Table 1.
Preclinical and clinical associations between metabolites and HCC.
| Study Design | Observations | Associations with HCC | Ref. | |
|---|---|---|---|---|
| Preclinical | ||||
| CA feeding | C57BL/6 DEN model Chow, HFD + cholesterol ± CA (HFHCCA) |
↗ Hepatic cholesterol ≈ Mitochondrial dysfunction genes |
≈ NAFLD/HCC | [27] |
| WKAH/HkmSlc rats Chow, +1.25 mmol/kg CA (M-CA), +5 mmol/kg CA (H-CA) |
(+ CA) ↗ Firmicutes (Blautia and Allobaculum) ↘ Bacteroidetes (H-CA vs. chow) ↗ Faecal CA, αMCA, DCA, TCA, TDCA, 7-oxo-DCA ↘ Caecal total SCFAs, acetate, butyrate |
[28] | ||
| DCA feeding | C57BL/6 DMBA + HFD; Abx ± DCA |
(HFD + Abx) ↘ Tumour, Clostridium spp., serum DCA (HFD + Abx + DCA) ↗ Tumour, Clostridium spp., serum DCA |
↗ HCC | [29] |
| Inulin feeding | C57BL/6, T5KO mice HFD + inulin |
(40% of mice) ↘ Metabolic syndrome ↗ serum bilirubin, ALT, AST, ALP ↗ Serum total BA, unconjugated and conjugated: CA, αMCA, βMCA, ωMCA, CDCA, DCA ↗ Cecal butyrate ↗ Serum immunoreactivity: LPS, flagellin |
↗ Liver disease and HCC ≈ Dysregulated bile acid metabolism ≈ Dysbiosis | [36] |
| C57BL/6, T5KO mice HFD + inulin; CoH; Cf; GF |
(CoH, Cf) ↗ Tumour, serum AFP, ALT (GF) ↘ Tumour, serum AFP, ALT |
Gut microbiota transfers risk of HCC | ||
| C57BL/6, T5KO mice HFD + inulin; Abx |
↘ Butyrate-producing bacteria ↘ Caecal butyrate, ↗ Serum AFP, ALT |
↘ HCC | ||
| Tryptophan | C57BL/6 HFD + high/low cholesterol (HC/LC) |
(HFD + HC diet) Spontaneous HCC ↗ Serum and hepatic cholesterol ↘ gut bacteria associated ≈ tryptophan metabolizing capacity ↘ Serum 3-indolepropionic acid |
↗ HCC | [43] |
| Clinical | ||||
| BA signalling | Singapore Chinese Health Study Sera of HCC patients |
↗ 1° BAs (Total, CA species, CDCA species) ↗ 2° BAs (Total, UDCA species) ↘ 2°:1° BA ratio |
↗ Risk of HCC | [30] |
| Sera of HCC patients | ↘ Serum 7-α-Hydroxy-4-Cholesten-3-one | ≈ HCC with cirrhosis | [31] | |
| SCFAs, others | Serum, liver, and stool samples from healthy, NAFLD-cirrhosis, and NAFLD-HCC patients, or healthy and HCC in vitro |
↗ Faecal oxaloacetate, acetate, butyrate, formate, kynurenine and kynurenic acid ↘ Faecal tryptophan and indole-3-carboxylate ↗ Serum butyrate, propionate, malonate |
≈ HCC | [37,44] |
| Linoleic acid and phenol | ↘ HCC cell line growth in vitro | [44] |
↗ increases/promotes; ↘ decreases/alleviates; ≈ associated with; (bolded text): experimental intervention examined. T5KO, TLR-5 deficient; Abx, antibiotics; CoH, cohousing; Cf, cross-fostering; DMBA, 7,12-dimethylbenz(a)anthracene; GF, germ-free; HC, high cholesterol; HFD, high fat diet; 1°, primary; 2°, secondary; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; MCA, muricholic acid; TCA, tauro-cholic acid; TDCA, tauro-deoxycholic acid; UDCA, ursodeoxycholic acid; SCFA, short-chain fatty acid.