ALD, the disease shows a direct correlation with an imbalance in BA equilibrium, which in turn may also affect the severity of the disease. Modulation of BA metabolism or signaling pathways is increasingly considered as a potential therapeutic strategy for ALD in humans. In this paper, we highlight the key advances made in the past two decades in characterizing the molecular regulatory mechanisms of BA synthesis, enterohepatic circulation, and BA homeostasis. We summarize recent insights into the nature of the linkage between BA dysregulation and ALD, including the abnormal expression of genes involved in BA metabolism, abnormal changes in receptors that regulate BA metabolism, and disturbance in the gut flora engaged in BA metabolism caused by alcohol consumption. Additionally, we provide novel perspectives on the changes in BAs in various stages of ALD. Finally, we propose potential pharmacological therapies for ALD targeting BA metabolism and signaling.

Alcoholic liver disease (ALD) involves a wide spectrum of diseases, including asymptomatic hepatic steatosis, alcoholic hepatitis, hepatic fibrosis, and cirrhosis, which leads to morbidity and mortality and is responsible for 0.9% of global deaths. Alcohol consumption induces bacterial translocation and alteration of the gut microbiota composition. These changes in gut microbiota aggravate hepatic inflammation and fibrosis. Alteration of the gut microbiota leads to a weakened gut barrier and changes host immunity and metabolic function, especially related to bile acid metabolism. Modulation and treatment for the gut microbiota in ALD has been studied using probiotics, prebiotics, synbiotics, and fecal microbial transplantation with meaningful results. In this review, we focused on the interaction between alcohol and gut dysbiosis in ALD. Additionally, treatment approaches for gut dysbiosis, such as abstinence, diet, pro-, pre-, and synbiotics, antibiotics, and fecal microbial transplantation, are covered here under ALD. However, further research through human clinical trials is warranted to evaluate the appropriate gut microbiota-modulating agents for each condition related to ALD.