Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease
Abstract
:1. Introduction
2. Oxidative Stress Formation in ALD
3. Alcohol-Induced Metabolic Inflammation and Cellular Alterations
4. Alcoholic Liver Diseases
4.1. Alcoholic Fatty Liver and Molecular Networking
4.2. Alcoholic Liver Fibrosis in Humans with Alcoholism
4.3. Alcoholic Steatohepatitis in Humans with Alcoholism
4.4. Alcoholic Cirrhosis in Humans with Alcoholism
4.5. Hepatocellular Carcinoma in Humans with Alcoholism
5. Probiotics and Antioxidant Activity in ALD
6. Microbiome-Wide Dynamic Microbial Proof-of-Concept Clinical Validation
7. Summary and Future Outlook
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Animals | Exposures | Main Results | Ref. | |
---|---|---|---|---|
Mice | C57BL/6J male (6–8 weeks old) | chronic 5% ethanol diet for 11, 22, and 33 days | (↑) AST, ALT, amount of G-MDSC. | [58] |
C57BL/6 mice | alcohol diet for 8 weeks | (↑) proportions of CA, total MCA, DCA in ileum unconjugated and total bile acid concentrations in the plasma hepatic Cyp7a1 protein expression, hepatic IL-1B, TNF protein. (↓) proportions of TCA and TDCA in ileum. | [59] | |
C57BL/6J female (7–8 weeks old) | 5% ethanol for 6 weeks in Lieber–DeCarli liquid diet | (↑) liver mRNA expression level of TNF-α, IL-6, Cc2, Ccr5 liver protein level of TNF-α, IL-1β, IL-6, CD14 serum protein level. | [60] | |
Rats | Male Wistar rats | Non-stop ethanol supply for 3 weeks. Gut sterilization with polymyxin B and neomycin | (↓) Plasma endotoxin levels (80–90 pg/mL → <25 pg/mL), average hepatic pathological score in ethanol-fed and antibiotic-treated rats. Antibiotics prevented elevated aspartate aminotransferase levels and hepatic surface hypoxia. | [61] |
Mice | Alcohol-fed NS5ATg mice | Lieber–DeCarli diet containing 3.5% ethanol or isocaloric dextrin for long-term alcohol feeding, repetitive LPS injection | (↑) Ethanol-induced endotoxemia, liver injury, and tumorigenesis after Toll-like receptor (TLR)-4 induction through hepatocyte-specific transgenic expression of the HCV non-structural protein NS5A. | [62] |
Mice | 60 male Kunming mice (18–22 g) (6–8 weeks old) | alcohol gavage for 2–13 days | (↑) AST, ALT, TG, Hepatic MDA, ADH, mRNA, and protein expression of Cyp2e1, CAT. (↓)Major endogenous antioxidant enzymes (SOD and GSH-Px) mRNA expression of Nrf2, NQO-1, ADH. | [63] |
Rats | Male Wistar rats (170–180 g) | chronic ethanol feeding | (↑) ROS production by LPS in Kupffer cells isolated from ethanol-fed mice. ROS production in Kupffer cells by LPS stimulation were increased NADPH oxidase dependently. ERK1/2 contributed to the increase in TNF-α production in Kupffer cells by LPS stimulation. | [64] |
Mice | C57BL/6 male | EtOH-containing diets (35% of total calories, AF) ad libitum for 4 weeks | (↑) Saturated fatty acid levels. PLS-DA performed for liver and fecal samples. Mouse liver damage can be improved. (↑) intestinal; (↓) hepatic fatty acids; (↑) amino acid concentration. | [65] |
Mice | C57BL/6 male (5–6 weeks old) | EtOH-containing Lieber– DeCarli liquid diet or an isocaloric control diet | (↑) ALT and AST. PCA, OPLS-DA, volcano maps, and correlation coefficient analyzed. | [66] |
Mice | C57BL/6 male (8 weeks old) | Intermittent hypoxia exposure | PCA, OPLS-DA, and volcano maps, heatmaps analyzed. (↑) N1-(5-Phospho-D-ribosyl)-AMP, stearidonic acid, adenine, arachidonic acid (peroxide-free), ergothioneine, betaine, cyclohexylamine, GSH, GSH disulfide. | [67] |
Mice | Kunming mice (7 weeks old) | 10% lard, 20% sucrose, 2.5% cholesterol, and 0.5% sodium cholate | (↑) Taurochenodeoxycholic acid, taurine, chenodeoxycholic acid, (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16, 19-docosahexaenoic acid, oleic acid, alpha-linolenic acid. Enrichment analysis. | [68] |
Rats | Male Sprague Dawley rats (1 year old, 180–200g) | CCl4 (1mL/kg 40% CCl4, diluted in olive oil); twice a week for eight weeks | H&E and Masson’s trichrome staining, PLS-DA, heatmap, ROC curve analysis. (↑) L-tryptophan, L-valine, cholesterol, glycocholate, methylmalonic acid. | [69] |
Mice | BALB/c mice (8 weeks old) | E. granulosus infection | 25mg of hepatic and fecal samples were analyzed. PCA, OPLS-DA, and volcano maps, heatmaps analyzed. (↑) 2-ethyl-2-hydroxybutyric acid, 2-hydroxyvaleric acid, cytidine 2’,3’-cyclic phosphate, sodium citrate, carboxytolbutamide, methylselenopyruvate. (↓) Pyronaridine, Bis(4-nitrophenyl) phosphate, Inosinic acid, 5-Phosphoribosyl-4-carboxy-5- aminoimidazole, tolclofos-methy, maduropeptin chromophore. | [70] |
