Gut–Liver Axis in Alcoholic Liver Disease

doi:10.1053/j.gastro.2014.10.042

Gastroenterology

Volume 148, Issue 1, January 2015, Pages 30-36

https://doi.org/10.1053/j.gastro.2014.10.042 Get rights and content

Alcoholic liver disease (ALD) has been among the leading causes of cirrhosis and liver-related death worldwide for decades. Early discoveries in alcoholic liver disease identified increased levels of bacterial endotoxin in the portal circulation, suggesting a role for gut-derived toxins in ALD. Indeed, alcohol consumption can disrupt the intestinal epithelial barrier and result in increased gut permeability that increasingly is recognized as a major factor in ALD. Bacterial endotoxin, lipopolysaccharide, is a prototypic microbe-derived inflammatory signal that contributes to inflammation in ALD through activation of the Toll-like receptor 4. Recent studies also have shown that alcohol consumption is associated with alterations in the gut microbiome, and the dysbalance of pathogenic and commensal organisms in the intestinal microbiome may contribute to the abnormal gut–liver axis in ALD. Indeed, bacterial decontamination improves ALD both in human and animal models. This short review summarizes recent findings and highlights emerging trends in the gut–liver axis relevant to ALD.

Section snippets

Alcoholic Liver Disease

Excessive alcohol use over a prolonged period of time often results in alcoholic liver disease (ALD). The spectrum of alcoholic liver disease includes steatosis, steatohepatitis, acute alcoholic steatohepatitis, alcoholic fibrosis, and cirrhosis (Laennec’s cirrhosis). Steatosis and early steatohepatitis are reversible after cessation of alcohol use. Based on current understanding, multiple pathogenic factors are involved in the development of alcoholic liver disease. Alcohol and its metabolites

Gut Barrier Function: Effects of Alcohol

The integrity of the intestinal mucosa is determined by the function of several components: protective layer of defensins on the intraluminal surface of the intestinal epithelium, tight junction proteins between intestinal epithelial cells, and the gut immune cells in the intestinal wall (Figure 1).⁵ Alcohol has both direct effects on these functions in the intestine and indirect effects by alcohol and/or its metabolites distributed via the blood stream (Figure 2).²³ An acute alcohol binge

Gut Microbiome and Alcohol

Perhaps the majority of the new information on the gut–liver axis in recent years is related to understanding the role of the microbiome in human health and disease. The intestinal microbiota has a major role in shaping the host immune response and commensal bacteria shape the integrity of the gut mucosa.³⁵ A wide array of human diseases including obesity, insulin resistance and the related metabolic syndrome, nonalcoholic steatohepatitis, cancer, chronic inflammatory diseases and infections,

Microbial Products, Pattern Recognition Receptors, and the Immune System

Pathogen-associated molecular patterns (PAMPs) are sensed by pattern recognition receptors including TLRs, Nod-like receptors, helicase receptors, and others.40, 41 The microbiome contains a broad variety of PAMPs and because of the intestinal barrier, these PAMPs do not reach the systemic circulation. The most studied gut-derived PAMP in the circulation is bacterial LPS, which is a component of the gram-negative bacterial wall. Many studies have shown that chronic alcohol consumption increases

Clinical Aspects of the Impaired Gut–Liver Axis in ALD

Excessive alcohol use in most cases is associated with alcohol dependence.⁵⁶ The role of intestinal permeability and inflammation has received recent attention in the biological and behavioral control of alcohol dependence.⁵⁷ A recent study found that intestinal permeability and LPS were increased in alcohol-dependent noncirrhotic subjects at hospitalization for detoxification compared with 3 weeks later after successful detoxification. An inflammatory cytokine increase was correlated with

Emerging Therapeutic Approaches That Target the Gut–Liver Axis

Given that alcohol disrupts the gut barrier function, it is attractive to explore therapeutic interventions that could prevent alcohol-induced gut leakiness and/or restore alcohol-induced defects. For example, it has been shown that alcohol-induced zinc deficiency contributes to the impaired gut barrier function.⁷² More important, administration of zinc in mice with chronic alcohol feeding restored the alcohol-induced gut dysfunction.⁷³

Another approach is to modify the microbiome dysbalance

Unanswered Questions

Although the number of reports on the gut–liver axis in alcoholic liver disease has increased drastically in recent years, there are many remaining questions. Increase in gut permeability is not unique to alcoholic liver disease. In disease conditions such as Crohn’s colitis or human immunodeficiency virus infection serum LPS levels are increased yet there is no liver disease. It appears that increased gut permeability is just one of potentially several factors that contributes to ALD. It is

Acknowledgment

The author thanks Dr Pranoti Mandrekar for critical review of the manuscript.

