Table 2.

Gut derived metabolites in hepatocarcinogenesis.

Gut Metabolite	Mechanism of Action	Effects	Reference
Bile Acids	DCA induces SASP phenotype in HSCs DCA and G-CDCA induce endoplasmic reticulum (ER) stress with Ca2+ release and promotion of ROS CA, GCA, LCA and CDCA interact with TRAIL and Fas > PKC/MAPK/NFkB and JAk-STAT3 and the PI3-K CDCA and DCA act on EGFR, on Erg-1/MAPK signaling [80] and PKC/MAPK/NFkB BAs reduce FXR activity through SIRT1 in hepatocytes via the Wnt/β-catenin pathway	fibrogenesis chronic inflammation chronic inflammation, fibrogenesis cell proliferation cell proliferation	[32] [6,25,83] [81,82] [79,80,85] [90]
Choline and TMAo	↑ ROS ↓ intrahepatic triglycerides, resulting in a higher risk of metabolic-associated disease, including HCC [101,102,103] activation of mTOR signaling upregulation POSTN gene ↑ f FXR-antagonists ↑ Wnt/β-catenin pathway	DNA damage cell necrosis cell proliferation	[98,99,100,101] [105,106,107] [109,110,111] [90,114]
SCFAs	GPR41, GPR43 or GPR109/PKC/ERK, PKA/ERK activation DNA epigenetic modifications and HDAC inhibition Butyrate ↑ regulatory T cells ↑ IL-10 by microbiota antigen-specific Th 1 cells ↓macrophages in the lamina propria	cell proliferation DNA damage immune suppression	[125,129] [137] [139] [134]
Ethanol	↑ ADH, NADH, CYP2E1	DNA synthesis and repair mucosal injury and cellular DNA instability cell necrosis	[153,154,162,164]
BCAA	↑ IRS1/PI3K/AKT/mTORC1 ↑ catabolic enzymes of BCAAs in tumor cells, ↑ accumulation of branched-chain ketoacids	cell proliferation, angiogenesis and apoptosis	[167,168,169,170,171,172]
Indoles	↓ indole-3-acetate intestinal levels in HFD ↓ fatty acid oxidation	disruption of the intestinal barrier, overexpression of inflammatory cytokines and inhibition of immune cells	[117,118,119]

Abbreviations: alcohol dehydrogenase (ADH), bile acids (BAs), branched-chain amino acids (BCAAs), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), endoplasmic reticulum (ER), farnesoid X receptor (FXR), glycocholic acid (GCA), hepatic stellate cells (HSCs), histone deacetylase activity (HDAC), lithocholic acid (LCA), mammalian target of rapamycin (mTOR), nicotinamide adenine dinucleotide (NADH), periostin (POSTN), prostaglandin E2 (PGE2), reactive oxygen species (ROS), senescence-associated secretory phenotype (SASP), short-chain fatty acids (SCFAs), TNF related apoptosis inducing ligand (TRAIL), trimethylamine-N-oxide (TMAo).