Mice | Fat-1 transgenic mice (10–12 weeks old) | EtOH diet | (↑) neutrophil accumulation, Pai-1 expression in wild-type mice. (↓) neutrophil accumulation, pai-1 expression, KC M1 abundance in fat-1 mice. Flow cytometry analysis of hepatic immune cells. | [71] |
Animals | Exposures | Main results | Ref. | |
---|---|---|---|---|
Human | 14 alcoholic patients | chronic alcohol intake | (↑) Plasma endotoxin levels and serum IL-6 and IL-8 levels of patients compared to healthy subjects. Serum LBP was positively correlated with white blood cell and neutrophil counts as an indicator of an inflammatory response. | [152] |
recombinant HepG2 ADH1/CYP2E1 cells | 100 mM ethanol for 6, 24, 48, 72, 96, and 110 h | (↓) CYP1A2, CYP2B6, CYP2C9, CYP2E1, and CYP3A4 expression. (↓) AGO1 knockdown, HNF4A RNA levels. | [153] | |
severe AH (n = 161), and HC (n = 28) | chronic alcohol intake | (↑) level of sST2 was increased in SAH, higher levels of 3-HM in patients compared with controls, expression at baseline of GRK2 in circulating PMNs. (↓) expression of the chemokine receptor CXCR2 on the surface of circulating PMNs. | [154] | |
Human | 51 alcoholic patients | consumed excessive alcohol, tobacco smoking | (↑) CYP2E1 activity, oxidative stress. (↑) chlorzoxazone oxidation. | [109] |
10 liver samples of AC | chronic alcohol intake | (↑) increased CCL2, CCL3, CCL4, CCL5, CCL8, CCL5 mRNA expression in AC liver, increased MØ infiltration. | [60] | |
healthy control (n = 33), alcoholic liver cirrhosis (n = 23) | chronic alcohol intake | (↑) tumor volume and tumor maximum diameter expression of BCL-xl, CCL2, IL-4, IL-10, TIMP1, col1a1, and PCNA the frequency and number of macrophages in the liver hepatic CD206 expression. M2-associated protumor genes in the liver. | [151] | |
Human | 53 cirrhosis cohort patients | alcohol intake, 1 yr follow-up, underwent liver transplantation | Small intestinal bacterial overgrowth was seen in 59% of patients with cirrhosis and was significantly related to systemic endotoxemia. | [155] |
AH patients (n = 6); HC persons (n = 6) | Ethanol consumption of at least 80 g/day | (↑) NF-kB activity in the monocytes of six patients with AH as compared with normal subjects. (↑) NF-kB activity, TNF-α RNA expression, and TNF-α release by endotoxin in AH patients. | [156] | |
Human | HCC, Late intrahepatic recurrence (n = 18); Early intrahepatic recurrence (n = 22) | HCC patients | (↓) Plasma specimens, tryptophan, cholesterol glucuronide, LysoPC (20:5), LysoPC (22:6). ROC curves based on methionine, GCDCA, and cholesterol sulfate was selected. AUC equal to 0.95. | [157] |
Human | 46 patients | HCV-related HCC patients | PCA and PLS-DA score-plot has found. ROC curve analyzed for N-acetyl-lysine, L-glutamine, L-aspartate, and L-proline. Heatmap presenting the hierarchical clustering analysis. | [158] |
Human | 248 serum samples | AHB, CHB, CHC with many types of liver disease | Heatmap analysis, γ-glutamyl peptides mechanism, GSH oxidation and reduction. (↓) GSH level. | [159] |
Human | 52 serum samples | HCV, HCC patients | Serum sample analysis, 73 metabolites detected, Sensitivity of 97%, specificity of 95%, and an AUROC of 0.98 found. Sixteen metabolites were significantly altered. | [159] |
Human | 559 patients | NAFLD patients | AUROC of 0.92, sensitivity of 73%, and specificity of 94%. | [160] |
Human | 117 patients | HCV (n = 67), HBV (n = 50 patients) | OPLS-DA analysis, metabolites and their pathway analysis, Fold-change analysis. | [161] |
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Hyun, J.Y.; Kim, S.K.; Yoon, S.J.; Lee, S.B.; Jeong, J.-J.; Gupta, H.; Sharma, S.P.; Oh, K.K.; Won, S.-M.; Kwon, G.H.; et al. Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease. Int. J. Mol. Sci. 2022, 23, 8749. https://doi.org/10.3390/ijms23158749
Hyun JY, Kim SK, Yoon SJ, Lee SB, Jeong J-J, Gupta H, Sharma SP, Oh KK, Won S-M, Kwon GH, et al. Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease. International Journal of Molecular Sciences. 2022; 23(15):8749. https://doi.org/10.3390/ijms23158749
Chicago/Turabian StyleHyun, Ji Ye, Seul Ki Kim, Sang Jun Yoon, Su Been Lee, Jin-Ju Jeong, Haripriya Gupta, Satya Priya Sharma, Ki Kwong Oh, Sung-Min Won, Goo Hyun Kwon, and et al. 2022. "Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease" International Journal of Molecular Sciences 23, no. 15: 8749. https://doi.org/10.3390/ijms23158749