Table 3.

Studies characterizing the composition of the gut microbiota in hepatocellular carcinoma.

Author Reference	Country	Study Design	Participants	Changes in the Composition of Gut Microbiota in HCC	Key Findings
Human Studies
[79]	Poland	Cross-sectional	15 HCC 5 without HCC All participants had cirrhosis and underwent liver transplantation.	↑ Escherichia coli ↑ Enterobacteriaceae ↑ Enterococcus ↑ Lactobacillus ↑ H2O2-producing Lactobacillus species	↑ Fecal counts of E coli were noted in the cirrhotic-HCC group, demonstrating its role in HCC development
[88]	Australia	Cohort study; metagenomics and metabolomics analysis	32 NAFLD-HCC 28 NAFLD-cirrhosis 30 non-NAFLD controls	↑ Proteobacteria ↑ Enterobacteriaceae ↑ Bacteroides xylanisolvens ↑ B. caecimuris ↑ Ruminococcus gnavus ↑ Clostridium bolteae ↑ Veillonella parvula ↑ Bacteroides caecimuris ↑ Veillonella parvula ↑ Clostridium bolteae ↑ Ruminococcus gnavus ↓ Oscillospiraceae ↓ Erysipelotrichaceae ↓ Eubacteriaceae	↑ B. caecimuris and Veillonella parvula distinguished NAFLD-HCC from NAFLD-cirrhosis and non-NAFLD controls ↓ Gut microbial α-diversity ↑ SCFAs serum levels in NAFLD-HCC compared to NAFLD-cirrhosis and non-NAFLD control Gut microbiota in NAFLD-HCC microbiota contribute to immunosuppression
[89]	China	Cohort	75 with early HCC 40 liver cirrhosis 75 healthy controls	↑ Actinobacteria ↑ Gemmiger ↑ Parabacteroides ↑ Paraprevotella ↑ Klebsiella ↑ Haemophilus ↓ Verrucomicrobia ↓ Alistipes ↓ Phascolarctobacterium ↓ Ruminococcus ↓ Oscillibacter ↓ Faecalibacterium ↓ Clostridium IV ↓ Coprococcus	↓ Butyrate-producing bacteria ↑ LPS-producing bacteria in early HCC versus healthy controls
[82]	China	Case-control	57 HCC (35 with HBV related HCC, 22 with non-HBV non-HCV related HCC) 33 healthy controls	↑ Bifidobacterium ↑ Lactobacillus ↓ Proteobacteria ↓ Firmicutes	↓ Anti-inflammatory and ↑ pro-inflammatory bacteria in non-HBC non-HCV related HCC patients which correlated with their increased alcohol consumption
[81]	China	Case-control	68 with primary HCC: (23 Stage I, 13 Stage II, 30 Stage III, 2 Stage IV) 18 healthy controls	↑ Dysbiosis index Proteobacteria (Enterobacter, Haemophilus) ↑ Desulfococcus ↑ Prevotella ↑ Veillonella ↓ Cetobacterium	↑ Dysbiosis index in patients with primary HCC compared with healthy controls
[83]	Italy	Cohort	21 with NAFLD-related cirrhosis with HCC 20 NAFLD-related cirrhosis without HCC 20 healthy controls	↑ Bacteroides ↑ Ruminococcaceae ↓ Bifidobacterium	↑ Fecal calprotectin in HCC patients, which explains increased inflammation
[90]	Argentina	Case-control	407 Cirrhosis: 25 with HCC, 25 w/o HCC 25 healthy controls	↑ Erysipelotrichaceae ↑ Odoribacter ↑ Butyricimonas ↓ Leuconostocaceae ↓ Fusobacterium ↓ Lachnospiraceae	↓ Prevotella in cirrhotic patients with HCC, which is associated with the activation of several inflammatory pathways such as the NLR signalling pathways
[91]	China	Case-control	24 PLC 24 cirrhosis 23 healthy controls	↑ Enterobacter ludwigii ↑ Enterococcaceae ↑ Lactobacillales ↑ Bacilli ↑ Gammaproteobacteria ↑ Veillonella ↓ diversity of Firmicutes ↓ Clostridia ↓ Subdoligranulum	Veillonella positively correlated with AFP Subdoligranulum negatively correlated with AFP Subdoligranulum contains SCFA-producing lineages
[84]	China	Case-control	24 hepatitis 24 cirrhosis 75 HCC (35 with HBV, 25 with HCV, 15 with ALD) 20 healthy controls	↑ Neisseria ↑ Enterobacteriaceae ↑ Veillonella ↑ Limnobacter ↓ Enterococcus ↓ Phyllobacterium ↓ Clostridium ↓ Ruminococcus ↓ Coprococcus	↑ LPS by harmful bacteria generated liver inflammatory reactions through TLR4
Animal experimental model studies
[78]	Japan	Mice	24 STZ-HFD (streptozocin-high-fat diet)-induced 24 controls	↑ Bacteroides ↑ Bacteroides vulgatus ↑ Bacteroides uniformis ↑ Clostridium ↑ Clostridium xylanolyticum ↑ Clostridium fusiformis ↑ Roseburia ↑ Allobaculum sp. id4 ↑ Subdoligranulum ↑ Anaerotruncus ↑ Oscillibacter ↑ Xylanibacter ↑ Mucispirillum schaedleri ↑ Pseudobutyrivibrio ↑ Desulfovibrio ↑ Dehalobacterium ↑ Oscillospira ↑ Sarcina ↑ Atopobium ↑ Peptococcus ↓ Parasutterella ↓ Bacteroides acidofaciens ↓ Odoribacter ↓ Barnesiella ↓ Moryella ↓ Paraprevotella ↓ Lactobacillus intestinalis ↓ Akkermansia	Clostridium, Bacteroides, and Desulfovibrio were involved in bile acid dysregulation; their increased levels resulted in the preservation of high concentrations of bile acids, further contributing to hepatocarcinogenesis

AFP, alpha-fetoprotein; ALD, alcohol-associated liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; PLC, primary liver cancer; SCFAs, short-chain fatty acids; ↑, increase; and ↓, decrease.