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Ginseng fermentation solution affects the gut microbiota in zebrafish with alcoholic liver disease via PI3K/Akt pathway
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Ginsenosides have received increased amounts of attention due to their ability to modulate the intestinal flora, which may subsequently alleviate alcoholic liver disease (ALD). The effects of ginseng fermentation solution (GFS) on the gut microbiota and metabolism in ALD patients have not been explored.
This research aimed to explore the regulatory effect of GFS on ALD both in vitro and in vivo.
This study assessed the anti-ALD efficacy of GFS using an LO2 cell model and a zebrafish model. Untargeted metabolomics was used for differentially abundant metabolite analysis, and high-throughput 16S rRNA sequencing was used to examine the effect of GFS on ALD.
The LO2 cell line experiments demonstrated that GFS effectively mitigated alcohol-induced oxidative stress and reduced apoptosis by upregulating PI3K and Bcl-2 expression and decreasing the levels of malondialdehyde, total cholesterol, and triglycerides. In zebrafish, GFS improved morphological and physiological parameters and diminished oxidative stress-induced ALD. Meanwhile, the results from Western blotting indicated that GFS enhanced the expression of PI3K, Akt, and Bcl-2 proteins while reducing Bax protein expression, thereby ameliorating the ALD model in zebrafish. Metabolomics data revealed significant changes in a total of 46 potential biomarkers. Among them, metabolites such as prostaglandin F2 alpha belong to arachidonic acid metabolism. In addition, GFS also partly reversed the imbalance of gut microbiota composition caused by alcohol. At the genus level, alcohol consumption elevated the presence of Flectobacillus, Curvibacter, among others, and diminished Elizabethkingia within the intestinal microbes of zebrafish. Conversely, GFS reversed these effects, notably enhancing the abundance of Proteobacteria and Archaea. Correlation analyses further indicated a significant negative correlation between prostaglandin F2 alpha, 11,14,15-THETA, Taurocholic acid and Curvibacter.
This study highlights a novel mechanism by which GFS modulates anti-ALD activity through the PI3K/Akt signalling pathway by influencing the intestinal flora-metabolite axis. These results indicate the potential of GFS as a functional food for ALD treatment via modulation of the gut flora.
Recombinant Bacillus subtilis expressing functional peptide and its effect on the growth, antioxidant capacity and intestine in Megalobrama amblycephala
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P4 is a functional small peptide screened after enzymatic hydrolysis of cotton meal. Bacillus subtilis CM66 (OB) underwent recombination to yield Bacillus subtilis CM66-P4’ (RB), capable of secreting P4. This study aimed to assess the effects of RB on the growth, antioxidant capacity and intestine in blunt snout bream (Megalobrama amblycephala) through in vitro and in vivo experiments. Seven groups were formed: a control group (CG) with no additional bacteria, three groups with different concentrations of Bacillus subtilis CM66 (2 × 10⁷, 2 × 10⁸, 2 × 10⁹ CFU/kg - referred to as LOG, MOG, HOG), and three groups with corresponding concentrations of Bacillus subtilis CM66-P4’ (2× 10⁷, 2 × 10⁸, 2 × 10⁹ CFU/kg - referred to as LRG, MRG, HRG). After 8 weeks of feeding, the results showed that OB and RB had no significant impact on growth performance. Compared with CG and MOG, the MRG group exhibited a significant increase in protease and total anti-oxidative capacity (T-AOC) in the intestine (P < 0.05). The mRNA expression of mucin-2 in MOG and MRG were significantly increased (P < 0.05). Compared with CG, muscle layer thickness (MLT) of MOG and MRG were significantly increased (P < 0.05), villus height (VH) and goblet cells numbers of MRG were increased (P < 0.05). Species richness and diversity of intestinal microbes were significantly increased in MOG and MRG (P < 0.05). P4 demonstrated a significant alleviation of the increase in sod expression in intestinal epithelial cells (IECs) treated with H₂O₂ and mitigated the decrease in cells activity (P < 0.05). In conclusion, P4 effectively mitigated the impact of H₂O₂ on IECs in blunt snout bream. Dietary supplementation of 2 × 10⁸ CFU/kg RB (secreting P4) improved the intestinal microbes and intestinal barrier, resulting in enhanced antioxidant capacity.
A polysaccharide from Alhagi honey protects the intestinal barrier and regulates the Nrf2/HO-1-TLR4/MAPK signaling pathway to treat alcoholic liver disease in mice
2024, Journal of Ethnopharmacology
According to the theory of traditional Chinese medicine, the main factors related to alcoholic liver disease (ALD) are qi stagnation and blood stasis of the five viscera. Previously, we showed that the bioactive components of Alhagi honey have various pharmacological effects in treating liver diseases, but the influence of Alhagi honey on ALD (and its mechanism of action) is not known.
To determine the efficacy of the main active component of Alhagi honey, the polysaccharide AHPN80, in ALD and to explore the potential mechanism of action.
