Clin Mol Hepatol > Volume 28(3); 2022 > Article
Ganesan and Suk: Microbiome and metabolomics in alcoholic liver disease
The gastrointestinal microbiome and metabolomics are the candidate biomarkers for alcoholic liver disease (ALD) [1]. Alcohol-associated liver injury is characterized by oxidative stress, lipid peroxidation, steatosis, iron deposits, hepatocyte damage, and hepatocytes death. These features have been associated with liver inflammation, activation of Kupffer cells and hepatic stellate cells, liver fibrosis, and liver regeneration process. Alcohol use promotes a change in microbiome composition. Microbiota-host co-regulated metabolic pathways are promising targets for clinical needs.
Metabolite profiles such as lipids, fatty acids, carbohydrates, vitamins, proteins, enzymatic compounds, amino acids, and small-molecules profoundly affected host physiology and are being explored for their roles in ALD. The molecular families are shaped by the microbiome with short-chain fatty acids (SCFA; acetate, propionate, and butyrate), aromatic amino acid metabolites, indoles, complex polysaccharides, and host lipids such as sphingolipids and bile acids [2,3]. SCFA were found in human large intestine and involved in microbial fermentation. SCFA play intestinal homeostasis and potent immune regulators. SCFA indicate that gut-brain-liver axis could impaired by alcohol [4,5].
Acetaldehyde is mainly expressed in hepatocytes and acts on hepatic stellate cells (HSCs) in a paracrine manner. Acetaldehyde directly increases expression of collagen-I in HSCs through transcription factors. Acetaldehyde reacts with metabolic components, which help maintain HSC activation. Ethanol increases fatty liver acid synthesis in hepatocytes via sterol regulatory element-binding protein-1c by increasing expression of lipogenic genes [6]. Interleukin (IL)-22 might be used treat to ALD patients because of its antioxidant, anti-apoptotic, anti-steatotic, anti-proliferative, and anti-microbial effects. Corticosteroids increased survival in patients with alcoholic hepatitis.
CXC chemokines such as CXCL12, CXCR4, and vascular endothelial growth factor have increased survival and the degree of hypertension. IL-8 and growth-related oncogene-alpha are parts of CXC chemokines family. These might be industrialized as a therapeutic drug for ALD [7].
Anti-tumor necrosis factor (TNF)-α has an important role in the pathogenies of ALD in animal models. Pentoxifylline blocks transcription of TNF-α which can decrease serum level of TNF-α. S-adenosylmethionine (SAMe) acts as a methyl donor that has protect against ALD through antioxidant functions, and down regulation of TNF-α. SAMe plays as a safe drug for ALD. However, Cochrane report indicated that there have no evidences to support the use of SAMe in ALD patients [8].
The time has come to develop the therapeutic biomarkers via gut-microbiome and metabolome in ALD. Patients with ALD show gut barrier dysfunction. Now, gut-microbiome-centered therapies are novel and associated metabolomics signature that plays a big platform for biomarkers discovery in ALD.

ACKNOWLEDGMENTS

This research was funded by Hallym University Research Fund, and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF-2018M3A9F3020956, NRF-2019R1I1A3A01060447, NRF-2020R1I1A3073530 and NRF2020R1A6A1A03043026).

FOOTNOTES

Authors’ contributions
All authors wrote the manuscript and revised. Ki Tae Suk supervised and approved the manuscript for publication.
Conflicts of Interest
The authors have no conflicts to disclose.


cmh-2022-0171f1.jpg

Abbreviations

ALD
alcoholic liver disease
HSC
hepatic stellate cell
IL
interleukin
SAMe
S-adenosylmethionine
SCFA
short-chain fatty acids
TNF
tumor necrosis factor

REFERENCES

1. GBD 2016 Alcohol Collaborators. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2018;392:1015-1035.
pmid pmc
2. Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med 2018;24:1070-1080.
crossref pmid pmc pdf
3. Raja G, Gupta H, Gebru YA, Youn GS, Choi YR, Kim HS, et al. Recent advances of microbiome-associated metabolomics profiling in liver disease: principles, mechanisms, and applications. Int J Mol Sci 2021;22:1160.
crossref pmid pmc
4. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 2016;165:1332-1345.
crossref pmid
5. Mitchell RW, On NH, Del Bigio MR, Miller DW, Hatch GM. Fatty acid transport protein expression in human brain and potential role in fatty acid transport across human brain microvessel endothelial cells. J Neurochem 2011;117:735-746.
crossref
6. Mello T, Ceni E, Surrenti C, Galli A. Alcohol induced hepatic fibrosis: role of acetaldehyde. Mol Aspects Med 2008;29:17-21.
crossref pmid
7. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011;141:1572-1585.
crossref pmid pmc
8. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119:1637-1648.
crossref pmid

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: kasl@kams.or.kr
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 586
TOTAL : 972764
Close layer