Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review
Abstract
:1. Introduction
2. From NAFL to NASH: The Gut Microbiota-Associated Mechanisms
2.1. NASH and Dysbiosis
2.2. NASH and Leaky Gut
2.3. Gut Microbiota and Hepatic Inflammation
2.4. NASH and Gut Microbiota-Derived Metabolites
3. From NASH to HCC: The Gut Microbiota-Associated Mechanisms
4. Potential Therapeutic Strategies and Non-Invasive Diagnosis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
HCC | hepatocellular carcinoma |
NAFLD | non-alcoholic fatty liver disease |
NASH | non-alcoholic steatohepatitis |
HBV | hepatitis B viruses |
HCV | hepatitis C viruses |
SCFA | short chain fatty acid |
ZO-1 | zonula occludens-1 |
DSS | dextran sodium sulfate |
IL10 | interleukin-10 |
IL6 | interleukin-6 |
PPAR | peroxisome proliferator-activated receptor |
FMT | fecal microbial transplantation |
HFDs | high-fat diets |
NLRP6 | nucleotide-binding oligomerization domain -like receptor family pyrin domain containing 6 |
ASC | apoptosis-associated speck-like protein containing a caspase recruitment domain |
TLR4 | toll-like receptor 4 |
HSCs | hepatic stellate cells |
LSECs | liver sinusoidal endothelial cells |
MyD88 | myeloid differentiation primary response 88 |
TNF-α | tumor necrosis factor-α |
ROS | reactive oxygen species |
JNK | c-Jun N-terminal kinase |
PAMPs | pathogen-associated molecular patterns |
NEFAs | non-esterified fatty acids |
S1P | sphingosine 1-phosphate |
TRAIL | TNF-related apoptosis-inducing ligand |
DAMP | damage-associated molecular pattern |
GPR | G-protein coupled receptor |
HDAC | histone deacetylase |
CREB | cyclic adenosine monophosphate (cAMP) response element binding protein |
BCAAs | branched-chain amino acids |
AAAs | aromatic amino acids |
ACADSB | acyl-CoA dehydrogenase short/branched chain |
IA | indoleacrylic acid |
IAA | indole-3-acetic acid |
I3A | indole-3-aldehyde |
IPA | indole-3-propionic acid |
SREBP1c | sterol regulatory element-binding protein-1c |
AhR | aryl-hydrocarbon receptor |
PXR | pregnane X receptor |
CA | cholic acid |
CDCA | chenodeoxycholic acid |
DCA | deoxycholic acid |
LCA | lithocholic acid |
FXR | farnesoid X receptor |
TGR5 | takeda G-protein-coupled bile acid receptor 5 |
OCA | obeticholic acid |
FGF | fibroblast growth factor |
VLDL | very low-density lipoprotein |
TMA | trimethylamine |
TMAO | trimethylamine-N-oxide |
CXCL6 | chemokine ligand 6 |
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Metabolites | Effects | References |
Acetate | HDAC inhibition. | [65] |
Propionate | Induces PYY and GLP-1 release. HDAC inhibition. | [60,65] |
Butyrate | Promotes Th2, Th22, or Treg cell differentiation, further preventing hepatic inflammation. HDAC inhibition. | [61,65] |
PAA | Induces steatosis. | [67] |
BCAA | Alleviates hepatic steatosis and liver injury by suppressing FAS gene expression and protein levels. Suppresses the progression of NASH by reducing oxidative stress. | [71,72] |
Exacerbates hepatic oxidative stress, increases hepatic apoptosis. | [73] | |
Tryptamine | Reduces production of pro-inflammatory cytokines and migration of macrophages. | [74] |
I3A | Reduces production of pro-inflammatory cytokines and migration of macrophages. Reduces the expression of FAS and SREBP1c. | [74] |
IPA | Reduces weight gain. Improves intestinal barrier function. | [75,76] |
Ethanol | Transfer of high-alcohol-producing Klebsiella pneumoniae by oral gavage into mice induces NAFLD. | [81] |
Obeticholic acid (OCA) | Decreases hepatic inflammation by inhibition of pro-inflammatory cytokines. Decreases fibrogenesis by inhibition of pro-fibrotic cytokines. Inhibits LSEC and Kupffer cell activation. | [92] |
Cholic acid (CA) Deoxycholic acid(DCA) | Changes in the composition of gut microbiota. | [94] |
TMAO | Increases hepatic TG accumulation and lipogenesis. Shifts hepatic BA composition toward FXR-antagonistic activity. | [101] |
Human Studies | ||
Metabolites | Effects | References |
Propionate | Prevents weight gain and insulin resistance. | [60] |
BCAA | Positive correlation with insulin resistance and steatosis. | [67,68,69] |
IPA | Negative correlation with obesity. | [75,76] |
Ethanol | Positive correlation with NASH. | [79] |
DCA | Associated with fibrosis in NAFLD. | [87] |
OCA | Reduction in ALP, ALT and GGT. | [91] |
TMAO | Positively correlated with NAFLD. Positively correlated with the serum levels of total BA and hepatic CYP7A1 mRNA. | [100,101] |
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Chen, Y.-H.; Wu, W.-K.; Wu, M.-S. Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review. Int. J. Mol. Sci. 2020, 21, 5999. https://doi.org/10.3390/ijms21175999
Chen Y-H, Wu W-K, Wu M-S. Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review. International Journal of Molecular Sciences. 2020; 21(17):5999. https://doi.org/10.3390/ijms21175999
Chicago/Turabian StyleChen, Yi-Hsun, Wei-Kai Wu, and Ming-Shiang Wu. 2020. "Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review" International Journal of Molecular Sciences 21, no. 17: 5999. https://doi.org/10.3390/ijms21175999
APA StyleChen, Y. -H., Wu, W. -K., & Wu, M. -S. (2020). Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review. International Journal of Molecular Sciences, 21(17), 5999. https://doi.org/10.3390/ijms21175999