AHPN80 was isolated from dried Alhagi honey and identified by transmission electron microscopy, Fourier-transform infrared spectroscopy, and gas chromatography. Venous blood, liver tissue, and colon tissue were collected in a mouse model of alcohol-induced acute liver injury. Histology, staining (Oil Red O, Alcian Blue–Periodic Acid Schiff) and measurement of reactive oxygen species (ROS) levels were used to detect histopathologic and lipid-accumulation changes in the liver and colon. Lipopolysaccharide (LPS) levels and the content of proinflammatory cytokines in serum were measured by enzyme-linked immunosorbent assays. Commercial kits were employed to detect biochemistry parameters in serum and the liver. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining kit was used to identify hepatocyte apoptosis. Expression of tight junction-associated proteins in colon tissues and nuclear factor erythroid 2-related factor 2/heme oxygenase-1/toll-like receptor-4/mitogen-activated protein kinase (Nrf2/HO-1/TLR4/MAPK) pathway-related proteins in liver tissues and HepG2 cells were analyzed by immunofluorescence or western blotting.
In a mouse model of alcohol-induced acute liver injury, AHPN80 therapy: significantly improved liver parameters (cytochrome P450 2E1, alcohol dehydrogenase, aldehyde dehydrogenase, superoxide dismutase, malondialdehyde, glutathione peroxidase, catalase, total cholesterol, triglycerides, alanine transaminase, aspartate transaminase); reduced serum levels of LPS, interleukin (IL)-1β, IL-6, and tumor necrosis faction-α; increased levels of IL-10 and interferon-gamma. AHPN80 reduced ALD-induced lipid accumulation and ROS production, improved alcohol-induced inflammatory damage to hepatocytes, and inhibited hepatocyte apoptosis. Immunofluorescence staining and western blotting suggested that AHPN80 might eliminate hepatic oxidative stress by activating the Nrf2/HO-1 signaling pathway, repair the intestinal barrier, inhibit the LPS/TLR4/MAPK signaling pathway, and reduce liver inflammation.
AHPN80 may activate the Nrf2/HO-1 pathway to eliminate oxidative stress, protect the intestinal barrier, and regulate the TLR4/MAPK pathway to treat ALD in mice. AHPN80 could be a functional food and natural medicine to prevent ALD and its complications.
Porphyromonas gingivalis as a promotor in the development of the alcoholic liver disease via ferroptosis
2024, Microbes and Infection
Alcoholic liver disease (ALD) is a liver disease caused by heavy drinking. Porphyromonas gingivalis (P.g), a major cause of periodontitis, whose antibodies are elevated in severe ALD patients in the plasma. The purpose of this study is to further study the role and the molecular mechanism of P.g in the progress of ALD. In this study, saliva of patients with ALD was collected. Then, an animal model of ALD with oral P.g administration was established, pathology of liver and spleen, intestinal microorganisms and metabolites were analyzed. The molecular mechanism of P.g on ALD was analyzed in vitro. ALD and intestinal microflora and metabolite changes were observed more serious in the alcohol and P.g groups than the alcohol group. Moreover, ferroptosis was aggravated by P.g in the liver. Meanwhile, P.g promoted ferroptosis accomplication with alcohol in vitro, which can be reversed by ferroptosis inhibitors. In conclusion, P.g aggravates ALD through exacerbation gut microbial metabolic disorder in mice with alcohol, which maybe depend on ferroptosis activation in hepatocytes. The study provides a new strategy for prevention and treatment of ALD by improving the oral micro-environment.
Structural elucidation of an active polysaccharide from Radix Puerariae lobatae and its protection against acute alcoholic liver disease
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Radix Pueraria lobata can be used as medicine and food, whose polysaccharide is one of the main bioactive ingredients. To explore the effect and mechanism of Pueraria lobata polysaccharide, a homogeneous and novel water-soluble polysaccharide (PLP1) was successfully isolated and purified from P. lobata by column chromatography in the current study. Structure analysis revealed that PLP1 (M_w = 10.43 kDa) was constituted of the residues including (1 → 4)-α-d-glucose and (1 → 4, 6)-α-d-glucose, which were linked together at a ratio of 5:1 and represented the main glycosidic units. In vitro experiments indicated that PLP1 exhibited a better free radical-scavenging ability than amylose and amylopectin, meanwhile in vivo experiments indicated that PLP1 effectively protected against liver injury in mice with acute ALD through significantly inhibiting oxidative stress to regulate lipid metabolism, increasing short-chain fatty acid production, and maintaining intestinal homeostasis by regulating intestinal flora. Taken together, our results illustrate that PLP1 can regulate intestinal microecology as a feasible therapeutic agent for protecting against ALD on the ground of the gut-liver axis, thus laying a theoretical foundation for the rational exploitation and utilization of P. lobata resources in the clinic.
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2730 CESC

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: Conflicts of interest The author discloses no conflicts.

: Funding This work was supported by NIAAA grants AA021907, AA010744, and AA017729. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

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Reviews and PerspectivesBrief ReviewGut–Liver Axis in Alcoholic Liver Disease

Section snippets

Alcoholic Liver Disease

Gut Barrier Function: Effects of Alcohol

Gut Microbiome and Alcohol

Microbial Products, Pattern Recognition Receptors, and the Immune System

Clinical Aspects of the Impaired Gut–Liver Axis in ALD

Emerging Therapeutic Approaches That Target the Gut–Liver Axis

Unanswered Questions

Acknowledgment

Gastroenterology

Alcohol

J Hepatol

Free Radic Biol Med

Hepatology

Cancer Cell

Am J Gastroenterol

J Hepatol

Gastroenterology

Gastroenterology

J Hepatol

Biol Psychiatry

Gastroenterology

J Biol Chem

Cell Host Microbe

Trends Pharmacol Sci

Brain Behav Immun

Brain Behav Immun

Immunol Today

J Biol Chem

J Hepatol

J Hepatol

The liver as an immunological organ

Hepatology

Gut microbiota and liver disease

J Gastroenterol Hepatol

The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota

Sci Transl Med

Bile acids and the gut microbiome

Curr Opin Gastroenterol

Alcoholic liver disease and the gut-liver axis

World J Gastroenterol

Role of oxidative stress in alcohol-induced liver injury

Arch Toxicol

Autophagy in alcohol-induced liver diseases

Alcohol Clin Exp Res

Role of mitochondria in alcoholic liver disease

World J Gastroenterol

Mitochondrial glutathione: importance and transport

Semin Liver Dis

An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice

Hepatology

Innate immunity and alcoholic liver disease

Dig Dis

Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury

J Gastroenterol Hepatol

Toll-like receptors in the pathogenesis of alcoholic liver disease

Gastroenterol Res Pract

Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice

Hepatology

TLR4 enhances TGF-beta signaling and hepatic fibrosis

Nat Med

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Proc Natl Acad Sci U S A

Endotoxemia and gut barrier dysfunction in alcoholic liver disease

Hepatology

Reviews and Perspectives
Brief Review
Gut–Liver Axis in Alcoholic Liver Disease